Frailty, adherence to healthy diet and risk of inflammatory bowel disease: a large-scale prospective cohort study

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To evaluate the individual and joint effects of frailty and healthy diet on the risk of IBD. Methods Data on frailty and diet were collected from a prospective cohort of 338,716 UK Biobank participants. Cox proportional-hazard regression was used to analyze the association of frailty status and dietary pattern with incident IBD. A joint effect analysis was conducted to demonstrate the potential modification effect of healthy diet on the relationship between frailty and IBD. Results During a median follow-up of 12.47 years, 2032 RA were identified. Compared with non-frail participants, those with pre-frailty and frailty showed a significantly increased risk of IBD, which was 13% higher in pre-frailty (95% CI: 1.03, 1.23) and 33% higher in frailty (95% CI: 1.08, 1.62), respectively. Participants with moderate and ideal dietary patterns had a significantly lower incidence of IBD compared with those with poor dietary patterns. The adjusted hazard ratios (HRs) were 0.84 (95% CI: 0.74, 0.96) and 0.76 (95% CI: 0.67, 0.88) for moderate dietary pattern and ideal dietary pattern, respectively. Moreover, individuals with non-frailty and ideal dietary pattern had a 43% (95% CI: 0.32, 0.89) reduced risk of IBD in contrast with those with frailty and poor dietary patterns. Conclusion The study provides evidence linking frailty and unhealthy diet to the risk of IBD. Our findings suggested that adherence to a healthy diet might attenuate the deleterious effect of frailty on IBD risk. Frailty healthy diet Inflammatory bowel disease cohort study Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and Ulcerative colitis (UC), represents a progressive condition driven by immune responses that lead to persistent and cyclical gastrointestinal inflammation[ 1 ]. The current global age-standardized prevalence rate of IBD exceeds 0.08%, and with a rising incidence rate, it has brought a huge financial burden to the healthcare system[ 2 , 3 ]. Given that no treatment strategy is curative, it is necessary to search for modifiable risk factors and new treatment perspectives to ultimately combat the IBD epidemic[ 4 ]. Frailty is an emerging global health burden with major implications for clinical practice and public health. As the aging population grows rapidly, the incidence of frailty is set to rise[ 5 ]. Frailty is characterized by the decline of physical function in multiple systems and decreased reserve and endurance to stresses[ 6 ]. Emerging research indicates a potential correlation between frailty and inflammatory bowel diseases (IBD) because of overlapping mechanisms. Both conditions exhibit common features, including raised levels of inflammatory markers like tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), changes in gut microbiota profiles, disruptions in the gut-brain axis due to senescence, enhanced intestinal permeability, and reduced gut motility[ 7 – 11 ]. According to the findings from several recent studies, frailty is related with poor outcomes in patients with chronic diseases such as cirrhosis awaiting liver transplantation, chronic obstructive pulmonary disease, and AIDS, regardless of real age[ 12 – 14 ]. A previous study also reported the association between frailty status with the risk of irritable bowel syndrome[ 15 ]. However, longitudinal evidence on the association between frailty and incident IBD is limited. IBD is influenced by complex interactions between environmental factors, changes in intestinal flora, numerous vulnerable genetic features, and immune system changes, but dietary habits appear to have an underappreciated role in the disease's pathogenesis and progression[ 16 , 17 ]. However, studies regarding dietary and IBD is contradictory. Excess sugar, animal fats, and linoleic acid consumption are thought to be risk factors for the development of IBD[ 18 , 19 ], but a high-fiber diet and consumption of citrus fruits may be protective[ 20 , 21 ]. A healthy diet throughout various stages of the disease may aid in achieving or extending remission and, most significantly, improving the quality of life of IBD patients[ 17 ]. Meanwhile, a cross-sectional data showed that adherence to a healthy diet reduces pre-frailty and frailty risk[ 22 ]. Although diet is a focal point for people with IBD, the impact of diet on IBD remains under-explored with limited guidance. In addition, it is unclear whether pre-frail or frail participants who achieve ideal dietary patterns have a lower risk for IBD. For effective IBD prevention, it's essential to delve deeper into the intricate interplay between frailty and dietary habits. The UK Biobank research provides a rich foundation for this exploration as it is an expansive prospective cohort study. Our goal was to delve deeply into how frailty status correlates with IBD while also exploring the possible influence of wholesome dietary patterns on this relationship. Materials & Methods Study population The UK Biobank, initiated between 2006 and 2010, is a vast prospective cohort research initiative, encompassing over half a million participants from England, Wales, and Scotland. This endeavor has amassed extensive data on participants' sociodemographic backgrounds, lifestyles, physical health, and medical conditions[ 23 ]. All individuals participating provided written approval, with the study getting the green light from the North West-Haydock Research Ethics Committee (16/NW/0274). For our analysis, we omitted individuals with a cancer history, those diagnosed with IBD when entering the study, and those missing crucial data on IBD, dietary habits, frailty evaluation, and other vital variables. This left us with a cohort of 338,716 adults for our comprehensive analysis. A flow chart of the study design is presented in Fig. S1 . Outcome ascertainment The disease information was obtained by the hospital admission electronic health records and death register through linkage with the Hospital Episode Statistics for England, Scottish Morbidity Records for Scotland, and Patient Episode Database for Wales. Incidents of CD and UC were ascertained by a primary or secondary diagnosis following the International Classification of Diseases (ICD) codes (ICD-10: K50, K51) guidelines. 4187 individuals with IBD at baseline and 210 individuals with both CD and UC at baseline. Each participant's follow-up person-time was calculated from the date of initial assessment to the date of death, the first date of outcome diagnosis, the date of loss to follow-up, or the end of follow-up, whichever occurred first. Physical frailty status assessment The frailty of participants was evaluated using the Fried phenotype method, a widely-accepted model for determining frailty. It incorporates five critical indicators: weight reduction, feelings of fatigue, diminished grip strength, restricted physical activities, and a slower walking speed[ 24 , 25 ]. More comprehensive definitions and associated field IDs can be located in Table S1 . Each negative frailty component contributed one point to the cumulative frailty index, which varied between 0 and 5. Based on established guidelines by Fried and his team, participants were categorized as non-frailty (score of 0), pre-frailty (score between 1 and 2), or frailty (score of 3 or more). Evaluating Dietary Habits Using a touchscreen-based food frequency survey (FFQ), we gauged dietary habits. Respondents indicated their daily dietary choices, which covered a spectrum of items such as poultry, beef, lamb/mutton, preserved meats, various fish types, fruits, and vegetables. Table S2 offers a more in-depth insight into definitions and their corresponding field IDs. Positive dietary attributes added one point each, with the entire dietary score ranging between 0 and 5. Based on their scores, participants were grouped into poor (score of 0–1), medium (score of 2–3), or ideal (score of 4–5) dietary categories[ 26 ]. Covariates Covariates were selected based on previous epidemiological evidence and data availability at baseline[ 27 – 29 ]. Potential confounders included age (continuous), gender (male, female), ethnicity (white or other), socioeconomic status, smoking status (never, current, previous), alcohol drinking (never, current, previous), hypertension (Yes, No) diabetes (Yes, No). Socioeconomic status was assessed via the Townsend deprivation index (quartiles), calculated immediately prior to participant joining UKB using preceding national census output areas. Statistical analysis Characteristics at the outset were delineated based on IBD status, with