Administration of probiotics and synbiotics and systemic inflammation in Kenyan infants: an open label, randomised, phase II trial

Administration of probiotics and synbiotics and systemic inflammation in Kenyan infants: an open label, randomised, phase II trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Administration of probiotics and synbiotics and systemic inflammation in Kenyan infants: an open label, randomised, phase II trial Mary Iwaret Otiti, Micah June, Alloys K’Oloo, Miriam Chomba, James Dodd, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5929784/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Environmental enteric dysfunction (EED) in early life, caused by gut pathogen colonisation, contributes to chronic systemic inflammation (CSI) which impairs growth and organ development and increases non-communicable disease risk. Pro/synbiotics may prevent or ameliorate EED, and thereby reduce CSI, through boosting colonisation resistance against enteropathogens and provide other intestinal and immune benefits. We evaluated three pro/synbiotics consisting of live, multi-strain Bifidobacterium spp. and Lactobacillaceae in reducing CSI. In this open-label, randomised, four-arm, phase II trial, 600 healthy Kenyan newborns (1–3 days old, birthweight ≥2000g) were allocated 1:1:1:1, stratified by HIV exposure, to receive Labinic synbiotic, Lab4b synbiotic or Lab4b probiotic or no intervention daily for ten days, then weekly until six months. The primary outcome was CSI (plasma α 1 -acid glycoprotein > 1g/L) at six months with blinded laboratory assessments. At six months, CSI occurred in 60/138 (43%) controls versus 4/144 (3%; relative risk (RR) 0.06, 95% CI 0.02–0.17; p < 0.0001) infants in the Labinic synbiotic, 3/132 (2%; RR = 0.05, 0.02–0.16; P < 0.0001) in the Lab4b synbiotic, and 3/141 (2%; RR = 0.05, 0.02–0.15; P < 0.0001) in the Lab4b probiotic arm. Serious adverse events and mortality over 0–24 months were similar across study arms. Pro/synbiotics safely and markedly reduced CSI in this disadvantaged population, warranting investigation of health impacts. Gastroenterology & Hepatology Nutrition & Dietetics Pediatrics Environmental enteric dysfunction systemic inflammation Probiotics Synbiotics Gut health Biomarkers Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Undernutrition remains a persistent problem in childhood in low- and middle-income countries (LMICs) with impaired linear growth (stunting; length/height-for-age z score <-2) affecting about 1 in 2 children in Asia and 2 out of 5 children in Africa. 1 The occurrence of systemic inflammation in stunting has been reported in many studies in LMICs from different world regions 2 – 5 and likely mediates many of the short- and longer-term adverse outcomes associated with stunting. Chronic systemic inflammation (CSI) contributes to stunting through growth hormone resistance 6 , 7 and is an underlying disease mechanism for impaired organ development, 8 including cognitive development 8 – 10 and longer-term non-communicable diseases (NCDs). 11 The resistance of undernutrition to nutritional supplements, water, sanitation and hygiene (WASH) and other interventions has focussed attention on gut health. 2 Environmental enteric dysfunction (EED), an asymptomatic disorder manifesting as growth faltering, is characterised by small intestinal inflammation, villous atrophy and increased mucosal permeability. EED results from enteropathogen colonisation without overt diarrhoea, is universal in people exposed to poor sanitation and hygiene and likely impairs childhood growth and development through malabsorption and as a major driver of CSI. 2 , 12 In newborns, prebiotic human milk oligosaccharides result in a dominance of Bifidobacterium in the gut which drive microbial community assembly and have a key role in colonisation resistance against enteropathogens as well as development of the gut and mucosal and systemic immunity. 13 – 16 However, multiple adverse environmental factors such as poor sanitation and hygiene, caesarean section delivery, faulty feeding practices, and antibiotic exposure 14 may result in a “dysbiosis” (used here to mean a perturbation or delay in the development of the gut microbiota) which may compromise colonisation resistance and gut and immune system development. 14 , 15 Gut dysbiosis has been reported in several studies of children with malnutrition. 17 , 18 A microbiota-directed complementary food in children aged 12 to 18 months with moderate acute malnutrition in Bangladesh was associated with changes to the microbiota and improved weight gain. 19 However, 0–3 months is the age period with the highest incidence of stunting onset with few catching-up in later childhood 20 and EED and CSI occur as early as age 6–12 weeks, even in exclusively breast-fed infants. 3 , 21 , 22 Therefore, intervention during the first 6 months before complementary feeding starts is required. 20 The PRObiotics and SYNbiotics in infants in Kenya (PROSYNK) study aimed to assess whether administration of pro/synbiotics from 0 to 6 months reduced CSI through improved gut health. Probiotics are defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.”23 A prebiotic is “a substrate that is selectively utilised by host microorganisms conferring a health benefit”. 24 A synbiotic is “a mixture comprising live microorganisms and substrate(s) selectively utilised by host microorganisms that confer a health benefit on the host”. 25 Pro/synbiotics may boost colonisation resistance against enteropathogens, enhance gut development and provide immune benefits. 26 , 27 Given concerns that beneficial effects might be limited to specific probiotic strains, 21 we evaluated two different multi-strain preparations of live Bifidobacterium spp. and Lactobacillaceae , the most frequently used probiotics. 14 We selected preparations that had evidence of safe administration in newborns (Lab4b) 30 including preterm infants (Labinic). 29 We tested the Lab4b probiotic consortium and, based on the favourable results of synbiotic administration in the prevention of sepsis in newborns in India, 30 we combined each preparation with a prebiotic resulting in three intervention arms. To maximise the potential to modulate the developing gut microbiome and intervene before the onset of EED, pro/synbiotic administration was started within 3 days of birth, given daily for 10 days and then weekly to age 6 months (total of 32 doses). The primary outcome was CSI (defined as plasma α 1 -acid glycoprotein (AGP) > 1g/dl) at age 6 months. We also evaluated acute inflammation (plasma C-reactive protein; CRP) and the growth hormones insulin-like growth factor (IGF)-1 and IGF binding protein-3 (IGFBP-3). To explore whether EED was associated with systemic inflammation, we measured biomarkers of EED including intestinal inflammation (faecal myeloperoxidase, MPO), intestinal permeability (faecal α 1 -antitrypsin, AAT), mucosal integrity (plasma intestinal fatty acid binding protein, IFABP) and stool pH. Results The PROSYNK study screened 816 newborns delivered at the Homa Bay County Teaching and Referral Hospital, western Kenya between October 28, 2020 and January 13, 2022. Newborns not meeting the inclusion criteria were excluded: parents/carers planned to leave the study area (n = 82) or declined to participate (n = 79) or where health staff had concerns regarding the infant’s health (n = 55). Six hundred newborns were enrolled and random allocation resulted in 150 infants in the Labinic synbiotic, 151 Lab4b synbiotic, 150 Lab4b probiotic and 149 controls (Fig. 1 ). Overall, two thirds of the participants (64%) resided in the rural parts of Homa Bay County. Most (78%) mothers were married and 18% were HIV infected. Antibiotic exposure before delivery was uncommon (< 3% in any study arm). Nearly all women had a vaginal delivery (96%) and delivered in hospital (91%). Overall, 7% infants were low birthweight (< 2500g) and the mean time to first feed was between 1 to 2 hours in each study arm. These baseline demographic and clinical variables for mothers and newborns were similar across the study arms (Table 1 ). WASH practices were also similar across study arms and reflected a high level of disadvantage (Supplementary Table 1). In 9 out of 10 participants’ homes, the youngest child’s stool was disposed in the garbage. Almost half (47%) of the homes were using a pit latrine with a slab. More than one third (39%) of participants’ homes collected rainwater for drinking. Table 1: Baseline maternal, delivery and infant demographic and clinical characteristics according to intervention arm Data are n (%) or mean (standard deviation). Residence type was missing for one family in the Lab4b synbiotic arm Follow-up at 6 months was completed in 559 (93%) infants and was 89% or greater in each study arm (Fig. 1 ). In total, 39 (7%) children withdrew from the study with a similar frequency and reasons for withdrawal in the study arms (Supplementary Table 2). Follow-up at 24 months was completed in January 2024 and included 546 (91%) of children enrolled (Fig. 1 ). The number of infants taking all 32 doses of pro/synbiotics was 128 (85%) in the Labinic synbiotic, 124 (82%) in the Lab4b synbiotic and 124 (82%) in the Lab4b probiotic arm. In the control arm, 126 (85%) infants completed all 32 visits (Supplementary Table 3). Viability of the probiotic organisms at point-of-use was confirmed although with some reduction in numbers of bacteria compared with the manufactured product (Supplementary Note 1). Whole Genome Sequencing revealed that the Bifidobacterium possessed partial or complete HMO gene clusters signifying ability to metabolise and utilize HMOs (Supplementary Note 2). Overall, 484/565 (86%) infants were exclusively breastfed at 3 months and 220/559 (39%) at 6 months, with a similar frequency across study arms (Supplementary Table 4). Primary endpoint At 6 months, the frequency of CSI (plasma AGP > 1g/L) was markedly reduced in each of the intervention arms versus the control arm: CSI occurred in 60/138 (44%) controls versus 4/144 (3%; risk ratio (RR) 0.06, 95% CI 0.02–0.17) infants in the Labinic synbiotic arm, 3/132 (2%; RR = 0.05, 0.02–0.16) in the Lab4b synbiotic and 3/141 (2%; RR = 0.05, 0.02–0.15) in the Lab4b arm in the crude analysis. Results were similar in adjusted analysis accounting for potential confounders (Fig. 2 ). Secondary endpoints Systemic inflammation At age 6 weeks, no infants had CSI and median AGP concentrations were similar in each of the study arms (Fig. 3 A; Supplementary Table 5). However, there were marked differences in the frequency of CSI between control and intervention arms at 3 months and also at 12 months even though pro/synbiotic administration had stopped at 6 months, although the proportion of infants with CSI in the intervention arms at 12 months had risen to between 8–10% (Fig. 2 ; Supplementary Fig. 1). Median AGP concentrations had increased at 3, 6 and 12 months in the controls, but, in marked contrast, increased only slightly from values at 6 weeks in each of the intervention arms including at 12 months. Median AGP concentrations were significantly lower in each of the intervention arms vs. the controls at 3, 6 and 12 months (Fig. 3 A; Supplementary Table 5). Increased acute inflammation (plasma CRP concentration > 0.45mg/dL) was seen in half or more of the infants in all arms and at all visits. However, median CRP was significantly higher in the controls versus each of the intervention arms at 3 and 12 months and the Lab4b probiotic arm at 6 months (Fig. 3 B; Supplementary Table 5). Biomarkers of EED Intestinal inflammation (faecal MPO concentration ≥0.2 mg/dL) was evident as early as 6 weeks being present in between about 1 in 3 and 1 in 2 infants in all study arms and median levels were significantly higher in the Labinic synbiotic and Lab4b synbiotic arms than in the controls. Intestinal inflammation was present in more than 1 in 2 infants in all study arms at 3 and 6 months. Median levels were similar in all study arms at 3 months but were significantly lower in all three intervention arms than the control arm at 6 months. Levels had increased markedly by 12 months and were similar across the study arms (Fig. 4 A; Supplementary Table 5). Intestinal permeability was increased (faecal AAT ≥26.8 mg/dl) in up to 1 in 4 infants and similar across study arms at 6 weeks and 3 months. Levels had increased at 6 months in controls and were significantly higher than in each intervention arm. Levels increased further at 12 months with 1 in 2 or more infants in all study arms having raised levels and with similar median concentrations across the study arms (Fig. 4 B; Supplementary Table 5). The concentration of plasma IFABP, a biomarker of intestinal integrity, was below the manufacturer’s upper limit of normal (1.8 ng/ml) in the majority of infants in all study arms at all timepoints. However, median levels were significantly raised in