Social isolation, loneliness, and incident irritable bowel syndrome: a prospective cohort study

Social isolation, loneliness, and incident irritable bowel syndrome: a prospective cohort study | 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 Social isolation, loneliness, and incident irritable bowel syndrome: a prospective cohort study Tianyu Zhou, Zhenhe Jin, Kexin Ye, Zhe Shen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6465123/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background The disease burden of irritable bowel syndrome (IBS) is well recognized as the dysfunction of gut-brain axis. We aimed to investigate the association between social isolation, loneliness, and the risk of developing IBS. Methods A total of 441114 participants not diagnosed with IBS at baseline enrolled in the UK Biobank from 2006 to 2010 were included in this cohort study. The exposures of interest were social isolation and loneliness. The primary endpoint was incident IBS. Cox proportional hazard regression models were used to calculate the hazard ratios (HR) and 95% confidence intervals (CI) of the separate and joint effects of social isolation and loneliness on incident IBS. Results This study documented 9593 IBS cases during a mean follow-up of 14.6 years. Social isolation (HR 1.15, 95% CI 1.08–1.23) and loneliness (HR 1.45, 95% CI 1.33–1.57) were significantly associated with an increased risk of developing IBS. With the accelerating levels of social isolation and loneliness, participants showed a progressively higher tendency to develop IBS ( P trend < 0.0001). No substantial changes were found in the further subgroup and sensitivity analyses. Conclusions Social isolation and loneliness were associated with an increased risk of developing IBS. These findings suggested that interventions to enhance objective and subjective social connection should be considered as important prevention strategies for IBS management. Social isolation Loneliness Irritable bowel syndrome Figures Figure 1 Figure 2 Background Irritable bowel syndrome (IBS) is a functional gastrointestinal disease characterized by recurrent abdominal pain and abnormal bowel habits. Based on clinical manifestation, IBS is further subdivided into constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), mixed stool pattern (IBS-M), and un-subtyped (IBS-U) [ 1 ]. Approximately 10.1% and 4.1% of the global population are estimated suffering from IBS according to Rome III and IV criteria, respectively [ 2 ]. As is widely recognized, the dysfunction of gut-brain axis contributes to intestinal motility disturbances, visceral hypersensitivity, and altered processing within the central nervous system, which directly cause IBS [ 3 ]. Meanwhile, from a biopsychosocial modal, neurophysiology and psychological traits influence the symptoms of IBS in a complex manner [ 4 , 5 ]. Social isolation is characterized as an objective shortage of social connections and a diminished social network size, whereas loneliness is defined as a subjective feeling of being alone or lacking companionship [ 6 – 8 ]. Approximately 2.4 to 24.2% of European adults claim suffering from loneliness or social isolation, which has dramatically increased since the onset of the coronavirus disease 2019 pandemic [ 9 – 12 ]. Adequate social connection is necessary for maintaining both mental and physical health [ 11 ]. Social isolation and loneliness are associated with a wide range of adverse health consequences, such as increasing mortality [ 13 ], dementia [ 14 ], coronary heart disease [ 7 ], stroke [ 15 ], and sleep disturbances [ 15 ]. From theoretical models, social isolation and loneliness may initiate a lot of biological and behavioral mechanisms, including excessive stress response, higher inflammation status, and inhibited reward or motivation, which are potential risk factors for triggering the onset of IBS [ 16 – 19 ]. Since population-based evidence on the association between social isolation, loneliness, and incident IBS is scarce and a clear appraisal of the association not only deepens the understanding of the IBS etiology, but also provides clues for IBS prevention. Therefore, to ascertain the association between social isolation, loneliness, and the risk of incident IBS, we conducted a prospective cohort study with a lone-term follow-up based on the UK Biobank (UKB). Methods Study design and participants The UKB study is a large-scale prospective cohort study that recruited more than 500000 participants aged 37–73 years from 22 assessment centers across England, Wales, and Scotland between 2006 and 2010 [ 20 ]. Participants completed touchscreen questionnaires and physical measurements, and provided biological samples at recruitment [ 20 ]. The study was approved by the North West Multicenter Research Ethics Committee (REC reference for UK Biobank 11/NW/0382), and all participants provided written informed consent [ 20 ]. In the current study, 502174 participants were initially screened. We excluded those with missing data on social isolation or loneliness (n = 33949), a prior diagnosis of IBS at recruitment (n = 25814), and lost to follow-up (n = 1297), resulting in 441114 participants in the analyses (Fig. 1 ). Ascertainment of exposure The exposure of interest were social isolation and loneliness, which were collected at baseline. Social isolation was assessed by asking three questions: (1) “Including yourself, how many people are living together in your household? (include those who usually live in the house such as students living away from home during term, partners in the armed forces or professions such as pilots)” (1 point for living alone); (2) “How often do you visit friends or family or have them visit you?” (1 point for less than one friend or family visit per month); (3) “Which of the following do you attend once a week or more often? (you can select more than one)” (1 point for not participating in any social activities at least weekly). The social isolation score was calculated by summing up the points of these three questions (ranging from 0 to 3). Participants with 2 or 3 points were defined as socially isolated. Loneliness was assessed by two questions: (1) “Do you often feel lonely?” (0 point for the response of “no”, 1 point for the response of “yes”); (2) “How often are you able to confide in someone close to you?” (0 point for almost daily-once every few months, 1 point for never or almost never). Participants who responded positively to both questions were defined as lonely. Ascertainment of outcome Incident IBS was the primary outcome of this cohort, which was defined via the International Classification of Diseases 10th Revision (ICD-10) code: K58. The data of first occurrence were yielded from data-fields “First occurrences” (Field ID: 131638, 131639), which were generated by mapping primary care data, hospital inpatient data, death register records, and self-reported medical conditions. Ascertainment of covariates Covariates for this study were collected at baseline, including age (continuous), sex (male or female), body mass index (BMI, continuous), Townsend deprivation index (TDI, continuous), education (college or non-college), current smoker (yes or no). Ethnicity was categorized into “White” (White, British, Irish, or any other White background) and “others”. Alcohol intake was categorized into “low” (once or twice a week, one to three times a month, special occasions only, never) and “high” (daily or almost daily, three or four times a week). The diet score was constructed by the previous study [ 21 ]. Shortly, we calculated the diet score according to the frequency of seven food groups (fruits, vegetables, fish, processed meats, unprocessed red meats, whole grains, and refined grains) and we defined a healthy diet when a diet score ≥ 4 (Table S1 ). Physical activity was categorized into “adequate” (at or above moderate/vigorous/walking recommendation [150 minutes of walking or moderate activity per week or 75 minutes of vigorous activity]) and “inadequate” (below recommendation). Depressed mood was categorized into “low” (not at all, several days) and “high” (more than half of my days, nearly every day). Long-term illness, which was defined as self-reported long-standing illness without any specific diagnosis, was categorized into “yes” and “no” (Table S2). Statistical analyses Variates were presented as means ± standard deviation (SD) for continuous variables and frequency (percentages) for categorical variables. For missing data with a missing rate < 5%, we imputed the median for continuous variables and the value of the largest group for categorical variables. And we treated missing data as a separate category for variables with a missing rate ≥ 5%. The missing rates of all the variates are presented in Table 1 . Table 1 Baseline characteristics of the participants from the UK Biobank study. Overall (n = 441114) Social isolation Loneliness Non-isolated (n = 401116) Isolated (n = 39998) No loneliness (n = 420249) Loneliness (n = 20865) Sex Female 236195 (53.6) 215902 (53.8) 20293 (50.7) 226249 (53.8) 9946 (47.7) Male 204919 (46.5) 185214 (46.2) 19705 (49.3) 194000 (46.2) 10919 (52.3) Age, years Mean (SD) 56.5 (8.1) 56.5 (8.1) 56.7 (7.8) 56.6 (8.1) 56.0 (7.9) Age groups, years < 50 103212 (23.4) 94668 (23.6) 8544 (21.4) 98038 (23.3) 5174 (24.8) 50–59 146711 (33.3) 132190 (33.0) 14521 (36.3) 139234 (33.1) 7477 (35.8) 60 and older 191191 (43.3) 174258 (43.4) 16933 (42.3) 182977 (43.5) 8214 (39.4) Ethnicity White 419245/439881 (95.3) 382017/400067 (95.5) 37228/39814 (93.5) 399747/419110 (95.4) 19498/20771 (93.9) Other 20636/439881 (4.7) 18050/400067 (4.5) 2586/39814 (6.5) 19363/419110 (4.6) 1273/20771 (6.1) Missing 1233 (0.3) 1049 (0.3) 184 (0.5) 1139 (0.3) 94 (0.5) Education College 145670/437768 (33.3) 133728/398181 (33.6) 11942/39587 (30.2) 140741/417142 (33.7) 4929/20626 (23.9) Non-college 292098/437768 (66.7) 264453/398181 (66.4) 27645/39587 (69.8) 276401/417142 (66.3) 15697/20626 (76.1) Missing 3346 (0.8) 2935 (0.7) 411 (1.0) 3107 (0.7) 239 (1.1) Alcohol intake a Low 245387/440885 (55.7) 218463/400934 (54.5) 26924/39951 (67.4) 231970/420047 (55.2) 13417/20838 (64.4) High 195498/440885 (44.3) 182471/400934 (45.5) 13027/39951 (32.6) 188077/420047 (44.8) 7421/20838 (35.6) Missing 229 (0.1) 182 (0.0) 47 (0.1) 202 (0.0) 27 (0.1) Current smoker No 393796/439747 (89.6) 361485/399932 (90.4) 32311/39815 (81.2) 376771/418976 (89.9) 17025/20771 (82.0) Yes 45951/439747 (10.5) 38447/399932 (9.6) 7504/39815 (18.9) 42205/418976 (10.1) 3746/20771 (18.0) Missing 1367 (0.3) 1184 (0.3) 183 (0.5) 1273 (0.3) 94 (0.5) Dietary habit Poor diet 95898/340294 (28.2) 87168/312644 (27.9) 8730/27650 (31.6) 90503/325863 (27.8) 5395/14431 (37.4) Healthy diet 244396/340294 (71.8) 225476/312644 (72.1) 18920/27650 (68.4) 235360/325863 (72.2) 9036/14431 (62.6) Missing 100820 (22.9) 88472 (22.1) 12348 (30.9) 94386 (22.5) 6434 (30.8) Body mass index, kg/m 2 < 18.5 2157/439005 (0.5) 1800/399316 (0.5) 357/39689 (0.9) 2017/418293 (0.5) 140/20712 (0.7) 18.5–24.9 142716/439005 (32.5) 130246/399316 (32.6) 12470/39689 (31.4) 137150/418293 (32.8) 5566/20712 (26.9) 25-29.9 187359/439005 (42.7) 172022/399316 (43.1) 15337/39689 (38.6) 179125/418293 (42.8) 8234/20712 (39.8) > 29.9 106773/439005 (24.3) 95248/399316 (23.9) 11525/39689 (29.0) 100001/418293 (23.9) 6772/20712 (32.7) Missing 2109 (0.5) 1800 (0.4) 309 (0.8) 1956 (0.5) 153 (0.7) Body mass index, kg/m 2 Mean (SD) 27.4 (4.8) 27.4 (4.7) 27.9 (5.4) 27.4 (4.7) 28.5 (5.5) Missing 2109 (0.5) 1800 (0.4) 309 (0.8) 1956 (0.5) 153 (0.7) Physical activity b Adequate 286244/349458 (81.9) 263550/319268 (82.6) 22694/30190 (75.2) 274378/333831 (82.2) 11866/15627 (75.9) Inadequate 63214/349458 (18.1) 55718/319268 (17.5) 7496/30190 (24.8) 59453/333831 (17.8) 3761/15627 (24.1) Missing 91656 (20.8) 81848 (20.4) 9808 (24.5) 86418 (20.6) 5238 (25.1) Depressed mood Low 404434/424419 (95.3) 370148/386319 (95.8) 34286/38100 (90.0) 389175/404926 (96.1) 15259/19493 (78.3) High 19985/424419 (4.7) 16171/386319 (4.2) 3814/38100 (10.0) 15751/404926 (3.9) 4234/19493 (21.7) Missing 16695 (3.8) 14797 (3.7) 1898 (4.7) 15323 (3.6) 1372 (6.6) Long-term illness No 295328/431973 (68.4) 272573/393101 (69.3) 22755/38872 (58.5) 284390/411843 (69.1) 10938/20130 (54.3) Yes 136645/431973 (31.6) 120528/393101 (30.7) 16117/38872 (41.5) 127453/411843 (31.0) 9192/20130 (45.7) Missing 9141 (2.1) 8015 (2.0) 1126 (2.8) 8406 (2.0) 735 (3.5) Townsend index tertile c Bottom 147783 (33.5) 139373 (34.8) 8410 (21.0) 142542 (33.9) 5241 (25.1) Intermediate 146570 (33.2) 135535 (33.8) 11035 (27.6) 140470 (33.4) 6100 (29.2) Top 146761 (33.3) 126208 (31.5) 20553 (51.4) 137237 (32.7) 9524 (45.7) Townsend index tertile Mean (SD) -1.4 (3.0) -1.5 (3.0) 0.0 (3.5) -1.4 (3.0) -0.4 (3.5) Data are n (%), unless otherwise specified. SD, standard deviation. a Alcohol intake was defined as low (once or twice a week, one to three times a month, special occasions only, never) and high (daily or almost daily, three or four times a week). b Physical activity was categorized as at or above 150 minutes of walking or moderate activity per week or 75 minutes of vigorous activity or not. c Townsend index tertile was dichotomized as bottom (≤ -3.18), intermediate (-3.18 ~ -0.7), and top (> -0.7). The separate and joint effects of social isolation and loneliness on incident IBS, and the interaction between social isolation and loneliness in the risk of IBS were assessed in a multivariable Cox proportional hazard regression model and presented as hazard ratios (HR) with 95% confidence intervals (CI). Three models were generated: Model 1 adjusted for age (continuous) and sex. Model 2 further adjusted for ethnicity, BMI (continuous), education level, and TDI (continuous). Model 3 further adjusted for currently smoking, alcohol drinking, physical activity, and healthy diet. Among the three models, model 3 was considered as the best fit model for the lowest score of the Akaike information criterion (AIC) and Bayesian information criterion (BIC) and was thus chosen for subsequent analyses (Table S3). We