continuous variables shown as mean (standard deviation [SD]) and categorical ones displayed as counts (proportions). The Cox proportional hazard model was conducted to examine the association between frailty and diet and incident IBD. Model 1 was adjusted for age and gender whereas Model 2 was adjusted for age, gender, ethnicity, Townsend deprivation index, smoking status, alcohol drinker status, hypertension, and diabetes. We also examined the association between 5 components of frailty and the risk of IBD individually and mutually. To depict the dose-response relationship between the frailty index score, the healthy diet score, and IBD onset, we utilized the restricted cubic spline model (RCS). To examine the joint association between frailty and diet on the hazard of IBD, we treated participants with frailty and poor dietary pattern as the reference group to conduct a joint analysis on the association between frailty and diet risk of IBD with 3 × 3 groups. Meanwhile, we also estimated the association between frailty and IBD stratified by the dietary pattern. We performed stratified analyses to examine the association between frailty and incident IBD by age [older (age ≥ 60 years) or middle-aged adults (age < 60 years)], gender (male or female). Meanwhile, sensitivity analyses were undertaken to assess the robustness of the findings. Firstly, we re-modeled by excluding IBD cases occurring in the first 2 years to minimize the influence of reverse causation. Secondly, we analyzed the results in the UC and CD subgroups. Thirdly, we defined frailty status as a binary variable reanalysis. All statistical analyses were performed using the R Software, version 4.2.2. The Cox proportional hazards model was fitted using the R package “survival”, and the restricted cubic spline analysis was assessed by the R package “rms”. P values were two-sided, and P < 0.05 was considered statistically significant. Results Baseline characteristics Baseline characteristics, stratified by IBD status, are represented in Table 1 . The primary analysis included 338,716 participants from UKB. During a mean follow-up time of 12.47 years, 2,032 participants developed IBD, of which 665 were CD and 1367 were UC (Table 1 , Table S3 and S4) . In general, 14237 (4.2%) and 155430 (45.9%) were frailty and pre-frailty at baseline. 134102 (39.6%) of the participants had an ideal dietary pattern. Participants with IBD were more likely to be frail and pre-frail status, and have a lower proportion of ideal dietary pattern. Table 1 Baseline characteristics of UK Biobank participants by inflammatory bowel disease. Overall (N = 338716) No incident IBD (N = 336684) Incident IBD (N = 2032) P Value Age, mean (SD), y 56.0 (8.12) 56.0 (8.12) 56.8 (8.00) < 0.001 Gender, n (%) < 0.001 Male 163540 (48.3%) 162475 (48.3%) 1065 (52.4%) Female 175176 (51.7%) 174209 (51.7%) 967 (47.6%) Ethnicity, n (%) 1.000 White 322806 (95.3%) 320869 (95.3%) 1937 (95.3%) Other 15910 (4.7%) 15815 (4.7%) 95 (4.7%) Townsend Deprivation Index, mean (SD) -1.46 (3.00) -1.46 (3.00) -1.23 (3.16) < 0.001 Smoking status, n (%) < 0.001 Never smoker 187405 (55.3%) 186476 (55.4%) 929 (45.7%) Former smoker 117351 (34.6%) 116499 (34.6%) 852 (41.9%) Current smoker 33960 (10.0%) 33709 (10.0%) 251 (12.4%) Alcohol status, n (%) 0.029 Never drinker 12550 (3.7%) 12463 (3.7%) 87 (4.3%) Former drinker 10892 (3.2%) 10809 (3.2%) 83 (4.1%) Current drinker 315274 (93.1%) 313412 (93.1%) 1862 (91.6%) Hypertension, n (%) 166431 (49.1%) 165401 (49.1%) 1030 (50.7%) 0.167 Diabetes, n (%) 16341 (4.8%) 16210 (4.8%) 131 (6.4%) < 0.001 Frailty status, n (%) < 0.001 Non-frailty 169049 (49.9%) 168114 (49.9%) 935 (46.0%) Pre-frailty 155430 (45.9%) 154445 (45.9%) 985 (48.5%) Frailty 14237 (4.2%) 14125 (4.2%) 112 (5.5%) Frailty component Weight loss, n (%) 51842 (15.3%) 51542 (15.3%) 300 (14.8%) 0.516 Exhaustion, n (%) 38151 (11.3%) 37900 (11.3%) 251 (12.4%) 0.128 Low physical activity, n (%) 67038 (19.8%) 66587 (19.8%) 451 (22.2%) 0.007 Slow walking pace, n (%) 22032 (6.5%) 21851 (6.5%) 181 (8.9%) < 0.001 Low grip strength, n (%) 61684 (18.2%) 61255 (18.2%) 429 (21.1%) < 0.001 Dietary pattern, n (%) < 0.001 Poor dietary pattern 40376 (11.9%) 40076 (11.9%) 300 (14.8%) Medium dietary pattern 164238 (48.5%) 163238 (48.5%) 1000 (49.2%) Ideal dietary pattern 134102 (39.6%) 133370 (39.6%) 732 (36.0%) IBD: Inflammatory bowel disease; SD: Standard deviation. Association between frailty status and dietary pattern and IBD risk Participants in the pre-frail and frail categories exhibited a markedly heightened risk of IBD onset compared to their non-frail counterparts. After accounting for potential confounding factors, the HR for pre-frail and frail individuals stood at 1.13 (95% CI: 1.03, 1.23) and 1.33 (95% CI: 1.08, 1.62) respectively (Figs. 1 and 2 C). Upon examining restricted cubic splines, a direct association between the frailty index score and IBD onset was discerned. ( P for nonlinear = 0.718) (Fig. 2 A ) . For each one-point increase in frailty status score was positively associated with IBD risk (HR = 1.09; 95%CI: 1.04, 1.14) (Fig. 1 ). The study further analyzed 5 components of frailty and their association with incident IBD independently. In the fully adjusted model, the study observed that low physical activity (HR = 1.15; 95%CI: 1.04, 1.28), slow gait speed (HR = 1.28; 95%CI: 1.09, 1.50), and low grip strength (HR = 1.15; 95%CI: 1.03, 1.29) were significantly associated with incident IBD, while the null association was observed for weight loss and exhaustion (Fig. 1 ). In addition, participants with moderate and ideal dietary patterns had a significantly lower incidence of IBD compared with participants with poor dietary patterns. the HRs of those with moderate dietary patterns and ideal dietary patterns were 0.84 (95% CI: 0.74, 0.96) and 0.76 (95% CI: 0.67, 0.88) after adjustment for covariates (Figs. 1 and 2 D). In restricted cubic splines, we also observed a linear relationship between healthy diet score and incidence of IBD ( P for nonlinear = 0.589) (Fig. 2 B ) . For each one-point increase in diet was inversely associated with IBD risk (HR = 0.94; 95%CI: 0.90, 0.97) (Fig. 1 ). In sensitivity analyses, the associations between frailty status and dietary pattern with IBD risk remained stable. The results of Model 1 and Model 2 remained consistent ( Table S5 ). Moreover, the association between frailty status and dietary pattern and IBD risk still existed after excluding IBD cases occurring in the first 2 years ( Table S8 ). The results also remained consistent when pre-frail and frail participants were combined as compared with non-frail participants ( Table S9 ). For the CD and UC subgroups, the relationship between frailty status, dietary pattern and CD risk remained consistent with IBD, whereas no association between frailty and UC was observed. Moreover, in model 3, polygenic risk score related variables were added for adjustment, and the results did not change. ( Table S6 and S7 ). Diet alters the frailty contribution to IBD risk Further analysis was done on the combined impact of frailty state and dietary pattern on IBD. Participants with non-frailty and ideal dietary patterns had the lowest risk of IBD (HR = 0.57; 95% CI: 0.32–0.89) in contrast with those with frailty and poor dietary patterns (Fig. 3 ). Meanwhile, in poor dietary patterns, we only found a statistically significant trend test between frailty status and the risk of developing IBD ( P for trend = 0.020) ( Fig. S2 ). These results were consistent only in the CD subgroup ( Fig. S2 - S4) . Subgroup analysis Within subgroups of age and gender, we found that frailty was more strongly associated with IBD risk in middle-aged individuals and males than in older adults and females (Fig. 4 ). Frailty status was positively correlated with the risk of IBD in middle-aged people (HR = 1.54; 95%CI: 1.17, 2.03). Additionally, men were more likely to develop IBD (HR = 1.50; 95%CI: 1.13, 2.00). Discussion Spanning a median duration of 12 years, our extensive cohort study encompassing almost 300,000 adults revealed that the risks of developing IBD were increased by factors of 1.13 and 1.33 for those identified as pre-frail and frail, respectively. Furthermore, for every unit increase in the frailty score, there was an associated 9% surge in IBD risk. Such association was modified by the ideal dietary patterns of IBD, where the lowest risk of IBD was observed in those with ideal dietary patterns and non-frailty. What makes it noteworthy is that frailty was more strongly associated with IBD risk in middle-aged adults and males than in older adults and females. Frailty is defined as the loss of physiologic reserve and