the controls versus the Lab4b probiotic arm at 3 months and versus all 3 intervention arms at 6 and 12 months (Fig. 4 C; Supplementary Table 5). Stools tended to be more acidic in all study arms at 6 weeks (median pH 5.04–5.23) with pH rising gradually to 12 months (pH 5.47–5.68). At 6 weeks, stools were significantly more acidic in the Labinic synbiotic, Lab4b synbiotic and Lab4b probiotic arms than controls (Fig. 4 D; Supplementary Table 5). Investigating correlations between EED biomarkers and plasma AGP in all infants, significant positive associations were with plasma IFABP at 3 months, faecal AAT at 6 months, and all three biomarkers at 12 months (Table 2 A). In multiple linear regression analysis with all three biomarkers as explanatory variables and plasma AGP as the dependent variable, a significant negative association was faecal MPO at 6 weeks (coefficient= -0.061; 95% CI -0.122, -0.000) and positive associations for plasma IFABP at 3 months (0.11; 0.080, 0.14), faecal AAT at 6 months (0.006; 0.004, 0.009) and faecal MPO (0.13; 0.043, 0.22), and plasma IFABP (0.098; 0.074, 0.12) at 12 months (Table 2 ). Table 2 Associations between biomarkers of environmental enteric dysfunction (EED) and plasma α 1 -acid glycoprotein (AGP) in all infants according to timepoint 2A) Correlations between plasma AGP and biomarkers of EED and growth hormones in all infants Biomarkers Time point 6 weeks 3 months 6 months 12 months Rho (95% CI) P- value Rho (95% CI) P- value Rho (95% CI) P- value Rho (95% CI) P- value AGP vs MPO -0.08 (-0.16, 0.00) 0.051 0.04 (-0.05, 0.12) 0.38 0.06 (-0.02, 0.14) 0.16 0.14 (0.05, 0.22) 0.0016 AGP vs AAT 0.05 (-0.04, 0.13) 0.26 0.03 (-0.05, 0.11) 0.50 0.24 (0.16, 0.32) < 0.0001 0.13 (0.04, 0.21) 0.0032 AGP vs IFABP -0.05 (-0.13, 0.03) 0.20 0.30 (0.22, 0.37) < 0.0001 0.06 (-0.02, 0.15) 0.14 0.31 (0.24, 0.39) < 0.0001 AGP vs IGF-1 0.12 (0.04, 0.20) 0.0031 0.00 (-0.08, 0.09) 0.95 -0.08 (-0.16, 0.00) 0.065 -0.22 (-0.30, -0.14) < 0.0001 AGP vs IGFBP-3 -0.09 (-0.17, -0.01) 0.027 -0.06 (-0.14, 0.02) 0.16 -0.10 (-0.18, -0.01) 0.024 -0.17 (-0.25, -0.09) 0.0001 2B) Multiple regression analysis of EED biomarkers and plasma AGP Biomarkers Time point 6 weeks Coefficient (95% CI) P- value 3 months Coefficient (95% CI) P- value 6 months Coefficient (95% CI) P- value 12 months Coefficient (95% CI) P- value MPO -0.061 (-0.12, -0.00) 0.049 0.019 (-0.12, 0.16) 0.79 0.060 (-0.037, 0.16) 0.22 0.13 (0.043, 0.22) 0.0035 AAT 0.00 (-0.00, 0.001) 0.23 0.001 (-0.003, 0.005) 0.56 0.006 (0.004, 0.009) <0.0001 -0.00 (-0.003, 0.002) 0.87 IFABP -0.002 (-0.004, 0.001) 0.14 0.11 (0.080, 0.14) <0.0001 0.014 (-0.001, 0.029) 0.071 0.098 (0.074, 0.12) <0.0001 Growth hormones IGF-1 concentrations were in the normal range in most infants at most timepoints. Median concentrations were significantly higher in the Lab4b synbiotic and Lab4b probiotic arms than controls at 3 months and in all 3 intervention arms at 6 months (Fig. 5 A; Supplementary Table 5). The number of infants with IGF-1 deficiency was similar across the study arms except at 6 months where 36/137 (26%) controls were deficient compared with 20/144 (14%; P = 0.009) in the Labinic synbiotic, 12/132 (9%; P < 0.001) in the Lab4b synbiotic and 18/141 (13%; P = 0.004) in the Lab4b probiotic arms (Supplementary Table 6). Compared with controls, IGFBP-3 concentrations were significantly higher in the Labinic synbiotic and Lab4b probiotic arms at 3 months and all 3 intervention arms at 6 months (Fig. 5 B; Supplementary Table S5). IGFBP-3 deficiency at 12 months (< 700 ng/mL) occurred in 32–43% infants across the study arms with a similar frequency in each arm (Supplementary Table 6). In all infants, plasma AGP was significantly negatively associated with IGF-1 at12 months (-0.22; -0.30, -0.14) and negatively associated with IGFBP-3 at 6 weeks (-0.09; -0.17, -0.01), 6 months (-0.10; -0.18, -0.01) and 12 months (-0.17; (-0.25, -0.09; Table 2 A). Adverse events In total, 102 SAEs occurred in 88 (15%) children during follow-up to 24 months (Supplementary Table 7a). Clinicians made more than one diagnosis for many SAEs with a total of 151 diagnoses; the most common diagnoses were pneumonia (31; 20%), malaria (20; 13%) and gastroenteritis (16; 11%; Supplementary Table 7b). The number of SAEs and diagnoses were similar across the study arms (Supplementary Table 7) and none were attributed to the interventions. Mortality from 0–24 months was 6/149 (4%) in the control arm, 3/150 (2%; P = 0.34) in the Labinic synbiotic, 4/151 (3%; P = 0.54) in the Lab4b synbiotic and 2/150 (1%; P = 0.17) in the Lab4b probiotic arms (Supplementary Table 7a). Discussion Administration in early life of live, multi-strain pro/synbiotics comprising of Bifidobacterium spp. and Lactobacillaceae was safe and markedly reduced CSI in highly disadvantaged infants exposed to poor sanitation and hygiene. From 3–12 months, pro/synbiotics improved biomarkers of gut health and one or more biomarkers of EED was significantly associated with increased CSI. CSI was significantly associated with reduced growth hormone levels at 6 weeks and 6 and 12 months. We consider that the magnitude of differences in AGP concentrations between the control arm and intervention arms from age 3 months (differences in medians ranging from 0.25–0.53 g/L according to timepoint and intervention arm; Supplementary Table 5) are clinically meaningful as they are greater than those between non-stunted and stunted children at similar ages in Zimbabwe (mean differences ranging from 0.06–0.13 g/L) 22 and between non-stunted and moderately stunted (difference in medians 0.10 g/L) and severely stunted (0.11 g/L) 6-month olds in rural Uganda. 31 There are multiple potential short and longer-term adverse effects of CSI in infancy. Increased plasma AGP has been shown to be significantly associated with impaired linear growth in early life in previous studies in Pakistan, 4 , 32 Uganda 31 Tanzania 33 and the multi-country MAL-ED 34 and BRINDA 5 studies. Our finding of a negative association between plasma AGP and plasma IGF-1 at 12 months is consistent with studies in Pakistan, 32 Mali, 35 Malawi 36 and Zimbabwe. 22 Negative associations between plasma AGP and plasma IGFBP-3, an indicator of adequate growth hormone signaling, 7 at 6 weeks and 6 and 12 months in our study is consistent with lower levels in children in Zimbabwe with stunting compared with controls from ages 6 weeks to 18 months. 22 Overall, the increased plasma IGF-1 and IGBP-3 levels observed at 3, 6 and 12 months in some intervention arms compared with controls in PROSYNK indicate that pro/synbiotics may be an appropriate intervention for growth hormone resistance in malnutrition. 6 , 7 Systemic inflammation during the first year of life impairs organ development 8 including cognitive development. 9 , 10 Early life CSI also increases the risk of longer-term non-communicable diseases (NCDs), with strong empirical evidence regarding disease onset or progression for metabolic syndrome, type 2 diabetes and cardiovascular disease. 11 Therefore, reduced CSI in infancy through pro/synbiotic administration is directly relevant to LMICs where 250 million or 43% of children fail to reach their developmental potential 37 and where the burden of NCDs is greatest. 38 The raised plasma CRP concentrations in half or more infants at all timepoints and in all study arms likely reflect frequent acute infections in this vulnerable population as well as a consequence of intestinal inflammation. The reduced CRP concentrations in all intervention arms at 3 and 12 months may reflect less severe gastrointestinal infections or modulation of the inflammatory or immune response to infection. 26 In a recent scoping review that identified 29 clinical trials of pre-, pro- or synbiotics in children, there was no consistent effect on inflammatory biomarkers. 39 However, the trials were undertaken in different geographical regions, included both newborns and older children who were healthy or had a wide range of different diseases, evaluated many different pre-, pro- and synbiotic preparations and measured many different pro- and anti-inflammatory biomarkers. The review included a 5-arm randomised controlled trial in Mexico of 600 infants aged 20 ± 7 days who received infant formula only or formula supplemented with one of two fructans, a single-strain probiotic ( L. rhamnosus) or synbiotic (fructans + L. rhamnosus ) daily that reported no significant difference in CRP concentration between study arms at age 3 months. 40 Further research is needed to identify optimal pre-, pro- or synbiotic preparations for countering inflammation occurring in specific populations and disease contexts. We selected biomarkers in plasma and stool that reflect different elements of EED, that have been measured in many other studies and are associated with impaired linear growth. 2 , 12 , 41 In PROSYNK, mothers often followed advice provided by research staff and started complementary foods after the 6-month follow-up visit. As a result, around 40% infants were still exclusively breastfed at 6 months. A potential controversy of PROSYNK is the administration of an oral product in exclusively breastfed infants. However, we consider that this is justified given evidence of intestinal inflammation, increased intestinal permeability and enterocyte damage in many infants as early as age 6 weeks despite exclusive breastfeeding in PROSYNK and other studies 21 , 22 and that the onset of stunting is highest in the first 3 months of life. 20 Our findings suggest that intestinal inflammation occurs early and increased intestinal permeability and enterocyte damage occur later in infancy in this population. The significant positive correlations at the 3, 6 and 12-month timepoints in the multiple regression analysis between the biomarkers of intestinal inflammation, permeability and enterocyte damage and plasma AGP suggest that each intestinal pathology drives CSI and possibly with different pathologies driving CSI at different time periods during infancy. However, these pathologies are inter-related and measurement of a wider range of biomarkers of EED may provide greater insights into the progression of the intestinal lesion and pathways to CSI in different populations. 41 The statistically significant, though marginal, increase in intestinal inflammation in the Labinic synbiotic and Lab4b synbiotic arms vs. the controls at 6 weeks was unexpected. Further research to provide greater insights and determine potential mechanisms in these young infants is required. Pro/synbiotics may improve gut health through multiple mechanisms including boosting intestinal colonisation against pathogens, modulating innate and adaptive immunity and reducing intestinal permeability through an enhanced mucus barrier and strengthened tight junction integrity. 26 , 27 The positive findings in PROSYNK support the critical roles for Bifidobacterium spp. and Lactobacillaceae in early life including the ability of pro/synbiotics to modulate the developing gut microbiota before it is well-established in the specific context of countering exposure to poor sanitation and hygiene. 14 , 16 The more acidic stools at 6 weeks in the intervention arms vs. the controls suggest an early increase in Bifidobacterium with increased production of short-chain fatty acids. 13 , 14 Although we did not evaluate the three pro/synbiotics head-to-head, a striking finding was that improved gut health and reduced systemic inflammation was present to a similar degree in the Lab4b and Labinic arms. This suggests either that different strains of Bifidobacterium spp. and Lactobacillaceae share beneficial “core” properties 24 or strain-specific differences can be overcome by using multi-strain products. Our study design contrasts with a previous trial where Lactobacillus GG administered to children aged 3–5 years at risk of EED in Malawi did not affect intestinal integrity assessed by a site-specific sugar-absorption test. 42 The discrepancy with our findings might be due to the use of a single probiotic and/or the older age of the participants in the Malawi study. Although the similar gut health biomarker and CSI levels in the Lab4b probiotic and the Lab4b synbiotic arms suggest no benefit of the addition of prebiotic fructooligosaccharide (FOS), this needs to be confirmed in further research especially in non-breastfed infants that do not receive prebiotics in the form of human milk oligosaccharides. 