further performed some subgroup analyses stratified by age (< 50, 50–59, or 60 and older), sex (male or female), ethnicity (White or non-White), BMI ( 29.9), education level (college or non-college), current smoker (yes or no), alcohol intake (low or high), and TDI (bottom, intermediate, or top). Using likelihood ratio tests, we compared Cox models with and without an interaction term of strata factor and exposure to determine the interaction effects. We also performed several sensitivity analyses to validate the separate and joint effects of social isolation and loneliness on incident IBS, and the interaction between social isolation and loneliness in the risk of IBS: (1) the analysis excluding participants who developed IBS in the first three years; (2) the analysis excluded participants who missing any data on covariates; (3) the analysis after multiple imputations by chained equations of missing values (see in Supplementary Materials); (4) the analysis additionally adjusted for depressed mood and long-term illness; (5) the analysis excluding those died during the follow-up period; (6) the analyses based on Fine-Gray sub-distribution hazard model to account for the potential impact of mortality as a competing event. All analyses were conducted using SAS version 9.4. The P values for all the statistical analyses were two-sided, with a significance level of 0.05. Results Baseline characteristics The cohort included a total of 441114 participants, and among these, 236195 were females and 204919 were males, with a mean age of 56.5 years. In this study, 39998 (9.1%) participants were socially isolated, and 20865 (4.7%) had feelings of loneliness. Baseline characteristics are presented in Table 1 . Participants with a higher level of social isolation or loneliness were more likely to be male, more deprived, lower education level, lower alcohol intake, current smoker, a higher percentage of obesity, have a poor diet, have lower physical activity, have a depressed mood, and be lone-term illness. Social isolation, loneliness, and incident IBS The incidence pattern of IBS for social isolation and loneliness is presented in Table 2 . During a mean follow-up of 14.6 years (standard deviation: 2.7), 9593 participants were diagnosed with IBS. Incident cases among the non-isolated and isolated, and no loneliness and loneliness participants were 8582, 1011, 8943, and 650, respectively, and the corresponding incident cases per 100000 persons-years were 143.9, 175.5, 143.4, and 214.3, respectively. Table 2 IBS incidence during the follow-up. Overall Social isolation Loneliness Non-isolated Isolated No loneliness Loneliness Person-years at risk 6539801 5963740 576062 6236430 303371 Incident cases 9593 8582 1011 8943 650 Incident cases per 100000 person-years 146.7 143.9 175.5 143.4 214.3 IBS, irritable bowel syndrome. Compared to non-socially isolated participants, socially isolated participants had a significantly higher risk of IBS (HR 1.15, 95% CI 1.08–1.23), after adjusting for age, sex, ethnicity, BMI, education level, TDI, currently smoking, alcohol drinking, physical activity, and healthy diet (Fig. 2 ). Similarly, individuals in the loneliness group were more susceptible to IBS than individuals in the no-loneliness group (HR 1.45, 95% CI 1.33–1.57) (Fig. 2 ). Meanwhile, with the accelerating levels of social isolation and loneliness, participants showed a progressively higher tendency to develop IBS ( P trend < 0.0001) (Fig. 2 ). There was significant association between social isolation and the risk of developing IBS among individuals without loneliness (HR 1.13, 95% CI 1.05–1.22), but not among individuals with loneliness (HR 1.02, 95% CI 0.85–1.23), when stratified by loneliness status (Table S4). However, the association between loneliness and incident IBS was significant regardless of social isolation level (HR 1.46, 95% CI 1.33–1.60 vs. HR 1.31, 95% CI 1.10–1.55) (Table S4). Subgroup and sensitivity analyses The separate and joint association between social isolation, loneliness, and incident IBS was robust in the subgroup analyses, stratified by age, sex, ethnicity, BMI, education, smoking status, alcohol intake, and TDI (Table S5-S7). No significant interaction was found between these covariates and social isolation or loneliness in the risk of developing IBS (all P interaction > 0.05). Several sensitivity analyses were performed to test the robustness. The separate and joint effects on the association between social isolation, loneliness, and incident IBS, and the interaction between social isolation and loneliness in the risk of IBS remained significant in the analysis performed by excluding participants who developed IBS in the first 3 years of follow-up (Table S8 and S9), the analysis performed by excluding participants with missing data on social isolation, loneliness, and covariates (Table S10 and S11), the analysis based on the multiple imputed datasets (Table S12 and S13), the analysis further adjusted for depressed mood, and long-term illness (Table S14 and S15), the analysis performed by excluding participants who died during the follow-up period (Table S16 and S17), and the analysis based on Fine-Gray sub-distribution hazard model to account for the potential impact of mortality as a competing event (Table S18). Discussion In this large-scale prospective cohort study of more than 400000 participants in the UKB, we discovered that social isolation and loneliness were separately and jointly associated with a higher risk of developing IBS. The increased risk was not explained by the differences in age, sex, socioeconomic background, and lifestyle risk factors. And there was no interaction between social isolation and loneliness with respect to the risk of IBS. This study, to the best of our knowledge, is the first large-scale cohort study to confirm the relationship between social isolation, loneliness, and the incident IBS. Several prospective cohort studies indicated that the gut-brain axis is bidirectional, through which the development of IBS could contribute to mental illness and vice versa [ 22 – 24 ]. Recently, Anna et al. conducted a cohort study including 798 participants and reported that anxiety and resilience were associated with IBS [ 25 ]. Jasmine et al. performed a meta-analysis and indicated that stress and psychological disorders were associated with abdominal pain-related disorders of gut-brain interaction [ 26 ]. However, to our knowledge, no study to date has examined the association of social isolation and loneliness with IBS. In this study, we discovered that social isolation and loneliness were separately and jointly associated with a higher risk of developing IBS, which underscore the valuable role of social interaction in the primary prevention of IBS and fostering social connection could effectively alleviate the risk of developing IBS. Systematic and effective strategies across individuals and society should be implemented to relieve the burden of social isolation and loneliness. For example, psychological therapy, social-skill