represents a compounded risk of age- and disease-related deficits that, through synergistic effects, lead to dysfunction of multiple physiologic systems[ 30 ]. While the precise biological pathways linking frailty to IBD are yet to be comprehensively understood, emerging research hints at intricate crosstalk between frailty, inflammation, and cellular aging potentially driving the connection[ 31 – 33 ]. Previous study has indicated that older persons with frailty or pre-frailty had higher levels of proinflammatory cytokines (TNF-α, IL-6), which are associated with compromised intestinal epithelial barrier function and may hence accelerate the onset of IBD symptoms[ 7 ]. A further logical cause could be the development of compromised intestinal permeability in conjunction with aging and frailty. Growing research has shown that there are significant changes in tight junction proteins linked with frailty, such as increased zonulin and claudin-2, decreased ZO-1, and occluding. These changes may cause disruptions in epithelial permeability and increase the risk of IBD[ 8 , 34 ]. Our study also found that components of frailty, including low physical activity, slow gait speed, and low grip strength may correlate with IBD. According to a study by Klare et al., moderate exercise reduces plasma IL-6 levels in individuals with chronic inflammation and relieves the inflammatory condition, which in turn lowers the intensity of the disease in IBD patients[ 35 , 36 ]. Furthermore, during physical activity, nuclear factor (NF-κB) activity is inhibited in muscle cells via peroxisome proliferator-activated receptor γ coactivator 1α, which suppresses the proliferation of pro-inflammatory cytokines[ 37 ]. While in two other cohort studies, it was indicated that frailty increases the risk of developing IBD more significantly in older adults[ 27 , 28 ], we showed in our subgroup analysis that frailty increases the risk of developing IBD more significantly in the middle-aged population. This suggests that age by itself may not be sufficient to predict the risk of infection in IBD[ 38 ]. Kirchgesner and colleagues noted that while advancing age correlated with a surge in opportunistic infections' absolute risk, the relative risk didn't show a significant rise when accounting for disease activity and other health conditions[ 39 ]. The plausible explanations for sex differences are genetically that the presence of two X chromosomes, longer telomeres and slower telomere shortening processes may give females a survival advantage[ 40 ]. Immunological mechanisms explain it as the immune system of males may deteriorate more severely and faster than that of females, resulting in lower survival rates[ 41 ]. Interestingly, our data suggests that healthier dietary habits might offset the links between frailty and IBD. It appears that risks of IBD due to frailty are less pronounced in those following a nutritious diet. The biological reasoning behind this interaction between diet and frailty seems valid. Diets abundant in antioxidant and anti-inflammatory foods, rich in vitamins, carotenoids from fruits and vegetables, and omega-3 polyunsaturated fatty acids from fish oil, play a crucial role in curbing oxidative and inflammatory responses[ 42 – 44 ]. We hypothesize that the diminished link between frailty and IBD in individuals adhering to nutritious diets might be attributed to the antioxidant and anti-inflammatory properties of their food intake. The major strengths of this study include the cohort design, large sample size and comprehensive analysis strategy. Furthermore, the overwhelming information provided by the UK Biobank favors us considering a large array of confounders. It's also vital to acknowledge certain limitations. To begin with, frailty determination relied on both self-reported factors (like exhaustion, walking pace, weight loss, and physical activity) and objective metrics (like grip strength). Hence, the reliance on subjective symptoms might introduce inaccuracies in frailty definition. Additionally, frailty undergoes continuous transitions—shifting among non-frail, pre-frail, and frail stages. As frailty was assessed only at the study's commencement, we couldn't scrutinize how ongoing changes in frailty might correlate with the prolonged risk of IBD. Furthermore, despite meticulous controls, there's potential for residual biases given the presence of unaccounted or unidentified variables influencing the frailty-IBD relationship. Lastly, it's worth noting that the dietary data sourced from the UK Biobank was based on participant recollection and was quite rudimentary, so the diet score might not exactly reflect overall healthy dietary behaviors. Finally, while our study was conducted in the UK general population, with the majority of participants being White, the generalizability of our results to diverse groups or ethnic backgrounds remains an open question. To corroborate our observations, extensive cohort evaluations across various ethnic groups are imperative. Conclusion To sum up, our research underscores frailty's pronounced influence on the likelihood of developing IBD. Frailty emerges as a significant, alterable risk factor for IBD, signaling a need for targeted lifestyle modifications. Concurrently, our investigation offers insights into the modulating effects of dietary choices. Emphasizing the significance of a balanced diet can help mitigate the IBD risks connected to frailty. Integrating these insights into clinical guidelines could revolutionize IBD management strategies, offering both innovative perspectives for future research and strategies to decrease the societal impact of IBD. Declarations Acknowledgments This research was conducted using the UK Biobank study under Application Number 80827. We want to thank all UK Biobank participants and the management team for their participation and assistance. Authors' contributions All authors were involved in drafting the article or revising it critically for important intellectual contact, and all authors approved the final version to be published. HFP takes responsibility for the content of the manuscript, including the conception and design of the study and final approval of the version to be submitted. JN contributed to the conception and design. LQJ, CNZ and YZ contributed to the acquisition, analysis, interpretation of the data and wrote the manuscript. YQZ, XF and RDZ contributed to the analysis and interpretation of the data. CC, YF and PW contributed to the statistical expertise. Fundings This study was funded by grants from the National Natural Science Foundation of China (82273710, 82103932), Anhui Provincial Natural Science Foundation (2108085Y26), Research Fund of Anhui Institute of Translational Medicine (2021zhyx-B04), and Research Funds of Center for Big Data and Population Health of IHM (JKS2022017). Data availability The data of current study can be requested from the UK Biobank (https://www.ukbiobank.ac.uk/). This work was conducted under UK Biobank application number 80827. Competing interests The authors declare that they do not have conflicts of interest. Ethics approval and consent to participate The UK Biobank has been approved by the Northwest Multicenter Research Ethics Committee (16/NW/0274). All participants gave written informed consent. References Wright, EK, NS Ding, and O Niewiadomski, Management of inflammatory bowel disease. Med J Aust, 2018; 209:318-23. 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Klare, P, J Nigg, J Nold, B Haller, AB Krug, S Mair, et al., The impact of a ten-week physical exercise program on health-related quality of life in patients with inflammatory bowel disease: a prospective randomized controlled trial. Digestion, 2015; 91:239-47. Ng, V, W Millard, C Lebrun, and J Howard, Low-intensity exercise improves quality of life in patients with Crohn's disease. Clin J Sport Med, 2007; 17:384-8. Eisele, PS, S Salatino, J Sobek, MO Hottiger, and C Handschin, The peroxisome proliferator-activated receptor γ coactivator 1α/β (PGC-1) coactivators repress the transcriptional activity of NF-κB in skeletal muscle cells. J Biol Chem, 2013; 288:2246-60. Faye, AS and JF Colombel, Age Is Just a Number-Frailty Associates With Outcomes of Patients With Inflammatory Bowel Disease. Gastroenterology, 2020; 158:2041-3. Kirchgesner, J, M Lemaitre, F Carrat, M Zureik, F Carbonnel, and R Dray-Spira, Risk of Serious and Opportunistic Infections Associated With Treatment of Inflammatory Bowel Diseases. Gastroenterology, 2018; 155:337-46.e10. Eskes, T and C Haanen, Why do women live longer than men? Eur J Obstet Gynecol Reprod Biol, 2007; 133:126-33. Gubbels Bupp, MR, Sex, the aging immune system, and chronic disease. Cell Immunol, 2015; 294:102-10. Di Giosia, P, CA Stamerra, P Giorgini, T Jamialahamdi, AE Butler, and A Sahebkar, The role of nutrition in inflammaging. Ageing Res Rev, 2022; 77:101596. Galland, L, Diet and inflammation. Nutr Clin Pract, 2010; 25:634-40. Adolph, TE and J Zhang, Diet fuelling inflammatory bowel diseases: preclinical and clinical concepts. Gut, 2022; 71:2574-86. Additional Declarations No competing interests reported. 