43 Strikingly, the reduced acute and CSI and enterocyte damage in all three intervention arms were still evident at 12 months even though pro/synbiotic administration stopped at 6 months. Further research is needed to determine if a beneficial modulation of the gut microbiota, once established, persists long-term and whether this is due to long-term engraftment of probiotic organisms. Alternatively, improved early gut health and/or immunity may provide longer term resilience against adverse environmental factors. The early onset of intestinal inflammation, marked increase in intestinal inflammation at 12 months and increased CSI at 12 months in some infants in the intervention arms indicate that further research is needed to optimise the pro/synbiotic intervention and the administration regimen. This could include alternative pro/synbiotics formulations, more frequent administration and continuing administration beyond 6 months. Selection of specific probiotic strains, including microbes isolated from healthy Kenyan infants, could be guided by genomic and in vitro analyses to identify important functional pathways such as ability to metabolise human milk oligosaccharides, as demonstrated here for the Bifidobacterium spp. (Supplementary Note 2) and production of bacteriocins. 13 , 26 Qualitative research during PROSYNK revealed that mothers/carers and health professionals were highly supportive of the pro/synbiotic intervention. 44 Also, experience gained revealed that many mothers/carers were able to administer the pro/synbiotics to their infants themselves after initial training. Our findings regarding long-term stability at ambient temperature in Kenya for the Lab4b probiotic and the potential for stability to be improved by use of alternative formulations, indicate that pro/synbiotics could be transported and stored in children’s homes without the use of a cold chain. An economic analysis undertaken during PROSYNK estimated that the incremental economic costs to the Ministry of Health of delivering the pro/synbiotic programmatically in the community was $ 9.15 per infant per 32 dose course (range $ 6.93 - $ 34.11 depending on supply and delivery scenarios). 45 Strengths of our study were that randomisation resulted in similar baseline demographic and clinical variables across study arms. We maintained the same contact and general support for the control infants as occurred in the intervention arms so that differences between study arms could be attributed to the interventions. We also supervised dosing of the pro/synbiotics and confirmed probiotic viability at point-of-use. Although laboratory analyses were undertaken by staff blinded to treatment allocation, a limitation was that assessment of morbidity may be biased in an open label study. The marked effects of early life pro/synbiotics on reducing CSI and improving gut health represents a significant step-forward in addressing the multiple adverse outcomes associated with undernutrition and EED in vulnerable children in LMICs. The potential of pro/synbiotics as a public health intervention including impact on health outcomes, cost-effectiveness and affordability when used at scale needs to be determined. Although food supplements, WASH and/or nutritional supplements in older infants appear to have limited effects on growth, 2 future trials may assess pro/synbiotic administration as part of a package of interventions. Further research is also needed to assess the effects of reduced CSI in early life, whether or not growth is improved, on organ development, including cognitive development, and reduced risk of longer-term NCDs. Methods Ethical approval was obtained from the Kenya Medical Research Institute - Scientific and Ethics Review Unit (KEMRI/SERU/CGHR/320/3917), Kenyan Pharmacy & Poison Board, Kenya (PPB/ECCT/20/04/02/2020(063)), the National Commission for Science Technology and Innovation, Kenya (PPB/ECCT/20/04/02/2020(063) and the Liverpool School of Tropical Medicine (19–048). The trial was conducted in accordance with the principles of the Declaration of Helsinki and was monitored by a Data Safety and Monitoring Board. The trial was registered with the Pan African Clinical Trials Registry ( https://pactr.samrc.ac.za/ ; PACTR202003893276712) on 02 March 2020 and before recruitment of the first participant and the protocol was published. 45 Supplementary materials include a CONSORT checklist (Supplementary Note 3). Study design and participants The study was a prospective, open-label, individually randomised, 4-arm, phase 2 trial in Homa Bay County, western Kenya where approximately 13% of under 5s are stunted (height-for-age z score <-2). 46 The study was conducted in Homa Bay County Teaching and Referral Hospital, a 280-bed government facility. Singleton, term infants aged 0–3 days, with a birth weight of ≥ 2000g, who were breastfed, had taken a breastfeed well and lived in the hospital catchment area were enrolled by research clinicians. Exclusion criteria were suspicion or presence of any acute illness (e.g. fever; treated with antibiotics), congenital anomalies that might be life-threatening or impair growth, potential contraindication to pro/synbiotics (e.g. suspected immune suppression; cardiac abnormality), mother unlikely to stay in study area for the duration of the study and any health or research staff concerns regarding safety to participate in the trial. Baseline demographic and clinical data were collected using standardised questionnaires. All infants were examined by a research clinician including determination of gender. Information regarding the mother, pregnancy and delivery was determined by review of ante-natal and hospital records. Trial procedures Newborns were allocated according to a computer-generated random sequence with blocks of random size and stratified by HIV exposure, generated by the research statistician and withheld from all other research staff until databases were cleaned and locked. Newborns were allocated 1:1:1:1 to one of four study arms by the research clinicians opening a sealed opaque envelope. Investigational products and administration Study staff visited infants’ homes to administer under supervision Labinic synbiotic (recently named “Labisyn” by the supplier; BENEO Orafti Synergy1; 50 oligofructose:50 FOS; 200mg + Lactobacillus (L.) acidophilus NCFM, Bifidobacterium (B.) longum subsp. infantis Bi-26 and B. bifidum Bb-06; total of 5x10 9 organisms/day, Biofloratech Ltd., Walton-on-Thames, UK); Lab4b probiotic ( Ligilactobacillus salivarius CUL61 (NCIMB30211), Lacticaseibacillus paracasei CUL08 (NCIMB 30154), B. bifidum CUL20 (NCIMB 30153), and B. animalis subsp. lactis CUL34 (NCIMB 30172); total of 10 10 organisms/day), Lab4b synbiotic (Lab4b probiotic combined with long-chain FOS 150mg/day, Cultech Ltd., Port Talbot, UK) or no pro/synbiotic (controls). The pro/synbiotics were presented as powder in capsules of a different colour for each product. The capsules were opened, and the powder sprinkled directly into the infant’s open mouth before feeding or mixed in a clean container with sterile water. Administration was repeated once if the infant vomited within 30 minutes. Administration occurred daily for the first 10 days and then weekly to age 6 months (total of 32 doses). All bacterial strains were live; products were shipped, transported and delivered to homes using a cold chain. Quantitative culture of the pro/synbiotics at point-of-use (Supplementary Note 1) and whole genome sequencing of probiotic organisms to identify human milk oligosaccharide (HMO) gene clusters (Supplementary Note 2) were undertaken. In addition, to explore the feasibility of pro/synbiotic administration without use of a cold chain, the viability of probiotic organisms when stored at ambient temperature in Kenya was also evaluated. Viability for the Labinic organisms fell rapidly. However, after some initial decrease, viability of the Lab4b organisms was maintained for up to 12 months (Supplementary Note 4). Control infants received the same home visits and contact with the research team as those in the intervention arms, except that some scheduled visits were done by mobile phone to comply with COVID-19 restrictions. During all home visits/phone calls, research staff gave general advice on infant feeding, hygiene and care to all mothers/carers and facilitated referral for clinical review if the infant was unwell. Laboratory assessments for primary and secondary outcomes Biomarkers of systemic inflammation, EED and growth were measured in capillary blood (up to 1 ml) and stool samples collected either at the research clinic or from homes using a cool box (temperature range 9-11 o C) at 6 weeks, 3 months, 6 months and 12 months. The primary outcome was CSI at age 6 months assessed by plasma α 1 -acid glycoprotein ( AGP) > 1 g/L. Secondary outcomes were acute inflammation assessed by plasma C-reactive protein (CRP) and biomarkers of EED including intestinal inflammation (faecal myeloperoxidase, MPO), intestinal permeability (faecal α 1 -antitrypsin, AAT), mucosal integrity (plasma intestinal fatty acid binding protein, IFABP) and stool pH using a pH metre. Biomarkers of growth included insulin-like growth factor (IGF)-1 and IGF binding protein-3. Biomarkers were measured by ELISA (Supplementary Table 8). All the laboratory assays were carried out in duplicate and including control samples, according to the manufacturer’s instructions and analysed sequentially so that samples from all study arms were likely to be analysed on each ELISA plate. Laboratory staff were blinded to the study arms. We also recorded serious adverse events to age 24 months, including mortality, during home visits and parents/carers informed staff of illnesses by mobile phone. Medical records were reviewed for infants admitted to hospital. Sample size A total of 524 infants (131 per am) would allow the detection of a 50% reduction (risk ratio = 0.50) in the prevalence of CSI at age 6 months from 35% in the control arm 22 to 17.5% in any of the intervention arms with 80% power and with α = 0.0167 to allow for 3 primary comparisons against the control arm based on the intention to treat population. We aimed to recruit 150 infants/arm to allow for 13% dropouts. Statistical methods Statistical analyses were performed using STATA v.17 (StataCorp LLC, Texas, USA). For demographic, clinical, laboratory, feeding, WASH and environmental variables in subjects with non-missing data, continuous variables were summarised as median (interquartile range; IQR) or mean (standard deviation; SD) and categorical variables as number and percent. For the primary outcome, (AGP > 1g/L), we used generalised linear models with binomial distribution and log link function, with treatment as the sole predictor, expressed as risk ratios with corresponding 95% confidence intervals (CI). Adjusted analysis included pre-specified covariates that were predicted to modulate the effects of the interventions: season of birth, residence (urban vs. rural), HIV exposure, maternal antibiotic exposure prior to delivery, mode of delivery, sex, low birthweight (< 2500g) and breastfed to 3 months. Median values for biomarkers were compared between each intervention arm and the control arm using the Mann-Whitney U test. Concentrations of biomarkers according to timepoint and intervention arm are illustrated in boxplots where the boxes summarise the median (midline) and interquartile ranges (IQR), whiskers are drawn to the nearest value within 1.5 times the IQR, values outside of this range shown as circles and values at or beyond the maximum value shown are grouped at the maximum value and the number shown. Declarations Data availability Data are presented in the article and supplementary materials. Anonymised datasets and study documents (participant information sheets, informed consent forms) are available on reasonable request to the corresponding author. Requests will be reviewed by the investigators or their representatives at LSTM and Kenya and the KEMRI SERU and LSTM Research Ethics Committees notified of any agreements to share data. Competing interests All authors declare no competing interests. Funding Children’s Investment Fund Foundation. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Author contributions SA: conceptualisation and secured funding; MIO, MJ, LH, DW, SK, FtK, SA: study design; MIO, MJ: administration and supervision of data collection; AK: data curation; MC, KO: laboratory analyses; RK, LH: advice on quantitative culture of probiotic organisms, genome wide sequencing and bioinformatics analysis of probiotic organisms; MIO, AK, JD formal analysis; MIO, AK, JD: validation; all authors had permission to access all the data in the study if they wished; MIO, SA: first draft; AK, JD: figures; all authors reviewed, edited and had final responsibility for the decision to submit for publication. Acknowledgements We thank all of the children and their parents/carers for participation in the study. We thank Sue Plummer, Cultech Ltd. UK and Elspeth Small, Biofloratech Ltd., UK for advice regarding quantitative culture and provision of pro/synbiotic formulations; Angela Allen for advice and guidance in undertaking laboratory analyses; Benjamin Momo Kadia for assistance with developing methods of pro/synbiotic administration in homes and training field staff; Drs Tony Sang and Ruth Njoroge (Kisumu, Kenya), for the advice and support in the delivery and administration of trial interventions to participants; Jane Rawlinson (LSTM, Liverpool, UK), Benta Kamire and Sheila Nyarinda (LSTM-Kenya, Kenya) for administrative support. We would like to thank Sellinah Okumu, Chair of the Community Advisory Board, Homa Bay, Kenya; TSC members (Pauline Andang’o (Chair; Maseno University, Kisumu, Kenya), Walter Otieno (Maseno Medical School, Kisumu, Kenya), the late Rachel Musoke (University of Nairobi, Nairobi, Kenya), Sellinah Okumu (Homa Bay, Kenya), Sufia Askari (Children’s Investment Fund Foundation; London, UK) and Martina Oneko (Local Safety Monitor; KEMRI, Kisumu, Kenya)) and DSMB members (Robert Bandsma (Chair; Hospital for Sick Children, Toronto, Canada), Janet Berrington (Newcastle University, Newcastle, UK) and Paul Milligan (London School of Hygiene and Tropical Medicine, London, UK)) for their expert oversight and guidance. 