training, and communication technology promotion are essential for individuals to enhance social connection [ 27 ], meanwhile, organizing community activities and establishing clubs are effective choices across society level [ 28 ]. In this cohort, we did not find the significant interaction of social isolation, loneliness, and IBS risk. Nevertheless, we discovered that the association between loneliness and the incident IBS remained significant regardless the level of social isolation, while the relationship of social isolation and IBS risk was only confirmed significant across no-loneliness individuals. Similar conclusion was also drawn on the relationship between social isolation, loneliness and the risk of heart failure and type 2 diabetes mellitus [ 28 , 29 ], which indicated that subjective feeling of loneliness played a more important role than objective level of social connection. Loneliness is a subjective feeling mostly derived from social isolation, and could potentially contribute to stress and depression, which directly cause healthy burdens [ 30 – 32 ]. Therefore, in addition to merely enhance social connection, psychological therapy is also indispensable for individuals with negative emotions. Several potential mechanisms have been proposed to explain the association between social isolation, loneliness, and incident IBS. First, social isolation and loneliness activate hypothalamic-pituitary-adrenocortical axis and sympathetic nervous system, which triggers gut dysbiosis and further increase the risk of developing IBS [ 33 , 34 ]. Second, social isolated and lonely individuals show higher expression of genes related to proinflammatory cytokine signaling and prostaglandin synthesis, as well as a higher C-reactive protein and lipid levels [ 35 – 37 ]. Pro-inflammatory immune response is critical to the risk of developing IBS. Third, social isolated or lonely individuals are more prompt to have negative emotions such as stress, anger, anxiety, and depression [ 38 , 39 ], and unhealthy lifestyles like alcohol abuse, physical inactivity, and smoking [ 40 – 42 ], thus leading to increased risk of IBS. Our results showed the association between social isolation, loneliness and incident IBS through a population-based cohort study from the UKB, which allowed for real world impact demonstration. Furthermore, this study explored the separate and joint effects of social isolation and loneliness, and the interaction between social isolation and loneliness in the risk of IBS, accounting for more convincing conclusions. In addition, the large sample size and long follow-up duration supplied strong statistical power to determine the association between social isolation, loneliness, and incident IBS. Admittedly, this study also has some limitations. First, it is noteworthy that some subclinical symptoms of undiagnosed IBS could contribute to changes in life styles like diet, alcohol abuse, sleep habits, and smoking, which biased the relationship between social isolation, loneliness, and incident IBS by reverse causality. However, we performed some sensitivity analyses such as excluding individuals diagnosed with IBS within 3 years, and draw the consistent conclusion, which indicated that this association was hardly caused by reverse causation. Second, lacking consideration for changes in social isolation and loneliness during the follow-up period means that there was no data for the duration and stability of social isolation and loneliness. Future cohort study with repeated measurements of social isolation and loneliness is necessary to test the cumulative risk of developing IBS among social isolated and lonely individuals. Third, the predominantly White ethnicity in the UKB cohort makes it hard to generalize the association to a broader population. Future study focus on other ethics is needed. Forth, since the non-randomized observational data was used, it was hard to exclude residual confounding, even though we have tried our best to adjust for various potential confounders. Fifth, the total response rate of the UKB was only 5.5%, therefore, selection bias should not be ignored [ 43 ], although previous study has confirmed the consistent results between from the UKB and the representative UK samples [ 44 ]. Conclusion This study demonstrates a significant association between social isolation, loneliness, and the risk of developing IBS. These findings suggested that interventions to enhance objective and subjective social connection should be considered as important prevention strategies for IBS management. Abbreviations AIC, Akaike information criterion; BMI, Body mass index; BIC, Bayesian information criterion; CI, confidence interval; HR, hazard ratio; IBS, irritable bowel syndrome; ICD, International classification of diseases; SD, standard deviation; TDI, Townsend deprivation index UKB, UK Biobank. Declarations Ethics approval and consent to participate The UKB study was approved by the UK North West Multi-Center Research Ethics Committee (11/NW/0382). All procedures performed in studies were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all participants through electronic signatures at baseline. Consent for publication Not applicable. Availability of data and materials Researchers can request the data we used from the UK Biobank (www.ukbiobank.ac.uk/). Competing interests The authors declare that they have no competing interests. Funding This work was supported by High-level Talents special support plan of Zhejiang Province (No. 2023R5239 to Zhe Shen). Author’s contributions TZ: data curation, formal analysis, writing - original draft. ZJ: investigation, visualization. KY: methodology, conceptualization. ZS: supervision, resources, funding acquisition, project administration. All authors read and approved the final manuscript. References Almario CV, Sharabi E, Chey WD, et al. Prevalence and Burden of Illness of Rome IV Irritable Bowel Syndrome in the United States: Results From a Nationwide Cross-Sectional Study. Gastroenterology. 2023;165(6):1475–87. Epub 2023/08/19. Sperber AD, Bangdiwala SI, Drossman DA, et al. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study. Gastroenterology. 2021;160(1):99–e1143. Epub 2020/04/16. Ford AC, Sperber AD, Corsetti M, et al. 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Association of healthy lifestyle behaviours with incident irritable bowel syndrome: a large population-based prospective cohort study. Gut. 2024. Epub 2024/02/21. Koloski NA, Jones M, Talley NJ. Evidence that independent gut-to-brain and brain-to-gut pathways operate in the irritable bowel syndrome and functional dyspepsia: a 1-year population-based prospective study. Aliment Pharmacol Ther. 2016;44(6):592–600. Epub 2016/07/23. Koloski NA, Jones M, Kalantar J, et al. The brain–gut pathway in functional gastrointestinal disorders is bidirectional: a 12-year prospective population-based study. Gut. 2012;61(9):1284–90. Epub 2012/01/12. Lee AH, Mahurkar-Joshi S, Naliboff B et al. Role of Sex, Anxiety, and Resilience in the Association between Adverse Childhood Experiences and Irritable Bowel Syndrome. Clin Gastroenterol hepatology: official Clin Pract J Am Gastroenterological Association. 