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University，Department of Epidemiology and Biostatistics","correspondingAuthor":false,"prefix":"","firstName":"Chan-Na","middleName":"","lastName":"Zhao","suffix":""},{"id":269168878,"identity":"cef5ed2b-aaa3-406c-bbef-ce9af1556216","order_by":2,"name":"Yan Zhao","email":"","orcid":"","institution":"Anhui Medical University，Department of Epidemiology and Biostatistics","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Zhao","suffix":""},{"id":269168879,"identity":"526e759a-eba0-4bd4-a341-361e29ec9adf","order_by":3,"name":"Yu-Qiang Zhao","email":"","orcid":"","institution":"Anhui Medical University，Department of Epidemiology and Biostatistics","correspondingAuthor":false,"prefix":"","firstName":"Yu-Qiang","middleName":"","lastName":"Zhao","suffix":""},{"id":269168880,"identity":"d7650196-37f7-42e6-b7e6-1f349a3ba9fd","order_by":4,"name":"Xi Fang","email":"","orcid":"","institution":"Anhui Medical University，Department of Epidemiology and Biostatistics","correspondingAuthor":false,"prefix":"","firstName":"Xi","middleName":"","lastName":"Fang","suffix":""},{"id":269168882,"identity":"6f4c4dde-800b-49d4-b989-5d4118d3450a","order_by":5,"name":"Ruo-Di Zhang","email":"","orcid":"","institution":"Anhui Medical University，Department of Epidemiology and Biostatistics","correspondingAuthor":false,"prefix":"","firstName":"Ruo-Di","middleName":"","lastName":"Zhang","suffix":""},{"id":269168883,"identity":"e44bf553-67c8-4917-ae7d-0a29f6eea675","order_by":6,"name":"Cong Chen","email":"","orcid":"","institution":"Anhui Medical University，Department of Epidemiology and Biostatistics","correspondingAuthor":false,"prefix":"","firstName":"Cong","middleName":"","lastName":"Chen","suffix":""},{"id":269168887,"identity":"64ed99fe-da4b-406e-b86a-da1a0344ae4a","order_by":7,"name":"Yang Fang","email":"","orcid":"","institution":"Anhui Medical University，Department of Epidemiology and Biostatistics","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Fang","suffix":""},{"id":269168888,"identity":"a93a0f13-c409-4fe4-b46f-a912b840906d","order_by":8,"name":"Peng Wang","email":"","orcid":"","institution":"Teaching Center for Preventive Medicine, School of Public Health, Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"Wang","suffix":""},{"id":269168889,"identity":"7f3ba817-a379-41f5-931c-0533b657e65f","order_by":9,"name":"Jing NI","email":"","orcid":"","institution":"Anhui Medical University，Department of Epidemiology and Biostatistics","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"NI","suffix":""},{"id":269168891,"identity":"a5514fe0-7180-49d5-9114-904b2a99fb0b","order_by":10,"name":"Hai-Feng Pan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYHACNgYGAzkgzXyAGSKQQJQWYxCdQIoWBpAWHgPitJiznz324EeBgZw5/5qPnwtzDjPws+cYMPzcgVuLZU9eumGPgYGx5Yy3m6VnbjvMINnzxoCx9wxuLQYHcswkeAz+JG64cXaDNC9Qi8GNHANmxjY8Ws6/MZP8Y2BQv+HGmce/QVrsCWq5kWMmzWNgkGBwvocNYosEAS2WM96YScsYGBhuuMFmZs27LZ1H4syzgoO9eLSY8+eYSb75YyBvcP7w49u826zl+NuTNz74ic9hcJZEApjiAREHcGtA1sKPV90oGAWjYBSMZAAAyOxPCIKuqmIAAAAASUVORK5CYII=","orcid":"","institution":"Anhui Medical University，Department of Epidemiology and Biostatistics","correspondingAuthor":true,"prefix":"","firstName":"Hai-Feng","middleName":"","lastName":"Pan","suffix":""}],"badges":[],"createdAt":"2024-01-24 06:16:58","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3893115/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3893115/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50331575,"identity":"5f2ad907-2d96-49d7-aa99-c76cbec1e5c9","added_by":"auto","created_at":"2024-01-29 21:49:13","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":517416,"visible":true,"origin":"","legend":"\u003cp\u003eAssociations between frailty status,diet and the risk of inflammatory bowel disease.\u003c/p\u003e\n\u003cp\u003eThe model was adjusted for age, sex, Ethnicity, Townsend deprivation index, smoking status, alcohol intake, hypertension, and diabetes.\u003c/p\u003e\n\u003cp\u003eHR: Hazard ratio; CI: Confidence interval.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3893115/v1/a8e817ad1c0bb5513282a609.jpg"},{"id":50331577,"identity":"86c61590-b83e-45aa-9187-9041c5f189df","added_by":"auto","created_at":"2024-01-29 21:49:13","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1087392,"visible":true,"origin":"","legend":"\u003cp\u003eDose-response relationships and cumulative morbidity risk curves.\u003c/p\u003e\n\u003cp\u003e(A) Dose-response curves for frailty index scores and inflammatory bowel disease; (B) Dose-response curves for healthy diet scores and inflammatory bowel disease; (C) Standardized cumulative inflammatory bowel disease rates in non-frailty, pre-frailty and frailty; (D) Standardized cumulative inflammatory bowel disease rates in poor dietary pattern, medium dietary pattern and ideal dietary pattern.\u003c/p\u003e\n\u003cp\u003eFigures 2A-D were adjusted for age, sex, Ethnicity, Townsend deprivation index, smoking status, alcohol intake, hypertension, and diabetes.\u003c/p\u003e\n\u003cp\u003eHR: Hazard ratio; CI: Confidence interval.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3893115/v1/ce70ccb759e257968e75bca3.jpg"},{"id":50331578,"identity":"846e33a6-82fe-4b2f-b4c7-dafeb2daaa8c","added_by":"auto","created_at":"2024-01-29 21:49:13","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":243838,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of incident inflammatory bowel disease according to frailty status and dietary pattern.\u003c/p\u003e\n\u003cp\u003eThe model was adjusted for age, sex, Ethnicity, Townsend deprivation index, smoking status, alcohol intake, hypertension, and diabetes.\u003c/p\u003e\n\u003cp\u003eHR: Hazard ratio; CI: Confidence interval.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3893115/v1/08ab210612618ef9a1795241.jpg"},{"id":50332171,"identity":"9c1c3e7c-c455-40ea-b2bc-6ce60f7c427e","added_by":"auto","created_at":"2024-01-29 21:57:13","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":437723,"visible":true,"origin":"","legend":"\u003cp\u003eAssociations between frailty status and the risk of inflammatory bowel disease by age and gender.\u003c/p\u003e\n\u003cp\u003eThe model was adjusted for age, sex, Ethnicity, Townsend deprivation index, smoking status, alcohol intake, hypertension, and diabetes.\u003c/p\u003e\n\u003cp\u003eHR: Hazard ratio; CI: Confidence interval.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3893115/v1/ff8f64a5dd02e3e865e4989c.jpg"},{"id":65312544,"identity":"158afaa7-72da-4e5a-9e62-69d4aa0641f2","added_by":"auto","created_at":"2024-09-26 02:47:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2941599,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3893115/v1/66d33d34-3b6f-4c5c-ae31-2384a92e581d.pdf"},{"id":50331580,"identity":"95c493a1-1285-47a6-93f2-db9717785ff1","added_by":"auto","created_at":"2024-01-29 21:49:13","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":991642,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-3893115/v1/493db120d24cf9ef901f3e2f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Frailty, adherence to healthy diet and risk of inflammatory bowel disease: a large-scale prospective cohort study","fulltext":[{"header":"Background","content":"\u003cp\u003eInflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and Ulcerative colitis (UC), represents a progressive condition driven by immune responses that lead to persistent and cyclical gastrointestinal inflammation[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The current global age-standardized prevalence rate of IBD exceeds 0.08%, and with a rising incidence rate, it has brought a huge financial burden to the healthcare system[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Given that no treatment strategy is curative, it is necessary to search for modifiable risk factors and new treatment perspectives to ultimately combat the IBD epidemic[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFrailty is an emerging global health burden with major implications for clinical practice and public health. As the aging population grows rapidly, the incidence of frailty is set to rise[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Frailty is characterized by the decline of physical function in multiple systems and decreased reserve and endurance to stresses[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Emerging research indicates a potential correlation between frailty and inflammatory bowel diseases (IBD) because of overlapping mechanisms. Both conditions exhibit common features, including raised levels of inflammatory markers like tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), changes in gut microbiota profiles, disruptions in the gut-brain axis due to senescence, enhanced intestinal permeability, and reduced gut motility[\u003cspan additionalcitationids=\"CR8 CR9 CR10\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. According to the findings from several recent studies, frailty is related with poor outcomes in patients with chronic diseases such as cirrhosis awaiting liver transplantation, chronic obstructive pulmonary disease, and AIDS, regardless of real age[\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. A previous study also reported the association between frailty status with the risk of irritable bowel syndrome[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, longitudinal evidence on the association between frailty and incident IBD is limited.