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Nutrients 7:8939–8951 Guerrant RL et al (2016) Biomarkers of environmental enteropathy, inflammation, stunting, and impaired growth in children in northeast Brazil. PLoS ONE 11:e0158772 Galpin L et al (2005) Effect of Lactobacillus GG on intestinal integrity in Malawian children at risk of tropical enteropathy. Am J Clin Nutr 82:1040–1045 Zhang W et al (2024) Comprehensive review on dietary polysaccharides as prebiotics, synbiotics, and postbiotics in infant formula and their influences on gut microbiota. Nutrients 16:4122 Otiti MI et al (2024) Probiotics and synbiotics administered to young infants: perceptions and acceptability amongst carers and healthcare workers in western Kenya. Preprint at https://www.medrxiv.org/content/ 10.1101/2024.12.20.24319230v1 McCallum B et al (2024) An early-stage cost and implementation feasibility study of the administration of pro/synbiotics to infants 0–5 months in rural Kenya. Preprint at medRxiv 2024.12.17.24319142 Otiti MI et al (2022) PRObiotics and SYNbiotics to improve gut health and growth in infants in western Kenya (PROSYNK Trial): study protocol for a 4-arm, open-label, randomised, controlled trial. Trials 23:284 Kenya Demographic and Health Survey, 2022 . (Kenya National Bureau of Statistics; ICF, Nairobi, Kenya : Rockville, Maryland, USA, (2022) Additional Declarations The authors declare no competing interests. Supplementary Files 5719570supp10110064sp5rxq.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5929784","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":410320809,"identity":"304b2503-deab-4eea-af65-c318b4e5eaba","order_by":0,"name":"Mary Iwaret Otiti","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAklEQVRIiWNgGAWjYBAC+QYILcfAzMBw4EMBmGMAJiVwaGEDkwkMxjzMzAwHZxiAFRKnJbEHaA0zD1FaJJKfffj4gyFxPzv/wcM2BnV1uu3NGxh+1DAkzmzApSXNeOYMkC1Ahx3OMTgsYXbmWAFjzzGGxNm4bJFOMGbmQWg5IGF2I8eAgbeBIXEeTi3pn5n/wLRYGNRJmN1/Y8D4F6+WHGNmBpgWBgNmoC08BswgW3A6TP5NMWNPmoQxz2Fmg4M9Boclt51JKzgsc0zCGJf35XuOb2b4YWMjx95/8PGHHxV1/GbHD298+KbGRnbGARzWQABaHBzAHSujYBSMglEwCogBAMqQUlFx1JvjAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-5514-6846","institution":"Kenya Medical Research Institute (KEMRI) Centre for Global Health Research, Kisumu, Kenya; Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK","correspondingAuthor":true,"prefix":"","firstName":"Mary","middleName":"Iwaret","lastName":"Otiti","suffix":""},{"id":410320810,"identity":"60fad48c-8f93-41a7-b4f9-94eccda2dd24","order_by":1,"name":"Micah June","email":"","orcid":"","institution":"Kenya Medical Research Institute (KEMRI) Centre for Global Health Research, Kisumu, Kenya","correspondingAuthor":false,"prefix":"","firstName":"Micah","middleName":"","lastName":"June","suffix":""},{"id":410320811,"identity":"7e612927-0513-4ac2-99ed-a82d5dd807ce","order_by":2,"name":"Alloys K’Oloo","email":"","orcid":"","institution":"Kenya Medical Research Institute (KEMRI) Centre for Global Health Research, Kisumu, Kenya","correspondingAuthor":false,"prefix":"","firstName":"Alloys","middleName":"","lastName":"K’Oloo","suffix":""},{"id":410320812,"identity":"a4436c62-4f92-4dd7-bc7d-a1990980900f","order_by":3,"name":"Miriam Chomba","email":"","orcid":"","institution":"Kenya Medical Research Institute (KEMRI) Centre for Global Health Research, Kisumu, Kenya","correspondingAuthor":false,"prefix":"","firstName":"Miriam","middleName":"","lastName":"Chomba","suffix":""},{"id":410320813,"identity":"f3282922-79da-4a08-ab49-d94553122add","order_by":4,"name":"James Dodd","email":"","orcid":"","institution":"Global Health Trials Unit, Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK","correspondingAuthor":false,"prefix":"","firstName":"James","middleName":"","lastName":"Dodd","suffix":""},{"id":410320814,"identity":"d329c845-279a-41b0-91fc-ff0af0397205","order_by":5,"name":"Raymond Kiu","email":"","orcid":"","institution":"Department of Microbes, Infection and Microbiomes, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, UK; Quadram Institute Bioscience, Norwich, UK","correspondingAuthor":false,"prefix":"","firstName":"Raymond","middleName":"","lastName":"Kiu","suffix":""},{"id":410320815,"identity":"d10f6a76-3c0c-4f1b-83bc-925dd9df2f4d","order_by":6,"name":"Lindsay Hall","email":"","orcid":"","institution":"Department of Microbes, Infection and Microbiomes, College of Medicine and Health, University of Birmingham, Birmingham; Quadram Institute Bioscience, Norwich, UK","correspondingAuthor":false,"prefix":"","firstName":"Lindsay","middleName":"","lastName":"Hall","suffix":""},{"id":410320816,"identity":"a3eb3566-dca9-4646-83fd-5c17dc59a9bf","order_by":7,"name":"Duolao Wang","email":"","orcid":"","institution":"Global Health Trials Unit, Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK","correspondingAuthor":false,"prefix":"","firstName":"Duolao","middleName":"","lastName":"Wang","suffix":""},{"id":410320817,"identity":"e4125ffc-3bad-48bd-bc1d-0538e8338021","order_by":8,"name":"Kephas Otieno","email":"","orcid":"","institution":"Kenya Medical Research Institute (KEMRI) Centre for Global Health Research, Kisumu, Kenya","correspondingAuthor":false,"prefix":"","firstName":"Kephas","middleName":"","lastName":"Otieno","suffix":""},{"id":410320818,"identity":"5c84feb7-6313-4cad-b338-7f6502175984","order_by":9,"name":"Simon Kariuki","email":"","orcid":"","institution":"Kenya Medical Research Institute (KEMRI) Centre for Global Health Research, Kisumu, Kenya","correspondingAuthor":false,"prefix":"","firstName":"Simon","middleName":"","lastName":"Kariuki","suffix":""},{"id":410320819,"identity":"b5be5c04-551d-433e-8861-fd44cb13fe9a","order_by":10,"name":"Feiko O. 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The 6 weeks timepoint is not included as all infants had AGP within the normal range. RR=Risk Ratio; CI=confidence interval.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5929784/v1/8d08acc944ff3e28937c86ce.png"},{"id":75411930,"identity":"f17a8561-7429-45db-84ae-02e2b6daa94c","added_by":"auto","created_at":"2025-02-04 09:15:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":139821,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSystemic inflammation by intervention arm and timepoint. \u003c/strong\u003eA)\u003cstrong\u003e \u003c/strong\u003eChronic systemic inflammation: plasma a\u003csub\u003e1\u003c/sub\u003e-acid glycoprotein (AGP); B) Acute systemic inflammation: plasma C-reactive protein (CRP). Horizontal line shows upper limit of normal (ULN; AGP£1.0 g/L; CRP=0.45mg/dL). *\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05; ** \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001; *** \u003cem\u003eP\u003c/em\u003e£0.0001\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5929784/v1/6727d93b6b0b3671480db7dc.png"},{"id":75411985,"identity":"7c6980b3-cd11-424a-9455-f5792e4f61d7","added_by":"auto","created_at":"2025-02-04 09:15:50","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":176813,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBiomarkers of environmental enteric dysfunction and stool pH by timepoint and intervention arm. \u003c/strong\u003eA) Intestinal inflammation: faecal myeloperoxidase (MPO); B) Intestinal permeability: faecal a\u003csub\u003e1\u003c/sub\u003e-antitrypsin (AAT); C) Enterocyte damage: plasma intestinal fatty acid binding protein (IFABP); D) Stool pH. Horizontal line shows upper limit of normal (MPO \u0026lt;0.2 mg/dL; AAT \u0026lt;26.8 mg/dL; normal values for IFABP have not been determined). *\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05; ** \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001; ***\u003cem\u003e P\u003c/em\u003e £0.0001.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5929784/v1/3c352dd68aef2b377559770a.png"},{"id":75412807,"identity":"cee39ae0-8069-43f1-80cf-a134aeccefbf","added_by":"auto","created_at":"2025-02-04 09:23:47","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":145807,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGrowth hormones by timepoint and intervention arm. \u003c/strong\u003eA) Plasma insulin-like growth factor-1 (IGF-1); B) Plasma insulin-like growth factor binding protein 3 (IGFBP-3)\u003cstrong\u003e. \u003c/strong\u003eNormal ranges for IGF-1: age 0-11 months: males 18-156; females 14-192 ng/ml; age 12 months: males 14-203; females 23-243 ng/ml. Normal ranges for IGFBP-3: age 0-11 months: not established; age 12 months: 0.7-3.6 mg/L (\u003ca href=\"https://pediatric.testcatalog.org/show/IGFGP\"\u003ehttps://pediatric.testcatalog.org/show/IGFGP\u003c/a\u003e). *\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05; *** \u003cem\u003eP\u003c/em\u003e £0.0001.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-5929784/v1/f7bbb9d8aea2a3e0aeaf09c9.png"},{"id":75413513,"identity":"a4a89738-5966-40ca-b6f2-e66ab1d95f37","added_by":"auto","created_at":"2025-02-04 09:31:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1860880,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5929784/v1/9418a180-222f-4a47-a632-6f3b852ff269.pdf"},{"id":75411982,"identity":"ca2661fb-997e-4766-998c-5dcbc156c4a2","added_by":"auto","created_at":"2025-02-04 09:15:50","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1724624,"visible":true,"origin":"","legend":"","description":"","filename":"5719570supp10110064sp5rxq.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5929784/v1/dee64c351cbf6b9d4b063a81.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eAdministration of probiotics and synbiotics and systemic inflammation in Kenyan infants: an open label, randomised, phase II trial\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eUndernutrition remains a persistent problem in childhood in low- and middle-income countries (LMICs) with impaired linear growth (stunting; length/height-for-age z score \u0026lt;-2) affecting about 1 in 2 children in Asia and 2 out of 5 children in Africa.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e The occurrence of systemic inflammation in stunting has been reported in many studies in LMICs from different world regions\u003csup\u003e\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e and likely mediates many of the short- and longer-term adverse outcomes associated with stunting. Chronic systemic inflammation (CSI) contributes to stunting through growth hormone resistance\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e and is an underlying disease mechanism for impaired organ development,\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e including cognitive development\u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e and longer-term non-communicable diseases (NCDs).\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe resistance of undernutrition to nutritional supplements, water, sanitation and hygiene (WASH) and other interventions has focussed attention on gut health.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Environmental enteric dysfunction (EED), an asymptomatic disorder manifesting as growth faltering, is characterised by small intestinal inflammation, villous atrophy and increased mucosal permeability. EED results from enteropathogen colonisation without overt diarrhoea, is universal in people exposed to poor sanitation and hygiene and likely impairs childhood growth and development through malabsorption and as a major driver of CSI.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn newborns, prebiotic human milk oligosaccharides result in a dominance of \u003cem\u003eBifidobacterium\u003c/em\u003e in the gut which drive microbial community assembly and have a key role in colonisation resistance against enteropathogens as well as development of the gut and mucosal and systemic immunity.\u003csup\u003e\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e However, multiple adverse environmental factors such as poor sanitation and hygiene, caesarean section delivery, faulty feeding practices, and antibiotic exposure\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e may result in a \u0026ldquo;dysbiosis\u0026rdquo; (used here to mean a perturbation or delay in the development of the gut microbiota) which may compromise colonisation resistance and gut and immune system development.