2024. Epub 2024/06/16. Zia JK, Lenhart A, Yang PL, et al. Risk Factors for Abdominal Pain-Related Disorders of Gut-Brain Interaction in Adults and Children: A Systematic Review. Gastroenterology. 2022;163(4):995–e10233. Epub 2022/06/19. Holt-Lunstad J. Why Social Relationships Are Important for Physical Health: A Systems Approach to Understanding and Modifying Risk and Protection. Ann Rev Psychol. 2018;69:437–58. Epub 2017/10/17. Song Y, Zhu C, Shi B, et al. Social isolation, loneliness, and incident type 2 diabetes mellitus: results from two large prospective cohorts in Europe and East Asia and Mendelian randomization. EClinicalMedicine. 2023;64:102236. Epub 2023/09/28. Liang YY, Chen Y, Feng H, et al. Association of Social Isolation and Loneliness With Incident Heart Failure in a Population-Based Cohort Study. JACC Heart Fail. 2023;11(3):334–44. Epub 2023/02/04. Santini ZI, Jose PE, York Cornwell E, et al. Social disconnectedness, perceived isolation, and symptoms of depression and anxiety among older Americans (NSHAP): a longitudinal mediation analysis. Lancet Public health. 2020;5(1):e62–70. Epub 2020/01/09. Levine GN, Cohen BE, Commodore-Mensah Y, et al. Psychological Health, Well-Being, and the Mind-Heart-Body Connection: A Scientific Statement From the American Heart Association. Circulation. 2021;143(10):e763–83. Epub 2021/01/26. Hackett RA, Steptoe A. Type 2 diabetes mellitus and psychological stress - a modifiable risk factor. Nat reviews Endocrinol. 2017;13(9):547–60. Epub 2017/07/01. Xia N, Li H, Loneliness. Social Isolation, and Cardiovascular Health. Antioxid Redox Signal. 2018;28(9):837–51. Epub 2017/09/15. Matenchuk BA, Mandhane PJ, Kozyrskyj AL. Sleep, circadian rhythm, and gut microbiota. Sleep Med Rev. 2020;53:101340. Epub 2020/07/16. Cole SW, Hawkley LC, Arevalo JM, et al. Social regulation of gene expression in human leukocytes. Genome Biol. 2007;8(9):R189. Epub 2007/09/15. Hodgson S, Watts I, Fraser S, et al. Loneliness, social isolation, cardiovascular disease and mortality: a synthesis of the literature and conceptual framework. J R Soc Med. 2020;113(5):185–92. Epub 2020/05/15. Eisenberger NI, Taylor SE, Gable SL, et al. Neural pathways link social support to attenuated neuroendocrine stress responses. NeuroImage. 2007;35(4):1601–12. Epub 2007/03/31. Zhou J, Tang R, Wang X, et al. Improvement of Social Isolation and Loneliness and Excess Mortality Risk in People With Obesity. JAMA Netw open. 2024;7(1):e2352824. Epub 2024/01/22. Cacioppo JT, Hawkley LC, Ernst JM, et al. Loneliness within a nomological net: An evolutionary perspective. J Res Pers. 2006;40(6):1054–85. Akerlind I, Hörnquist JO. Loneliness and alcohol abuse: a review of evidences of an interplay. Social science & medicine (1982). 1992;34(4):405 – 14. Epub 1992/02/01. Hawkley LC, Thisted RA, Cacioppo JT. 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Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterials.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 22 May, 2025 Reviewers agreed at journal 20 May, 2025 Reviews received at journal 16 May, 2025 Reviewers agreed at journal 16 May, 2025 Reviewers invited by journal 15 May, 2025 Editor invited by journal 21 Apr, 2025 Editor assigned by journal 21 Apr, 2025 Submission checks completed at journal 21 Apr, 2025 First submitted to journal 16 Apr, 2025 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-6465123","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":457984193,"identity":"5e6f38d8-8fc7-473f-afd9-fa0231aa8fea","order_by":0,"name":"Tianyu Zhou","email":"","orcid":"","institution":"Zhejiang University School of Medicine First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tianyu","middleName":"","lastName":"Zhou","suffix":""},{"id":457984194,"identity":"b56cf69b-4ba2-464f-a59f-11344929c2f6","order_by":1,"name":"Zhenhe Jin","email":"","orcid":"","institution":"Zhejiang University School of Medicine First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhenhe","middleName":"","lastName":"Jin","suffix":""},{"id":457984195,"identity":"9f68a1cf-5fb1-4827-8afd-d6c29ac63d9a","order_by":2,"name":"Kexin Ye","email":"","orcid":"","institution":"Zhejiang University School of Medicine First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kexin","middleName":"","lastName":"Ye","suffix":""},{"id":457984196,"identity":"a0e62961-2993-4de1-b1ff-b88ac58a0db2","order_by":3,"name":"Zhe Shen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYDACCRDBxiDHwHAAzCBeizHpWhIbGBiI1CI/u/nYwx9l99LnN54xYPhQdpiBf3YDfi0Gd46lG0icK85tbDhjwDjj3GEGiTsHCGiRyDGTMGxLyG1mOGPAzNt2GCiSQMBhM/K/SSS2JaSzgbT8JUYLw40cNomDbQkJPCAtjMRoMbiRZibZcC7BcAbDsYKDPefSeSRuEHRY8jPJH2UJ8vIzDm988KPMWo5/BiGHwYHEAXBk8hCrHgj4G0hQPApGwSgYBSMKAACJCEHK9H/8tAAAAABJRU5ErkJggg==","orcid":"","institution":"Zhejiang University School of Medicine First Affiliated Hospital","correspondingAuthor":true,"prefix":"","firstName":"Zhe","middleName":"","lastName":"Shen","suffix":""}],"badges":[],"createdAt":"2025-04-16 15:53:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6465123/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6465123/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83291114,"identity":"e4e612dc-603f-4698-a424-bc3a78134399","added_by":"auto","created_at":"2025-05-22 13:07:31","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":64270,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the study population. UKB, UK Biobank; IBS, irritable bowel syndrome.\u003c/p\u003e","description":"","filename":"Figure1flowchart.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6465123/v1/8d92b02c3b3076f5f84c4050.jpg"},{"id":83291115,"identity":"7899d66e-c602-4f88-95a8-cab2411c36dd","added_by":"auto","created_at":"2025-05-22 13:07:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":340872,"visible":true,"origin":"","legend":"\u003cp\u003eSeparate and joint association of social isolation and loneliness with the risk of IBS. Model 1: adjusted for age and sex. Model 2: adjusted for age, sex, ethnicity, BMI, education level, and TDI. Model 3: adjusted for age, sex, ethnicity, BMI, education level, TDI, currently smoking, alcohol drinking, physical activity, and healthy diet. IBS, irritable bowel syndrome; HR, hazard ratio; CI, confidence interval; TDI, Townsend index tertile; BMI, body mass index.