\u003c/p\u003e \u003cp\u003eIBD is influenced by complex interactions between environmental factors, changes in intestinal flora, numerous vulnerable genetic features, and immune system changes, but dietary habits appear to have an underappreciated role in the disease's pathogenesis and progression[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, studies regarding dietary and IBD is contradictory. Excess sugar, animal fats, and linoleic acid consumption are thought to be risk factors for the development of IBD[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], but a high-fiber diet and consumption of citrus fruits may be protective[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A healthy diet throughout various stages of the disease may aid in achieving or extending remission and, most significantly, improving the quality of life of IBD patients[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Meanwhile, a cross-sectional data showed that adherence to a healthy diet reduces pre-frailty and frailty risk[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Although diet is a focal point for people with IBD, the impact of diet on IBD remains under-explored with limited guidance. In addition, it is unclear whether pre-frail or frail participants who achieve ideal dietary patterns have a lower risk for IBD.\u003c/p\u003e \u003cp\u003eFor effective IBD prevention, it's essential to delve deeper into the intricate interplay between frailty and dietary habits. The UK Biobank research provides a rich foundation for this exploration as it is an expansive prospective cohort study. Our goal was to delve deeply into how frailty status correlates with IBD while also exploring the possible influence of wholesome dietary patterns on this relationship.\u003c/p\u003e"},{"header":"Materials \u0026 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThe UK Biobank, initiated between 2006 and 2010, is a vast prospective cohort research initiative, encompassing over half a million participants from England, Wales, and Scotland. This endeavor has amassed extensive data on participants' sociodemographic backgrounds, lifestyles, physical health, and medical conditions[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. All individuals participating provided written approval, with the study getting the green light from the North West-Haydock Research Ethics Committee (16/NW/0274). For our analysis, we omitted individuals with a cancer history, those diagnosed with IBD when entering the study, and those missing crucial data on IBD, dietary habits, frailty evaluation, and other vital variables. This left us with a cohort of 338,716 adults for our comprehensive analysis. A flow chart of the study design is presented in \u003cb\u003eFig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eOutcome ascertainment\u003c/h2\u003e \u003cp\u003eThe disease information was obtained by the hospital admission electronic health records and death register through linkage with the Hospital Episode Statistics for England, Scottish Morbidity Records for Scotland, and Patient Episode Database for Wales. Incidents of CD and UC were ascertained by a primary or secondary diagnosis following the International Classification of Diseases (ICD) codes (ICD-10: K50, K51) guidelines. 4187 individuals with IBD at baseline and 210 individuals with both CD and UC at baseline. Each participant's follow-up person-time was calculated from the date of initial assessment to the date of death, the first date of outcome diagnosis, the date of loss to follow-up, or the end of follow-up, whichever occurred first.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePhysical frailty status assessment\u003c/h2\u003e \u003cp\u003eThe frailty of participants was evaluated using the Fried phenotype method, a widely-accepted model for determining frailty. It incorporates five critical indicators: weight reduction, feelings of fatigue, diminished grip strength, restricted physical activities, and a slower walking speed[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. More comprehensive definitions and associated field IDs can be located in \u003cb\u003eTable \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e. Each negative frailty component contributed one point to the cumulative frailty index, which varied between 0 and 5. Based on established guidelines by Fried and his team, participants were categorized as non-frailty (score of 0), pre-frailty (score between 1 and 2), or frailty (score of 3 or more).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eEvaluating Dietary Habits\u003c/h2\u003e \u003cp\u003eUsing a touchscreen-based food frequency survey (FFQ), we gauged dietary habits. Respondents indicated their daily dietary choices, which covered a spectrum of items such as poultry, beef, lamb/mutton, preserved meats, various fish types, fruits, and vegetables. \u003cb\u003eTable S2\u003c/b\u003e offers a more in-depth insight into definitions and their corresponding field IDs. Positive dietary attributes added one point each, with the entire dietary score ranging between 0 and 5. Based on their scores, participants were grouped into poor (score of 0\u0026ndash;1), medium (score of 2\u0026ndash;3), or ideal (score of 4\u0026ndash;5) dietary categories[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eCovariates\u003c/h2\u003e \u003cp\u003eCovariates were selected based on previous epidemiological evidence and data availability at baseline[\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Potential confounders included age (continuous), gender (male, female), ethnicity (white or other), socioeconomic status, smoking status (never, current, previous), alcohol drinking (never, current, previous), hypertension (Yes, No) diabetes (Yes, No). Socioeconomic status was assessed via the Townsend deprivation index (quartiles), calculated immediately prior to participant joining UKB using preceding national census output areas.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCharacteristics at the outset were delineated based on IBD status, with continuous variables shown as mean (standard deviation [SD]) and categorical ones displayed as counts (proportions). The Cox proportional hazard model was conducted to examine the association between frailty and diet and incident IBD. Model 1 was adjusted for age and gender whereas Model 2 was adjusted for age, gender, ethnicity, Townsend deprivation index, smoking status, alcohol drinker status, hypertension, and diabetes. We also examined the association between 5 components of frailty and the risk of IBD individually and mutually. To depict the dose-response relationship between the frailty index score, the healthy diet score, and IBD onset, we utilized the restricted cubic spline model (RCS). To examine the joint association between frailty and diet on the hazard of IBD, we treated participants with frailty and poor dietary pattern as the reference group to conduct a joint analysis on the association between frailty and diet risk of IBD with 3 \u0026times; 3 groups. Meanwhile, we also estimated the association between frailty and IBD stratified by the dietary pattern.