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Gut dysbiosis has been reported in several studies of children with malnutrition.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eA microbiota-directed complementary food in children aged 12 to 18 months with moderate acute malnutrition in Bangladesh was associated with changes to the microbiota and improved weight gain.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e However, 0\u0026ndash;3 months is the age period with the highest incidence of stunting onset with few catching-up in later childhood\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e and EED and CSI occur as early as age 6\u0026ndash;12 weeks, even in exclusively breast-fed infants.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Therefore, intervention during the first 6 months before complementary feeding starts is required.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe PRObiotics and SYNbiotics in infants in Kenya (PROSYNK) study aimed to assess whether administration of pro/synbiotics from 0 to 6 months reduced CSI through improved gut health. Probiotics are defined as \u0026ldquo;live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.\u0026rdquo;23 A prebiotic is \u0026ldquo;a substrate that is selectively utilised by host microorganisms conferring a health benefit\u0026rdquo;.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e A synbiotic is \u0026ldquo;a mixture comprising live microorganisms and substrate(s) selectively utilised by host microorganisms that confer a health benefit on the host\u0026rdquo;.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e Pro/synbiotics may boost colonisation resistance against enteropathogens, enhance gut development and provide immune benefits.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Given concerns that beneficial effects might be limited to specific probiotic strains,\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e we evaluated two different multi-strain preparations of live \u003cem\u003eBifidobacterium\u003c/em\u003e spp. and \u003cem\u003eLactobacillaceae\u003c/em\u003e, the most frequently used probiotics.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e We selected preparations that had evidence of safe administration in newborns (Lab4b)\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e including preterm infants (Labinic).\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e We tested the Lab4b probiotic consortium and, based on the favourable results of synbiotic administration in the prevention of sepsis in newborns in India,\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e we combined each preparation with a prebiotic resulting in three intervention arms.\u003c/p\u003e \u003cp\u003eTo maximise the potential to modulate the developing gut microbiome and intervene before the onset of EED, pro/synbiotic administration was started within 3 days of birth, given daily for 10 days and then weekly to age 6 months (total of 32 doses).\u003c/p\u003e \u003cp\u003eThe primary outcome was CSI (defined as plasma α\u003csub\u003e1\u003c/sub\u003e-acid glycoprotein (AGP)\u0026thinsp;\u0026gt;\u0026thinsp;1g/dl) at age 6 months. We also evaluated acute inflammation (plasma C-reactive protein; CRP) and the growth hormones insulin-like growth factor (IGF)-1 and IGF binding protein-3 (IGFBP-3). To explore whether EED was associated with systemic inflammation, we measured biomarkers of EED including intestinal inflammation (faecal myeloperoxidase, MPO), intestinal permeability (faecal α\u003csub\u003e1\u003c/sub\u003e-antitrypsin, AAT), mucosal integrity (plasma intestinal fatty acid binding protein, IFABP) and stool pH.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe PROSYNK study screened 816 newborns delivered at the Homa Bay County Teaching and Referral Hospital, western Kenya between October 28, 2020 and January 13, 2022. Newborns not meeting the inclusion criteria were excluded: parents/carers planned to leave the study area (n\u0026thinsp;=\u0026thinsp;82) or declined to participate (n\u0026thinsp;=\u0026thinsp;79) or where health staff had concerns regarding the infant\u0026rsquo;s health (n\u0026thinsp;=\u0026thinsp;55). Six hundred newborns were enrolled and random allocation resulted in 150 infants in the Labinic synbiotic, 151 Lab4b synbiotic, 150 Lab4b probiotic and 149 controls (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Overall, two thirds of the participants (64%) resided in the rural parts of Homa Bay County. Most (78%) mothers were married and 18% were HIV infected. Antibiotic exposure before delivery was uncommon (\u0026lt;\u0026thinsp;3% in any study arm). Nearly all women had a vaginal delivery (96%) and delivered in hospital (91%). Overall, 7% infants were low birthweight (\u0026lt;\u0026thinsp;2500g) and the mean time to first feed was between 1 to 2 hours in each study arm. These baseline demographic and clinical variables for mothers and newborns were similar across the study arms (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). WASH practices were also similar across study arms and reflected a high level of disadvantage (Supplementary Table\u0026nbsp;1). In 9 out of 10 participants\u0026rsquo; homes, the youngest child\u0026rsquo;s stool was disposed in the garbage. Almost half (47%) of the homes were using a pit latrine with a slab. More than one third (39%) of participants\u0026rsquo; homes collected rainwater for drinking.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1: Baseline maternal, delivery and infant demographic and clinical characteristics according to intervention arm\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cimg 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\"\u003e\u003c/strong\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cp\u003eData are n (%) or mean (standard deviation). Residence type was missing for one family in the Lab4b synbiotic arm\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eFollow-up at 6 months was completed in 559 (93%) infants and was 89% or greater in each study arm (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). In total, 39 (7%) children withdrew from the study with a similar frequency and reasons for withdrawal in the study arms (Supplementary Table 2). Follow-up at 24 months was completed in January 2024 and included 546 (91%) of children enrolled (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe number of infants taking all 32 doses of pro/synbiotics was 128 (85%) in the Labinic synbiotic, 124 (82%) in the Lab4b synbiotic and 124 (82%) in the Lab4b probiotic arm. In the control arm, 126 (85%) infants completed all 32 visits (Supplementary Table 3). Viability of the probiotic organisms at point-of-use was confirmed although with some reduction in numbers of bacteria compared with the manufactured product (Supplementary Note 1). Whole Genome Sequencing revealed that the \u003cem\u003eBifidobacterium\u003c/em\u003e possessed partial or complete HMO gene clusters signifying ability to metabolise and utilize HMOs (Supplementary Note 2).\u003c/p\u003e\n\u003cp\u003eOverall, 484/565 (86%) infants were exclusively breastfed at 3 months and 220/559 (39%) at 6 months, with a similar frequency across study arms (Supplementary Table\u0026nbsp;4).\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003ePrimary endpoint\u003c/h2\u003e\n \u003cp\u003eAt 6 months, the frequency of CSI (plasma AGP\u0026thinsp;\u0026gt;\u0026thinsp;1g/L) was markedly reduced in each of the intervention arms versus the control arm: CSI occurred in 60/138 (44%) controls versus 4/144 (3%; risk ratio (RR) 0.06, 95% CI 0.02\u0026ndash;0.17) infants in the Labinic synbiotic arm, 3/132 (2%; RR\u0026thinsp;=\u0026thinsp;0.05, 0.02\u0026ndash;0.16) in the Lab4b synbiotic and 3/141 (2%; RR\u0026thinsp;=\u0026thinsp;0.05, 0.02\u0026ndash;0.15) in the Lab4b arm in the crude analysis. Results were similar in adjusted analysis accounting for potential confounders (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eSecondary endpoints\u003c/h3\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eSystemic inflammation\u003c/h2\u003e\n \u003cp\u003eAt age 6 weeks, no infants had CSI and median AGP concentrations were similar in each of the study arms (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA; Supplementary Table 5). However, there were marked differences in the frequency of CSI between control and intervention arms at 3 months and also at 12 months even though pro/synbiotic administration had stopped at 6 months, although the proportion of infants with CSI in the intervention arms at 12 months had risen to between 8\u0026ndash;10% (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e; Supplementary Fig. 1). Median AGP concentrations had increased at 3, 6 and 12 months in the controls, but, in marked contrast, increased only slightly from values at 6 weeks in each of the intervention arms including at 12 months. Median AGP concentrations were significantly lower in each of the intervention arms vs. the controls at 3, 6 and 12 months (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA; Supplementary Table\u0026nbsp;5).\u003c/p\u003e\n \u003cp\u003eIncreased acute inflammation (plasma CRP concentration\u0026thinsp;\u0026gt;\u0026thinsp;0.45mg/dL) was seen in half or more of the infants in all arms and at all visits. However, median CRP was significantly higher in the controls versus each of the intervention arms at 3 and 12 months and the Lab4b probiotic arm at 6 months (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB; Supplementary Table\u0026nbsp;5).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eBiomarkers of EED\u003c/h3\u003e\n\u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eIntestinal inflammation (faecal MPO concentration \u0026ge;0.2 mg/dL) was evident as early as 6 weeks being present in between about 1 in 3 and 1 in 2 infants in all study arms and median levels were significantly higher in the Labinic synbiotic and Lab4b synbiotic arms than in the controls. Intestinal inflammation was present in more than 1 in 2 infants in all study arms at 3 and 6 months. Median levels were similar in all study arms at 3 months but were significantly lower in all three intervention arms than the control arm at 6 months. Levels had increased markedly by 12 months and were similar across the study arms (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eA; Supplementary Table\u0026nbsp;5).\u003c/p\u003e\n \u003cp\u003eIntestinal permeability was increased (faecal AAT \u0026ge;26.8 mg/dl) in up to 1 in 4 infants and similar across study arms at 6 weeks and 3 months. Levels had increased at 6 months in controls and were significantly higher than in each intervention arm. Levels increased further at 12 months with 1 in 2 or more infants in all study arms having raised levels and with similar median concentrations across the study arms (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eB; Supplementary Table\u0026nbsp;5).\u003c/p\u003e\n \u003cp\u003eThe concentration of plasma IFABP, a biomarker of intestinal integrity, was below the manufacturer\u0026rsquo;s upper limit of normal (1.8 ng/ml) in the majority of infants in all study arms at all timepoints. However, median levels were significantly raised in the controls versus the Lab4b probiotic arm at 3 months and versus all 3 intervention arms at 6 and 12 months (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eC; Supplementary Table\u0026nbsp;5).\u003c/p\u003e\n \u003cp\u003eStools tended to be more acidic in all study arms at 6 weeks (median pH 5.04\u0026ndash;5.23) with pH rising gradually to 12 months (pH 5.47\u0026ndash;5.68). At 6 weeks, stools were significantly more acidic in the Labinic synbiotic, Lab4b synbiotic and Lab4b probiotic arms than controls (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eD; Supplementary Table\u0026nbsp;5).