\u003c/p\u003e","description":"","filename":"Figure2multivariable.png","url":"https://assets-eu.researchsquare.com/files/rs-6465123/v1/b6654924f07dae485eb69dfc.png"},{"id":83294288,"identity":"8b2ee4f1-3473-4caf-96cd-a73ba43c81fe","added_by":"auto","created_at":"2025-05-22 13:31:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1238365,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6465123/v1/54eebbe5-9a5f-4ed4-9ae5-95eac73d5c38.pdf"},{"id":83292092,"identity":"063d83de-8c83-4050-a4ab-4afc693384cb","added_by":"auto","created_at":"2025-05-22 13:15:31","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":148233,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-6465123/v1/78d1ea6ca536947d90e6bc4c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Social isolation, loneliness, and incident irritable bowel syndrome: a prospective cohort study","fulltext":[{"header":"Background","content":"\u003cp\u003eIrritable bowel syndrome (IBS) is a functional gastrointestinal disease characterized by recurrent abdominal pain and abnormal bowel habits. Based on clinical manifestation, IBS is further subdivided into constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), mixed stool pattern (IBS-M), and un-subtyped (IBS-U) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Approximately 10.1% and 4.1% of the global population are estimated suffering from IBS according to Rome III and IV criteria, respectively [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. As is widely recognized, the dysfunction of gut-brain axis contributes to intestinal motility disturbances, visceral hypersensitivity, and altered processing within the central nervous system, which directly cause IBS [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Meanwhile, from a biopsychosocial modal, neurophysiology and psychological traits influence the symptoms of IBS in a complex manner [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSocial isolation is characterized as an objective shortage of social connections and a diminished social network size, whereas loneliness is defined as a subjective feeling of being alone or lacking companionship [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Approximately 2.4 to 24.2% of European adults claim suffering from loneliness or social isolation, which has dramatically increased since the onset of the coronavirus disease 2019 pandemic [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Adequate social connection is necessary for maintaining both mental and physical health [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Social isolation and loneliness are associated with a wide range of adverse health consequences, such as increasing mortality [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], dementia [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], coronary heart disease [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], stroke [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and sleep disturbances [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. From theoretical models, social isolation and loneliness may initiate a lot of biological and behavioral mechanisms, including excessive stress response, higher inflammation status, and inhibited reward or motivation, which are potential risk factors for triggering the onset of IBS [\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSince population-based evidence on the association between social isolation, loneliness, and incident IBS is scarce and a clear appraisal of the association not only deepens the understanding of the IBS etiology, but also provides clues for IBS prevention. Therefore, to ascertain the association between social isolation, loneliness, and the risk of incident IBS, we conducted a prospective cohort study with a lone-term follow-up based on the UK Biobank (UKB).\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eThe UKB study is a large-scale prospective cohort study that recruited more than 500000 participants aged 37\u0026ndash;73 years from 22 assessment centers across England, Wales, and Scotland between 2006 and 2010 [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Participants completed touchscreen questionnaires and physical measurements, and provided biological samples at recruitment [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The study was approved by the North West Multicenter Research Ethics Committee (REC reference for UK Biobank 11/NW/0382), and all participants provided written informed consent [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the current study, 502174 participants were initially screened. We excluded those with missing data on social isolation or loneliness (n\u0026thinsp;=\u0026thinsp;33949), a prior diagnosis of IBS at recruitment (n\u0026thinsp;=\u0026thinsp;25814), and lost to follow-up (n\u0026thinsp;=\u0026thinsp;1297), resulting in 441114 participants in the analyses (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAscertainment of exposure\u003c/h3\u003e\n\u003cp\u003eThe exposure of interest were social isolation and loneliness, which were collected at baseline. Social isolation was assessed by asking three questions: (1) \u0026ldquo;Including yourself, how many people are living together in your household? (include those who usually live in the house such as students living away from home during term, partners in the armed forces or professions such as pilots)\u0026rdquo; (1 point for living alone); (2) \u0026ldquo;How often do you visit friends or family or have them visit you?\u0026rdquo; (1 point for less than one friend or family visit per month); (3) \u0026ldquo;Which of the following do you attend once a week or more often? (you can select more than one)\u0026rdquo; (1 point for not participating in any social activities at least weekly). The social isolation score was calculated by summing up the points of these three questions (ranging from 0 to 3). Participants with 2 or 3 points were defined as socially isolated. Loneliness was assessed by two questions: (1) \u0026ldquo;Do you often feel lonely?\u0026rdquo; (0 point for the response of \u0026ldquo;no\u0026rdquo;, 1 point for the response of \u0026ldquo;yes\u0026rdquo;); (2) \u0026ldquo;How often are you able to confide in someone close to you?\u0026rdquo; (0 point for almost daily-once every few months, 1 point for never or almost never). Participants who responded positively to both questions were defined as lonely.\u003c/p\u003e\n\u003ch3\u003eAscertainment of outcome\u003c/h3\u003e\n\u003cp\u003eIncident IBS was the primary outcome of this cohort, which was defined via the International Classification of Diseases 10th Revision (ICD-10) code: K58. The data of first occurrence were yielded from data-fields \u0026ldquo;First occurrences\u0026rdquo; (Field ID: 131638, 131639), which were generated by mapping primary care data, hospital inpatient data, death register records, and self-reported medical conditions.