\u003c/p\u003e \u003cp\u003eWe performed stratified analyses to examine the association between frailty and incident IBD by age [older (age\u0026thinsp;\u0026ge;\u0026thinsp;60 years) or middle-aged adults (age\u0026thinsp;\u0026lt;\u0026thinsp;60 years)], gender (male or female). Meanwhile, sensitivity analyses were undertaken to assess the robustness of the findings. Firstly, we re-modeled by excluding IBD cases occurring in the first 2 years to minimize the influence of reverse causation. Secondly, we analyzed the results in the UC and CD subgroups. Thirdly, we defined frailty status as a binary variable reanalysis.\u003c/p\u003e \u003cp\u003eAll statistical analyses were performed using the R Software, version 4.2.2. The Cox proportional hazards model was fitted using the R package \u0026ldquo;survival\u0026rdquo;, and the restricted cubic spline analysis was assessed by the R package \u0026ldquo;rms\u0026rdquo;. \u003cem\u003eP\u003c/em\u003e values were two-sided, and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003eBaseline characteristics\u003c/h2\u003e\n\u003cp\u003eBaseline characteristics, stratified by IBD status, are represented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The primary analysis included 338,716 participants from UKB. During a mean follow-up time of 12.47 years, 2,032 participants developed IBD, of which 665 were CD and 1367 were UC (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cstrong\u003eTable S3 and S4)\u003c/strong\u003e. In general, 14237 (4.2%) and 155430 (45.9%) were frailty and pre-frailty at baseline. 134102 (39.6%) of the participants had an ideal dietary pattern. Participants with IBD were more likely to be frail and pre-frail status, and have a lower proportion of ideal dietary pattern.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline characteristics of UK Biobank participants by inflammatory bowel disease.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOverall\u003c/p\u003e\n\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;338716)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNo incident IBD\u003c/p\u003e\n\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;336684)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIncident IBD\u003c/p\u003e\n\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;2032)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e Value\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\u003eAge, mean (SD), y\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e56.0 (8.12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e56.0 (8.12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e56.8 (8.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eGender, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e163540 (48.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e162475 (48.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1065 (52.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e175176 (51.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e174209 (51.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e967 (47.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eEthnicity, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWhite\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e322806 (95.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e320869 (95.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1937 (95.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOther\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15910 (4.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15815 (4.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e95 (4.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTownsend Deprivation Index, mean (SD)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-1.46 (3.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-1.46 (3.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-1.23 (3.16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSmoking status, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNever smoker\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e187405 (55.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e186476 (55.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e929 (45.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFormer smoker\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e117351 (34.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e116499 (34.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e852 (41.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCurrent smoker\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e33960 (10.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e33709 (10.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e251 (12.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAlcohol status, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.029\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNever drinker\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e12550 (3.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e12463 (3.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e87 (4.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFormer drinker\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e10892 (3.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e10809 (3.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e83 (4.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCurrent drinker\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e315274 (93.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e313412 (93.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1862 (91.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHypertension, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e166431 (49.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e165401 (49.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1030 (50.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.167\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDiabetes, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e16341 (4.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e16210 (4.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e131 (6.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFrailty status, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNon-frailty\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e169049 (49.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e168114 (49.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e935 (46.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePre-frailty\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e155430 (45.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e154445 (45.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e985 (48.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFrailty\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e14237 (4.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e14125 (4.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e112 (5.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFrailty component\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWeight loss, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e51842 (15.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e51542 (15.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e300 (14.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.516\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eExhaustion, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e38151 (11.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e37900 (11.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e251 (12.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.128\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow physical activity, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e67038 (19.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e66587 (19.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e451 (22.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.007\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSlow walking pace, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e22032 (6.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e21851 (6.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e181 (8.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow grip strength, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e61684 (18.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e61255 (18.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e429 (21.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDietary pattern, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePoor dietary pattern\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e40376 (11.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e40076 (11.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e300 (14.