\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eInvestigating correlations between EED biomarkers and plasma AGP in all infants, significant positive associations were with plasma IFABP at 3 months, faecal AAT at 6 months, and all three biomarkers at 12 months (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA). In multiple linear regression analysis with all three biomarkers as explanatory variables and plasma AGP as the dependent variable, a significant negative association was faecal MPO at 6 weeks (coefficient= -0.061; 95% CI -0.122, -0.000) and positive associations for plasma IFABP at 3 months (0.11; 0.080, 0.14), faecal AAT at 6 months (0.006; 0.004, 0.009) and faecal MPO (0.13; 0.043, 0.22), and plasma IFABP (0.098; 0.074, 0.12) at 12 months (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e\u003cstrong\u003eAssociations between biomarkers of environmental enteric dysfunction (EED) and plasma \u0026alpha;\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e-acid glycoprotein (AGP) in all infants according to timepoint\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2A) Correlations between plasma AGP and biomarkers of EED and growth hormones in all infants\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth rowspan=\"3\" align=\"left\"\u003e\n \u003cp\u003eBiomarkers\u003c/p\u003e\n \u003c/th\u003e\n \u003cth colspan=\"4\" align=\"left\"\u003e\n \u003cp\u003eTime point\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e6 weeks\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e3 months\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e6 months\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e12 months\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRho (95% CI)\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRho (95% CI)\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRho (95% CI)\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRho (95% CI)\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAGP vs MPO\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.08 (-0.16, 0.00) 0.051\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04 (-0.05, 0.12)\u003c/p\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.06 (-0.02, 0.14)\u003c/p\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.14 (0.05, 0.22) \u003cstrong\u003e0.0016\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAGP vs AAT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05 (-0.04, 0.13)\u003c/p\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03 (-0.05, 0.11)\u003c/p\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.24 (0.16, 0.32)\u0026thinsp;\u003cstrong\u003e\u0026lt;\u0026thinsp;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.13 (0.04, 0.21) \u003cstrong\u003e0.0032\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAGP vs IFABP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.05 (-0.13, 0.03) 0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.30 (0.22, 0.37)\u0026thinsp;\u003cstrong\u003e\u0026lt;\u0026thinsp;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.06 (-0.02, 0.15)\u003c/p\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.31 (0.24, 0.39)\u0026thinsp;\u003cstrong\u003e\u0026lt;\u0026thinsp;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAGP vs IGF-1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.12 (0.04, 0.20) 0.0031\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00 (-0.08, 0.09)\u003c/p\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.08 (-0.16, 0.00) 0.065\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.22 (-0.30, -0.14)\u0026thinsp;\u003cstrong\u003e\u0026lt;\u0026thinsp;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAGP vs IGFBP-3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.09 (-0.17, -0.01) \u003cstrong\u003e0.027\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.06 (-0.14, 0.02) 0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.10 (-0.18, -0.01) \u003cstrong\u003e0.024\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.17 (-0.25, -0.09) \u003cstrong\u003e0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e2B) Multiple regression analysis of EED biomarkers and plasma AGP\u003c/p\u003e\n \u003ctable width=\"696\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 85px;\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eBiomarkers\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 611px;\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime point\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6 weeks\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCoefficient (95% CI)\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3 months\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCoefficient (95% CI)\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6 months\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCoefficient (95% CI)\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e12 months\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCoefficient (95% CI)\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMPO\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e-0.061 (-0.12, -0.00) \u003cstrong\u003e0.049\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e0.019 (-0.12, 0.16)\u003c/p\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e0.060 (-0.037, 0.16)\u003c/p\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e0.13 (0.043, 0.22)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.0035\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAAT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e0.00 (-0.00, 0.001)\u003c/p\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e0.001 (-0.003, 0.005) 0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e0.006 (0.004, 0.009) \u003cstrong\u003e\u0026lt;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e-0.00 (-0.003, 0.002)\u003c/p\u003e\n \u003cp\u003e0.87\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIFABP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e-0.002 (-0.004, 0.001) 0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e0.11 (0.080, 0.14) \u003cstrong\u003e\u0026lt;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e0.014 (-0.001, 0.029) 0.071\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e0.098 (0.074, 0.12) \u003cstrong\u003e\u0026lt;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003ch3\u003eGrowth hormones\u003c/h3\u003e\n\u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eIGF-1 concentrations were in the normal range in most infants at most timepoints. Median concentrations were significantly higher in the Lab4b synbiotic and Lab4b probiotic arms than controls at 3 months and in all 3 intervention arms at 6 months (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eA; Supplementary Table 5). The number of infants with IGF-1 deficiency was similar across the study arms except at 6 months where 36/137 (26%) controls were deficient compared with 20/144 (14%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009) in the Labinic synbiotic, 12/132 (9%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in the Lab4b synbiotic and 18/141 (13%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004) in the Lab4b probiotic arms (Supplementary Table\u0026nbsp;6).\u003c/p\u003e\n \u003cp\u003eCompared with controls, IGFBP-3 concentrations were significantly higher in the Labinic synbiotic and Lab4b probiotic arms at 3 months and all 3 intervention arms at 6 months (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eB; Supplementary Table S5). IGFBP-3 deficiency at 12 months (\u0026lt;\u0026thinsp;700 ng/mL) occurred in 32\u0026ndash;43% infants across the study arms with a similar frequency in each arm (Supplementary Table\u0026nbsp;6).\u003c/p\u003e\n \u003cp\u003eIn all infants, plasma AGP was significantly negatively associated with IGF-1 at12 months (-0.22; -0.30, -0.14) and negatively associated with IGFBP-3 at 6 weeks (-0.09; -0.17, -0.01), 6 months (-0.10; -0.18, -0.01) and 12 months (-0.17; (-0.25, -0.09; Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eAdverse events\u003c/h2\u003e\n \u003cp\u003eIn total, 102 SAEs occurred in 88 (15%) children during follow-up to 24 months (Supplementary Table 7a). Clinicians made more than one diagnosis for many SAEs with a total of 151 diagnoses; the most common diagnoses were pneumonia (31; 20%), malaria (20; 13%) and gastroenteritis (16; 11%; Supplementary Table 7b). The number of SAEs and diagnoses were similar across the study arms (Supplementary Table 7) and none were attributed to the interventions. Mortality from 0\u0026ndash;24 months was 6/149 (4%) in the control arm, 3/150 (2%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.34) in the Labinic synbiotic, 4/151 (3%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.54) in the Lab4b synbiotic and 2/150 (1%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.17) in the Lab4b probiotic arms (Supplementary Table\u0026nbsp;7a).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAdministration in early life of live, multi-strain pro/synbiotics comprising of \u003cem\u003eBifidobacterium\u003c/em\u003e spp. and \u003cem\u003eLactobacillaceae\u003c/em\u003e was safe and markedly reduced CSI in highly disadvantaged infants exposed to poor sanitation and hygiene. From 3\u0026ndash;12 months, pro/synbiotics improved biomarkers of gut health and one or more biomarkers of EED was significantly associated with increased CSI. CSI was significantly associated with reduced growth hormone levels at 6 weeks and 6 and 12 months.\u003c/p\u003e \u003cp\u003eWe consider that the magnitude of differences in AGP concentrations between the control arm and intervention arms from age 3 months (differences in medians ranging from 0.25\u0026ndash;0.53 g/L according to timepoint and intervention arm; Supplementary Table\u0026nbsp;5) are clinically meaningful as they are greater than those between non-stunted and stunted children at similar ages in Zimbabwe (mean differences ranging from 0.06\u0026ndash;0.13 g/L)\u003csup\u003e22\u003c/sup\u003e and between non-stunted and moderately stunted (difference in medians 0.10 g/L) and severely stunted (0.11 g/L) 6-month olds in rural Uganda.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThere are multiple potential short and longer-term adverse effects of CSI in infancy. Increased plasma AGP has been shown to be significantly associated with impaired linear growth in early life in previous studies in Pakistan,\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e Uganda\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e Tanzania\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e and the multi-country MAL-ED\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e and BRINDA\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e studies. Our finding of a negative association between plasma AGP and plasma IGF-1 at 12 months is consistent with studies in Pakistan,\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e Mali,\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e Malawi\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e and Zimbabwe.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Negative associations between plasma AGP and plasma IGFBP-3, an indicator of adequate growth hormone signaling,\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e at 6 weeks and 6 and 12 months in our study is consistent with lower levels in children in Zimbabwe with stunting compared with controls from ages 6 weeks to 18 months.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Overall, the increased plasma IGF-1 and IGBP-3 levels observed at 3, 6 and 12 months in some intervention arms compared with controls in PROSYNK indicate that pro/synbiotics may be an appropriate intervention for growth hormone resistance in malnutrition.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSystemic inflammation during the first year of life impairs organ development\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e including cognitive development.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Early life CSI also increases the risk of longer-term non-communicable diseases (NCDs), with strong empirical evidence regarding disease onset or progression for metabolic syndrome, type 2 diabetes and cardiovascular disease.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Therefore, reduced CSI in infancy through pro/synbiotic administration is directly relevant to LMICs where 250\u0026nbsp;million or 43% of children fail to reach their developmental potential\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e and where the burden of NCDs is greatest.\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe raised plasma CRP concentrations in half or more infants at all timepoints and in all study arms likely reflect frequent acute infections in this vulnerable population as well as a consequence of intestinal inflammation. The reduced CRP concentrations in all intervention arms at 3 and 12 months may reflect less severe gastrointestinal infections or modulation of the inflammatory or immune response to infection.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn a recent scoping review that identified 29 clinical trials of pre-, pro- or synbiotics in children, there was no consistent effect on inflammatory biomarkers.\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e However, the trials were undertaken in different geographical regions, included both newborns and older children who were healthy or had a wide range of different diseases, evaluated many different pre-, pro- and synbiotic preparations and measured many different pro- and anti-inflammatory biomarkers. The review included a 5-arm randomised controlled trial in Mexico of 600 infants aged 20\u0026thinsp;\u0026plusmn;\u0026thinsp;7 days who received infant formula only or formula supplemented with one of two fructans, a single-strain probiotic (\u003cem\u003eL. rhamnosus)\u003c/em\u003e or synbiotic (fructans\u0026thinsp;+\u0026thinsp;\u003cem\u003eL. rhamnosus\u003c/em\u003e) daily that reported no significant difference in CRP concentration between study arms at age 3 months.