\u003c/p\u003e\n\u003ch3\u003eAscertainment of covariates\u003c/h3\u003e\n\u003cp\u003eCovariates for this study were collected at baseline, including age (continuous), sex (male or female), body mass index (BMI, continuous), Townsend deprivation index (TDI, continuous), education (college or non-college), current smoker (yes or no). Ethnicity was categorized into \u0026ldquo;White\u0026rdquo; (White, British, Irish, or any other White background) and \u0026ldquo;others\u0026rdquo;. Alcohol intake was categorized into \u0026ldquo;low\u0026rdquo; (once or twice a week, one to three times a month, special occasions only, never) and \u0026ldquo;high\u0026rdquo; (daily or almost daily, three or four times a week). The diet score was constructed by the previous study [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Shortly, we calculated the diet score according to the frequency of seven food groups (fruits, vegetables, fish, processed meats, unprocessed red meats, whole grains, and refined grains) and we defined a healthy diet when a diet score\u0026thinsp;\u0026ge;\u0026thinsp;4 (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Physical activity was categorized into \u0026ldquo;adequate\u0026rdquo; (at or above moderate/vigorous/walking recommendation [150 minutes of walking or moderate activity per week or 75 minutes of vigorous activity]) and \u0026ldquo;inadequate\u0026rdquo; (below recommendation). Depressed mood was categorized into \u0026ldquo;low\u0026rdquo; (not at all, several days) and \u0026ldquo;high\u0026rdquo; (more than half of my days, nearly every day). Long-term illness, which was defined as self-reported long-standing illness without any specific diagnosis, was categorized into \u0026ldquo;yes\u0026rdquo; and \u0026ldquo;no\u0026rdquo; (Table S2).\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eVariates were presented as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) for continuous variables and frequency (percentages) for categorical variables. For missing data with a missing rate\u0026thinsp;\u0026lt;\u0026thinsp;5%, we imputed the median for continuous variables and the value of the largest group for categorical variables. And we treated missing data as a separate category for variables with a missing rate\u0026thinsp;\u0026ge;\u0026thinsp;5%. The missing rates of all the variates are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the participants from the UK Biobank study.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOverall (n\u0026thinsp;=\u0026thinsp;441114)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eSocial isolation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eLoneliness\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-isolated\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;401116)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIsolated\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;39998)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo loneliness\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;420249)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLoneliness\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;20865)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e236195 (53.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e215902 (53.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20293 (50.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e226249 (53.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9946 (47.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e204919 (46.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e185214 (46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19705 (49.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e194000 (46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10919 (52.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, years\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56.5 (8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56.5 (8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56.7 (7.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e56.6 (8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e56.0 (7.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge groups, years\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e103212 (23.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94668 (23.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8544 (21.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e98038 (23.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5174 (24.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50\u0026ndash;59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e146711 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e132190 (33.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14521 (36.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e139234 (33.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7477 (35.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e60 and older\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e191191 (43.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e174258 (43.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16933 (42.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e182977 (43.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8214 (39.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEthnicity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e419245/439881 (95.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e382017/400067 (95.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37228/39814 (93.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e399747/419110 (95.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e19498/20771 (93.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20636/439881 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18050/400067 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2586/39814 (6.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19363/419110 (4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1273/20771 (6.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1233 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1049 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e184 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1139 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e94 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEducation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCollege\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e145670/437768 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e133728/398181 (33.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11942/39587 (30.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e140741/417142 (33.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4929/20626 (23.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-college\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e292098/437768 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e264453/398181 (66.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27645/39587 (69.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e276401/417142 (66.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15697/20626 (76.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3346 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2935 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e411 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3107 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e239 (1.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAlcohol intake\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e245387/440885 (55.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e218463/400934 (54.