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedium dietary pattern\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e164238 (48.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e163238 (48.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1000 (49.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdeal dietary pattern\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e134102 (39.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e133370 (39.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e732 (36.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eIBD: Inflammatory bowel disease; SD: Standard deviation.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eAssociation between frailty status and dietary pattern and IBD risk\u003c/h2\u003e\n\u003cp\u003eParticipants in the pre-frail and frail categories exhibited a markedly heightened risk of IBD onset compared to their non-frail counterparts. After accounting for potential confounding factors, the HR for pre-frail and frail individuals stood at 1.13 (95% CI: 1.03, 1.23) and 1.33 (95% CI: 1.08, 1.62) respectively (Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC). Upon examining restricted cubic splines, a direct association between the frailty index score and IBD onset was discerned. (\u003cem\u003eP\u003c/em\u003e for nonlinear\u0026thinsp;=\u0026thinsp;0.718) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA\u003cstrong\u003e)\u003c/strong\u003e. For each one-point increase in frailty status score was positively associated with IBD risk (HR\u0026thinsp;=\u0026thinsp;1.09; 95%CI: 1.04, 1.14) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The study further analyzed 5 components of frailty and their association with incident IBD independently. In the fully adjusted model, the study observed that low physical activity (HR\u0026thinsp;=\u0026thinsp;1.15; 95%CI: 1.04, 1.28), slow gait speed (HR\u0026thinsp;=\u0026thinsp;1.28; 95%CI: 1.09, 1.50), and low grip strength (HR\u0026thinsp;=\u0026thinsp;1.15; 95%CI: 1.03, 1.29) were significantly associated with incident IBD, while the null association was observed for weight loss and exhaustion (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eIn addition, participants with moderate and ideal dietary patterns had a significantly lower incidence of IBD compared with participants with poor dietary patterns. the HRs of those with moderate dietary patterns and ideal dietary patterns were 0.84 (95% CI: 0.74, 0.96) and 0.76 (95% CI: 0.67, 0.88) after adjustment for covariates (Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eD). In restricted cubic splines, we also observed a linear relationship between healthy diet score and incidence of IBD (\u003cem\u003eP\u003c/em\u003e for nonlinear\u0026thinsp;=\u0026thinsp;0.589) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB\u003cstrong\u003e)\u003c/strong\u003e. For each one-point increase in diet was inversely associated with IBD risk (HR\u0026thinsp;=\u0026thinsp;0.94; 95%CI: 0.90, 0.97) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eIn sensitivity analyses, the associations between frailty status and dietary pattern with IBD risk remained stable. The results of Model 1 and Model 2 remained consistent (\u003cstrong\u003eTable S5\u003c/strong\u003e). Moreover, the association between frailty status and dietary pattern and IBD risk still existed after excluding IBD cases occurring in the first 2 years (\u003cstrong\u003eTable S8\u003c/strong\u003e). The results also remained consistent when pre-frail and frail participants were combined as compared with non-frail participants (\u003cstrong\u003eTable S9\u003c/strong\u003e). For the CD and UC subgroups, the relationship between frailty status, dietary pattern and CD risk remained consistent with IBD, whereas no association between frailty and UC was observed. Moreover, in model 3, polygenic risk score related variables were added for adjustment, and the results did not change. (\u003cstrong\u003eTable S6 and S7\u003c/strong\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eDiet alters the frailty contribution to IBD risk\u003c/h2\u003e\n\u003cp\u003eFurther analysis was done on the combined impact of frailty state and dietary pattern on IBD. Participants with non-frailty and ideal dietary patterns had the lowest risk of IBD (HR\u0026thinsp;=\u0026thinsp;0.57; 95% CI: 0.32\u0026ndash;0.89) in contrast with those with frailty and poor dietary patterns (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Meanwhile, in poor dietary patterns, we only found a statistically significant trend test between frailty status and the risk of developing IBD (\u003cem\u003eP\u003c/em\u003e for trend\u0026thinsp;=\u0026thinsp;0.020) (\u003cstrong\u003eFig. S2\u003c/strong\u003e). These results were consistent only in the CD subgroup (\u003cstrong\u003eFig. S2 - S4)\u003c/strong\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eSubgroup analysis\u003c/h2\u003e\n\u003cp\u003eWithin subgroups of age and gender, we found that frailty was more strongly associated with IBD risk in middle-aged individuals and males than in older adults and females (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Frailty status was positively correlated with the risk of IBD in middle-aged people (HR\u0026thinsp;=\u0026thinsp;1.54; 95%CI: 1.17, 2.03). Additionally, men were more likely to develop IBD (HR\u0026thinsp;=\u0026thinsp;1.50; 95%CI: 1.13, 2.00).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eSpanning a median duration of 12 years, our extensive cohort study encompassing almost 300,000 adults revealed that the risks of developing IBD were increased by factors of 1.13 and 1.33 for those identified as pre-frail and frail, respectively. Furthermore, for every unit increase in the frailty score, there was an associated 9% surge in IBD risk. Such association was modified by the ideal dietary patterns of IBD, where the lowest risk of IBD was observed in those with ideal dietary patterns and non-frailty. What makes it noteworthy is that frailty was more strongly associated with IBD risk in middle-aged adults and males than in older adults and females.\u003c/p\u003e \u003cp\u003eFrailty is defined as the loss of physiologic reserve and represents a compounded risk of age- and disease-related deficits that, through synergistic effects, lead to dysfunction of multiple physiologic systems[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. While the precise biological pathways linking frailty to IBD are yet to be comprehensively understood, emerging research hints at intricate crosstalk between frailty, inflammation, and cellular aging potentially driving the connection[\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Previous study has indicated that older persons with frailty or pre-frailty had higher levels of proinflammatory cytokines (TNF-α, IL-6), which are associated with compromised intestinal epithelial barrier function and may hence accelerate the onset of IBD symptoms[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. A further logical cause could be the development of compromised intestinal permeability in conjunction with aging and frailty. Growing research has shown that there are significant changes in tight junction proteins linked with frailty, such as increased zonulin and claudin-2, decreased ZO-1, and occluding. These changes may cause disruptions in epithelial permeability and increase the risk of IBD[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Our study also found that components of frailty, including low physical activity, slow gait speed, and low grip strength may correlate with IBD. According to a study by Klare et al., moderate exercise reduces plasma IL-6 levels in individuals with chronic inflammation and relieves the inflammatory condition, which in turn lowers the intensity of the disease in IBD patients[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Furthermore, during physical activity, nuclear factor (NF-κB) activity is inhibited in muscle cells via peroxisome proliferator-activated receptor γ coactivator 1α, which suppresses the proliferation of pro-inflammatory cytokines[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile in two other cohort studies, it was indicated that frailty increases the risk of developing IBD more significantly in older adults[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], we showed in our subgroup analysis that frailty increases the risk of developing IBD more significantly in the middle-aged population. This suggests that age by itself may not be sufficient to predict the risk of infection in IBD[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Kirchgesner and colleagues noted that while advancing