\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e Further research is needed to identify optimal pre-, pro- or synbiotic preparations for countering inflammation occurring in specific populations and disease contexts.\u003c/p\u003e \u003cp\u003eWe selected biomarkers in plasma and stool that reflect different elements of EED, that have been measured in many other studies and are associated with impaired linear growth.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e In PROSYNK, mothers often followed advice provided by research staff and started complementary foods after the 6-month follow-up visit. As a result, around 40% infants were still exclusively breastfed at 6 months. A potential controversy of PROSYNK is the administration of an oral product in exclusively breastfed infants. However, we consider that this is justified given evidence of intestinal inflammation, increased intestinal permeability and enterocyte damage in many infants as early as age 6 weeks despite exclusive breastfeeding in PROSYNK and other studies\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e and that the onset of stunting is highest in the first 3 months of life.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOur findings suggest that intestinal inflammation occurs early and increased intestinal permeability and enterocyte damage occur later in infancy in this population. The significant positive correlations at the 3, 6 and 12-month timepoints in the multiple regression analysis between the biomarkers of intestinal inflammation, permeability and enterocyte damage and plasma AGP suggest that each intestinal pathology drives CSI and possibly with different pathologies driving CSI at different time periods during infancy. However, these pathologies are inter-related and measurement of a wider range of biomarkers of EED may provide greater insights into the progression of the intestinal lesion and pathways to CSI in different populations.\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e The statistically significant, though marginal, increase in intestinal inflammation in the Labinic synbiotic and Lab4b synbiotic arms vs. the controls at 6 weeks was unexpected. Further research to provide greater insights and determine potential mechanisms in these young infants is required.\u003c/p\u003e \u003cp\u003ePro/synbiotics may improve gut health through multiple mechanisms including boosting intestinal colonisation against pathogens, modulating innate and adaptive immunity and reducing intestinal permeability through an enhanced mucus barrier and strengthened tight junction integrity.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e The positive findings in PROSYNK support the critical roles for \u003cem\u003eBifidobacterium\u003c/em\u003e spp. and \u003cem\u003eLactobacillaceae\u003c/em\u003e in early life including the ability of pro/synbiotics to modulate the developing gut microbiota before it is well-established in the specific context of countering exposure to poor sanitation and hygiene.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e The more acidic stools at 6 weeks in the intervention arms vs. the controls suggest an early increase in \u003cem\u003eBifidobacterium\u003c/em\u003e with increased production of short-chain fatty acids.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAlthough we did not evaluate the three pro/synbiotics head-to-head, a striking finding was that improved gut health and reduced systemic inflammation was present to a similar degree in the Lab4b and Labinic arms. This suggests either that different strains of \u003cem\u003eBifidobacterium\u003c/em\u003e spp. and \u003cem\u003eLactobacillaceae\u003c/em\u003e share beneficial \u0026ldquo;core\u0026rdquo; properties\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e or strain-specific differences can be overcome by using multi-strain products. Our study design contrasts with a previous trial where \u003cem\u003eLactobacillus\u003c/em\u003e GG administered to children aged 3\u0026ndash;5 years at risk of EED in Malawi did not affect intestinal integrity assessed by a site-specific sugar-absorption test.\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e The discrepancy with our findings might be due to the use of a single probiotic and/or the older age of the participants in the Malawi study.\u003c/p\u003e \u003cp\u003eAlthough the similar gut health biomarker and CSI levels in the Lab4b probiotic and the Lab4b synbiotic arms suggest no benefit of the addition of prebiotic fructooligosaccharide (FOS), this needs to be confirmed in further research especially in non-breastfed infants that do not receive prebiotics in the form of human milk oligosaccharides.\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eStrikingly, the reduced acute and CSI and enterocyte damage in all three intervention arms were still evident at 12 months even though pro/synbiotic administration stopped at 6 months. Further research is needed to determine if a beneficial modulation of the gut microbiota, once established, persists long-term and whether this is due to long-term engraftment of probiotic organisms. Alternatively, improved early gut health and/or immunity may provide longer term resilience against adverse environmental factors.\u003c/p\u003e \u003cp\u003eThe early onset of intestinal inflammation, marked increase in intestinal inflammation at 12 months and increased CSI at 12 months in some infants in the intervention arms indicate that further research is needed to optimise the pro/synbiotic intervention and the administration regimen. This could include alternative pro/synbiotics formulations, more frequent administration and continuing administration beyond 6 months. Selection of specific probiotic strains, including microbes isolated from healthy Kenyan infants, could be guided by genomic and \u003cem\u003ein vitro\u003c/em\u003e analyses to identify important functional pathways such as ability to metabolise human milk oligosaccharides, as demonstrated here for the \u003cem\u003eBifidobacterium\u003c/em\u003e spp. (Supplementary Note 2) and production of bacteriocins.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eQualitative research during PROSYNK revealed that mothers/carers and health professionals were highly supportive of the pro/synbiotic intervention.\u003csup\u003e \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e \u003c/sup\u003e Also, experience gained revealed that many mothers/carers were able to administer the pro/synbiotics to their infants themselves after initial training. Our findings regarding long-term stability at ambient temperature in Kenya for the Lab4b probiotic and the potential for stability to be improved by use of alternative formulations, indicate that pro/synbiotics could be transported and stored in children\u0026rsquo;s homes without the use of a cold chain. An economic analysis undertaken during PROSYNK estimated that the incremental economic costs to the Ministry of Health of delivering the pro/synbiotic programmatically in the community was \u003cspan\u003e$\u003c/span\u003e9.15 per infant per 32 dose course (range \u003cspan\u003e$\u003c/span\u003e6.93 - \u003cspan\u003e$\u003c/span\u003e34.11 depending on supply and delivery scenarios).\u003csup\u003e \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e \u003c/sup\u003e \u003c/p\u003e \u003cp\u003eStrengths of our study were that randomisation resulted in similar baseline demographic and clinical variables across study arms. We maintained the same contact and general support for the control infants as occurred in the intervention arms so that differences between study arms could be attributed to the interventions. We also supervised dosing of the pro/synbiotics and confirmed probiotic viability at point-of-use. Although laboratory analyses were undertaken by staff blinded to treatment allocation, a limitation was that assessment of morbidity may be biased in an open label study.\u003c/p\u003e \u003cp\u003eThe marked effects of early life pro/synbiotics on reducing CSI and improving gut health represents a significant step-forward in addressing the multiple adverse outcomes associated with undernutrition and EED in vulnerable children in LMICs. The potential of pro/synbiotics as a public health intervention including impact on health outcomes, cost-effectiveness and affordability when used at scale needs to be determined. Although food supplements, WASH and/or nutritional supplements in older infants appear to have limited effects on growth,\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e future trials may assess pro/synbiotic administration as part of a package of interventions. Further research is also needed to assess the effects of reduced CSI in early life, whether or not growth is improved, on organ development, including cognitive development, and reduced risk of longer-term NCDs.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eEthical approval was obtained from the Kenya Medical Research Institute - Scientific and Ethics Review Unit (KEMRI/SERU/CGHR/320/3917), Kenyan Pharmacy \u0026amp; Poison Board, Kenya (PPB/ECCT/20/04/02/2020(063)), the National Commission for Science Technology and Innovation, Kenya (PPB/ECCT/20/04/02/2020(063) and the Liverpool School of Tropical Medicine (19\u0026ndash;048). The trial was conducted in accordance with the principles of the Declaration of Helsinki and was monitored by a Data Safety and Monitoring Board. The trial was registered with the Pan African Clinical Trials Registry (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pactr.samrc.ac.za/\u003c/span\u003e\u003cspan address=\"https://pactr.samrc.ac.za/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e; PACTR202003893276712) on 02 March 2020 and before recruitment of the first participant and the protocol was published.\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e Supplementary materials include a CONSORT checklist (Supplementary Note 3).\u003c/p\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eThe study was a prospective, open-label, individually randomised, 4-arm, phase 2 trial in Homa Bay County, western Kenya where approximately 13% of under 5s are stunted (height-for-age z score \u0026lt;-2).\u003csup\u003e46\u003c/sup\u003e The study was conducted in Homa Bay County Teaching and Referral Hospital, a 280-bed government facility.\u003c/p\u003e \u003cp\u003eSingleton, term infants aged 0\u0026ndash;3 days, with a birth weight of \u0026ge;\u0026thinsp;2000g, who were breastfed, had taken a breastfeed well and lived in the hospital catchment area were enrolled by research clinicians. Exclusion criteria were suspicion or presence of any acute illness (e.g. fever; treated with antibiotics), congenital anomalies that might be life-threatening or impair growth, potential contraindication to pro/synbiotics (e.g. suspected immune suppression; cardiac abnormality), mother unlikely to stay in study area for the duration of the study and any health or research staff concerns regarding safety to participate in the trial. Baseline demographic and clinical data were collected using standardised questionnaires. All infants were examined by a research clinician including determination of gender. Information regarding the mother, pregnancy and delivery was determined by review of ante-natal and hospital records.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eTrial procedures\u003c/h2\u003e \u003cp\u003eNewborns were allocated according to a computer-generated random sequence with blocks of random size and stratified by HIV exposure, generated by the research statistician and withheld from all other research staff until databases were cleaned and locked. Newborns were allocated 1:1:1:1 to one of four study arms by the research clinicians opening a sealed opaque envelope.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eInvestigational products and administration\u003c/h2\u003e \u003cp\u003eStudy staff visited infants\u0026rsquo; homes to administer under supervision Labinic synbiotic (recently named \u0026ldquo;Labisyn\u0026rdquo; by the supplier; BENEO Orafti Synergy1; 50 oligofructose:50 FOS; 200mg\u0026thinsp;+\u0026thinsp;\u003cem\u003eLactobacillus (L.) acidophilus\u003c/em\u003e NCFM, \u003cem\u003eBifidobacterium (B.) longum\u003c/em\u003e subsp. \u003cem\u003einfantis\u003c/em\u003e Bi-26 and \u003cem\u003eB. bifidum\u003c/em\u003e Bb-06; total of 5x10\u003csup\u003e9\u003c/sup\u003e organisms/day, Biofloratech Ltd., Walton-on-Thames, UK); Lab4b probiotic (\u003cem\u003eLigilactobacillus salivarius\u003c/em\u003e CUL61 (NCIMB30211), \u003cem\u003eLacticaseibacillus paracasei\u003c/em\u003e CUL08 (NCIMB 30154), \u003cem\u003eB. bifidum\u003c/em\u003e CUL20 (NCIMB 30153), and \u003cem\u003eB. animalis\u003c/em\u003e subsp. \u003cem\u003elactis\u003c/em\u003e CUL34 (NCIMB 30172); total of 10\u003csup\u003e10\u003c/sup\u003e organisms/day), Lab4b synbiotic (Lab4b probiotic combined with long-chain FOS 150mg/day, Cultech Ltd., Port Talbot, UK) or no pro/synbiotic (controls). The pro/synbiotics were presented as powder in capsules of a different colour for each product. The capsules were opened, and the powder sprinkled directly into the infant\u0026rsquo;s open mouth before feeding or mixed in a clean container with sterile water. Administration was repeated once if the infant vomited within 30 minutes. Administration occurred daily for the first 10 days and then weekly to age 6 months (total of 32 doses). All bacterial strains were live; products were shipped, transported and delivered to homes using a cold chain. Quantitative culture of the pro/synbiotics at point-of-use (Supplementary Note 1) and whole genome sequencing of probiotic organisms to identify human milk oligosaccharide (HMO) gene clusters (Supplementary Note 2) were undertaken. In addition, to explore the feasibility of pro/synbiotic administration without use of a cold chain, the viability of probiotic organisms when stored at ambient temperature in Kenya was also evaluated. Viability for the Labinic organisms fell rapidly. However, after some initial decrease, viability of the Lab4b organisms was maintained for up to 12 months (Supplementary Note 4).\u003c/p\u003e \u003cp\u003e Control infants received the same home visits and contact with the research team as those in the intervention arms, except that some scheduled visits were done by mobile phone to comply with COVID-19 restrictions. During all home visits/phone calls, research staff gave general advice on infant feeding, hygiene and care to all mothers/carers and facilitated referral for clinical review if the infant was unwell.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLaboratory assessments for primary and secondary outcomes\u003c/h2\u003e \u003cp\u003eBiomarkers of systemic inflammation, EED and growth were measured in capillary blood (up to 1 ml) and stool samples collected either at the research clinic or from homes using a cool box (temperature range 9-11\u003csup\u003eo\u003c/sup\u003eC) at 6 weeks, 3 months, 6 months and 12 months. The primary outcome was CSI at age 6 months assessed by plasma α\u003csub\u003e1\u003c/sub\u003e-acid glycoprotein \u003cb\u003e(\u003c/b\u003eAGP)\u0026thinsp;\u0026gt;\u0026thinsp;1 g/L. Secondary outcomes were acute inflammation assessed by plasma C-reactive protein (CRP) and biomarkers of EED including intestinal inflammation (faecal myeloperoxidase, MPO), intestinal permeability (faecal α\u003csub\u003e1\u003c/sub\u003e-antitrypsin, AAT), mucosal integrity (plasma intestinal fatty acid binding protein, IFABP) and stool pH using a pH metre. Biomarkers of growth included insulin-like growth factor (IGF)-1 and IGF binding protein-3. Biomarkers were measured by ELISA (Supplementary Table\u0026nbsp;8). All the laboratory assays were carried out in duplicate and including control samples, according to the manufacturer\u0026rsquo;s instructions and analysed sequentially so that samples from all study arms were likely to be analysed on each ELISA plate. Laboratory staff were blinded to the study arms. We also recorded serious adverse events to age 24 months, including mortality, during home visits and parents/carers informed staff of illnesses by mobile phone. Medical records were reviewed for infants admitted to hospital.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eA total of 524 infants (131 per am) would allow the detection of a 50% reduction (risk ratio\u0026thinsp;=\u0026thinsp;0.50) in the prevalence of CSI at age 6 months from 35% in the control arm\u003csup\u003e22\u003c/sup\u003e to 17.5% in any of the intervention arms with 80% power and with α\u0026thinsp;=\u0026thinsp;0.0167 to allow for 3 primary comparisons against the control arm based on the intention to treat population. We aimed to recruit 150 infants/arm to allow for 13% dropouts.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methods\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using STATA v.17 (StataCorp LLC, Texas, USA). For demographic, clinical, laboratory, feeding, WASH and environmental variables in subjects with non-missing data, continuous variables were summarised as median (interquartile range; IQR) or mean (standard deviation; SD) and categorical variables as number and percent. For the primary outcome, (AGP\u0026thinsp;\u0026gt;\u0026thinsp;1g/L), we used generalised linear models with binomial distribution and log link function, with treatment as the sole predictor, expressed as risk ratios with corresponding 95% confidence intervals (CI). Adjusted analysis included pre-specified covariates that were predicted to modulate the effects of the interventions: season of birth, residence (urban vs. rural), HIV exposure, maternal antibiotic exposure prior to delivery, mode of delivery, sex, low birthweight (\u0026lt;\u0026thinsp;2500g) and breastfed to 3 months. Median values for biomarkers were compared between each intervention arm and the control arm using the Mann-Whitney U test. Concentrations of biomarkers according to timepoint and intervention arm are illustrated in boxplots where the boxes summarise the median (midline) and interquartile ranges (IQR), whiskers are drawn to the nearest value within 1.5 times the IQR, values outside of this range shown as circles and values at or beyond the maximum value shown are grouped at the maximum value and the number shown.\u003c/p\u003e \u003c/div\u003e "},{"header":"Declarations","content":"\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eData are presented in the article and supplementary materials. Anonymised datasets and study documents (participant information sheets, informed consent forms) are available on reasonable request to the corresponding author. Requests will be reviewed by the investigators or their representatives at LSTM and Kenya and the KEMRI SERU and LSTM Research Ethics Committees notified of any agreements to share data.\u003c/p\u003e \u003c/div\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eAll authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eChildren\u0026rsquo;s Investment Fund Foundation. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.\u003c/p\u003e\u003ch2\u003eAuthor contributions\u003c/h2\u003e \u003cp\u003eSA: conceptualisation and secured funding; MIO, MJ, LH, DW, SK, FtK, SA: study design; MIO, MJ: administration and supervision of data collection; AK: data curation; MC, KO: laboratory analyses; RK, LH: advice on quantitative culture of probiotic organisms, genome wide sequencing and bioinformatics analysis of probiotic organisms; MIO, AK, JD formal analysis; MIO, AK, JD: validation; all authors had permission to access all the data in the study if they wished; MIO, SA: first draft; AK, JD: figures; all authors reviewed, edited and had final responsibility for the decision to submit for publication.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eWe thank all of the children and their parents/carers for participation in the study. We thank Sue Plummer, Cultech Ltd. UK and Elspeth Small, Biofloratech Ltd., UK for advice regarding quantitative culture and provision of pro/synbiotic formulations; Angela Allen for advice and guidance in undertaking laboratory analyses; Benjamin Momo Kadia for assistance with developing methods of pro/synbiotic administration in homes and training field staff; Drs Tony Sang and Ruth Njoroge (Kisumu, Kenya), for the advice and support in the delivery and administration of trial interventions to participants; Jane Rawlinson (LSTM, Liverpool, UK), Benta Kamire and Sheila Nyarinda (LSTM-Kenya, Kenya) for administrative support. We would like to thank Sellinah Okumu, Chair of the Community Advisory Board, Homa Bay, Kenya; TSC members (Pauline Andang\u0026rsquo;o (Chair; Maseno University, Kisumu, Kenya), Walter Otieno (Maseno Medical School, Kisumu, Kenya), the late Rachel Musoke (University of Nairobi, Nairobi, Kenya), Sellinah Okumu (Homa Bay, Kenya), Sufia Askari (Children\u0026rsquo;s Investment Fund Foundation; London, UK) and Martina Oneko (Local Safety Monitor; KEMRI, Kisumu, Kenya)) and DSMB members (Robert Bandsma (Chair; Hospital for Sick Children, Toronto, Canada), Janet Berrington (Newcastle University, Newcastle, UK) and Paul Milligan (London School of Hygiene and Tropical Medicine, London, UK)) for their expert oversight and guidance.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLevels and trends in child malnutrition: UNICEF/WHO/World Bank Group joint child malnutrition estimates: key findings of the 2023 edition\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTickell KD, Atlas HE, Walson JL (2019) Environmental enteric dysfunction: a review of potential mechanisms, consequences and management strategies. 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Preprint at medRxiv 2024.12.17.24319142\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOtiti MI et al (2022) PRObiotics and SYNbiotics to improve gut health and growth in infants in western Kenya (PROSYNK Trial): study protocol for a 4-arm, open-label, randomised, controlled trial. Trials 23:284\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e\u003cem\u003eKenya Demographic and Health Survey, 2022\u003c/em\u003e. (Kenya National Bureau of Statistics; ICF, Nairobi, Kenya : Rockville, Maryland, USA, (2022)\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"f5cb059b-4dd2-49c5-8a5d-34785f9c616a","identifier":"10.13039/100010409","name":"Children's Investment Fund Foundation","awardNumber":"R-1806-02780","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Liverpool School of Tropical Medicine","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Environmental enteric dysfunction, systemic inflammation, Probiotics, Synbiotics, Gut health, Biomarkers","lastPublishedDoi":"10.21203/rs.3.rs-5929784/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5929784/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEnvironmental enteric dysfunction (EED) in early life, caused by gut pathogen colonisation, contributes to chronic systemic inflammation (CSI) which impairs growth and organ development and increases non-communicable disease risk. Pro/synbiotics may prevent or ameliorate EED, and thereby reduce CSI, through boosting colonisation resistance against enteropathogens and provide other intestinal and immune benefits. We evaluated three pro/synbiotics consisting of live, multi-strain \u003cem\u003eBifidobacterium\u003c/em\u003e spp. and \u003cem\u003eLactobacillaceae\u003c/em\u003e in reducing CSI. In this open-label, randomised, four-arm, phase II trial, 600 healthy Kenyan newborns (1\u0026ndash;3 days old, birthweight \u0026ge;2000g) were allocated 1:1:1:1, stratified by HIV exposure, to receive Labinic synbiotic, Lab4b synbiotic or Lab4b probiotic or no intervention daily for ten days, then weekly until six months. The primary outcome was CSI (plasma α\u003csub\u003e1\u003c/sub\u003e-acid glycoprotein\u0026thinsp;\u0026gt;\u0026thinsp;1g/L) at six months with blinded laboratory assessments. At six months, CSI occurred in 60/138 (43%) controls versus 4/144 (3%; relative risk (RR) 0.06, 95% CI 0.02\u0026ndash;0.17; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) infants in the Labinic synbiotic, 3/132 (2%; RR\u0026thinsp;=\u0026thinsp;0.05, 0.02\u0026ndash;0.16; P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) in the Lab4b synbiotic, and 3/141 (2%; RR\u0026thinsp;=\u0026thinsp;0.05, 0.02\u0026ndash;0.15; P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) in the Lab4b probiotic arm. Serious adverse events and mortality over 0\u0026ndash;24 months were similar across study arms. Pro/synbiotics safely and markedly reduced CSI in this disadvantaged population, warranting investigation of health impacts.\u003c/p\u003e","manuscriptTitle":"Administration of probiotics and synbiotics and systemic inflammation in Kenyan infants: an open label, randomised, phase II trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-04 09:15:41","doi":"10.21203/rs.3.rs-5929784/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"38568b80-4722-4dc3-ac01-e2e2b4634e0a","owner":[],"postedDate":"February 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":43745518,"name":"Gastroenterology \u0026 Hepatology"},{"id":43745519,"name":"Nutrition \u0026 Dietetics"},{"id":43745520,"name":"Pediatrics"}],"tags":[],"updatedAt":"2025-02-04T09:15:41+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-04 09:15:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5929784","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5929784","identity":"rs-5929784","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}