age correlated with a surge in opportunistic infections' absolute risk, the relative risk didn't show a significant rise when accounting for disease activity and other health conditions[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. The plausible explanations for sex differences are genetically that the presence of two X chromosomes, longer telomeres and slower telomere shortening processes may give females a survival advantage[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Immunological mechanisms explain it as the immune system of males may deteriorate more severely and faster than that of females, resulting in lower survival rates[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eInterestingly, our data suggests that healthier dietary habits might offset the links between frailty and IBD. It appears that risks of IBD due to frailty are less pronounced in those following a nutritious diet. The biological reasoning behind this interaction between diet and frailty seems valid. Diets abundant in antioxidant and anti-inflammatory foods, rich in vitamins, carotenoids from fruits and vegetables, and omega-3 polyunsaturated fatty acids from fish oil, play a crucial role in curbing oxidative and inflammatory responses[\u003cspan additionalcitationids=\"CR43\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. We hypothesize that the diminished link between frailty and IBD in individuals adhering to nutritious diets might be attributed to the antioxidant and anti-inflammatory properties of their food intake.\u003c/p\u003e \u003cp\u003eThe major strengths of this study include the cohort design, large sample size and comprehensive analysis strategy. Furthermore, the overwhelming information provided by the UK Biobank favors us considering a large array of confounders. It's also vital to acknowledge certain limitations. To begin with, frailty determination relied on both self-reported factors (like exhaustion, walking pace, weight loss, and physical activity) and objective metrics (like grip strength). Hence, the reliance on subjective symptoms might introduce inaccuracies in frailty definition. Additionally, frailty undergoes continuous transitions\u0026mdash;shifting among non-frail, pre-frail, and frail stages. As frailty was assessed only at the study's commencement, we couldn't scrutinize how ongoing changes in frailty might correlate with the prolonged risk of IBD. Furthermore, despite meticulous controls, there's potential for residual biases given the presence of unaccounted or unidentified variables influencing the frailty-IBD relationship. Lastly, it's worth noting that the dietary data sourced from the UK Biobank was based on participant recollection and was quite rudimentary, so the diet score might not exactly reflect overall healthy dietary behaviors. Finally, while our study was conducted in the UK general population, with the majority of participants being White, the generalizability of our results to diverse groups or ethnic backgrounds remains an open question. To corroborate our observations, extensive cohort evaluations across various ethnic groups are imperative.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTo sum up, our research underscores frailty's pronounced influence on the likelihood of developing IBD. Frailty emerges as a significant, alterable risk factor for IBD, signaling a need for targeted lifestyle modifications. Concurrently, our investigation offers insights into the modulating effects of dietary choices. Emphasizing the significance of a balanced diet can help mitigate the IBD risks connected to frailty. Integrating these insights into clinical guidelines could revolutionize IBD management strategies, offering both innovative perspectives for future research and strategies to decrease the societal impact of IBD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was conducted using the UK Biobank study under Application Number 80827. We want to thank all UK Biobank participants and the management team for their participation and assistance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors were involved in drafting the article or revising it critically for important intellectual contact, and all authors approved the final version to be published. HFP takes responsibility for the content of the manuscript, including the conception and design of the study and final approval of the version to be submitted. JN contributed to the conception and design. LQJ, CNZ and YZ contributed to the acquisition, analysis, interpretation of the data and wrote the manuscript. YQZ, XF and RDZ contributed to the analysis and interpretation of the data. CC, YF and PW contributed to the statistical expertise.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFundings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by grants from the National Natural Science Foundation of China (82273710, 82103932), Anhui Provincial Natural Science Foundation (2108085Y26), Research Fund of Anhui Institute of Translational Medicine (2021zhyx-B04), and Research Funds of Center for Big Data and Population Health of IHM (JKS2022017).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data of current study can be requested from the UK Biobank (https://www.ukbiobank.ac.uk/). This work was conducted under UK Biobank application number 80827.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they do not have conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe UK Biobank has been approved by the Northwest Multicenter Research Ethics Committee (16/NW/0274). All participants gave written informed consent.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWright, EK, NS Ding, and O Niewiadomski, Management of inflammatory bowel disease. Med J Aust, 2018; 209:318-23.\u003c/li\u003e\n\u003cli\u003eThe global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. 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Gut, 2022; 71:2574-86.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","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":"Frailty, healthy diet, Inflammatory bowel disease, cohort study","lastPublishedDoi":"10.21203/rs.3.rs-3893115/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3893115/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEmerging research indicates a potential correlation between frailty, healthy diet and IBD because of overlapping mechanisms. To evaluate the individual and joint effects of frailty and healthy diet on the risk of IBD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eData on frailty and diet were collected from a prospective cohort of 338,716 UK Biobank participants. Cox proportional-hazard regression was used to analyze the association of frailty status and dietary pattern with incident IBD. A joint effect analysis was conducted to demonstrate the potential modification effect of healthy diet on the relationship between frailty and IBD.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eDuring a median follow-up of 12.47 years, 2032 RA were identified. Compared with non-frail participants, those with pre-frailty and frailty showed a significantly increased risk of IBD, which was 13% higher in pre-frailty (95% CI: 1.03, 1.23) and 33% higher in frailty (95% CI: 1.08, 1.62), respectively. Participants with moderate and ideal dietary patterns had a significantly lower incidence of IBD compared with those with poor dietary patterns. The adjusted hazard ratios (HRs) were 0.84 (95% CI: 0.74, 0.96) and 0.76 (95% CI: 0.67, 0.88) for moderate dietary pattern and ideal dietary pattern, respectively. Moreover, individuals with non-frailty and ideal dietary pattern had a 43% (95% CI: 0.32, 0.89) reduced risk of IBD in contrast with those with frailty and poor dietary patterns.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe study provides evidence linking frailty and unhealthy diet to the risk of IBD. Our findings suggested that adherence to a healthy diet might attenuate the deleterious effect of frailty on IBD risk.\u003c/p\u003e","manuscriptTitle":"Frailty, adherence to healthy diet and risk of inflammatory bowel disease: a large-scale prospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-29 21:49:08","doi":"10.21203/rs.3.rs-3893115/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":"c6e1685a-3b75-4566-9300-2eed1b3fee1b","owner":[],"postedDate":"January 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-26T02:39:02+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-29 21:49:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3893115","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3893115","identity":"rs-3893115","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}