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26924/39951 (67.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e231970/420047 (55.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13417/20838 (64.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e195498/440885 (44.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e182471/400934 (45.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13027/39951 (32.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e188077/420047 (44.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7421/20838 (35.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e229 (0.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e182 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47 (0.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e202 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27 (0.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCurrent smoker\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e393796/439747 (89.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e361485/399932 (90.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32311/39815 (81.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e376771/418976 (89.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17025/20771 (82.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45951/439747 (10.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38447/399932 (9.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7504/39815 (18.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e42205/418976 (10.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3746/20771 (18.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1367 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1184 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e183 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1273 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e94 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDietary habit\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePoor diet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95898/340294 (28.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87168/312644 (27.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8730/27650 (31.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90503/325863 (27.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5395/14431 (37.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHealthy diet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e244396/340294 (71.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e225476/312644 (72.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18920/27650 (68.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e235360/325863 (72.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9036/14431 (62.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100820 (22.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88472 (22.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12348 (30.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e94386 (22.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6434 (30.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBody mass index, kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2157/439005 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1800/399316 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e357/39689 (0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2017/418293 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e140/20712 (0.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18.5\u0026ndash;24.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e142716/439005 (32.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e130246/399316 (32.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12470/39689 (31.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e137150/418293 (32.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5566/20712 (26.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25-29.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e187359/439005 (42.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e172022/399316 (43.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15337/39689 (38.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e179125/418293 (42.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8234/20712 (39.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;29.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e106773/439005 (24.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95248/399316 (23.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11525/39689 (29.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e100001/418293 (23.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6772/20712 (32.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2109 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1800 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e309 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1956 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e153 (0.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBody mass index, kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.4 (4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.4 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.9 (5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27.4 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28.5 (5.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2109 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1800 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e309 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1956 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e153 (0.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePhysical activity\u003c/b\u003e\u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdequate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e286244/349458 (81.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e263550/319268 (82.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22694/30190 (75.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e274378/333831 (82.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11866/15627 (75.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInadequate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63214/349458 (18.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55718/319268 (17.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7496/30190 (24.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e59453/333831 (17.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3761/15627 (24.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91656 (20.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81848 (20.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9808 (24.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e86418 (20.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5238 (25.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDepressed mood\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e404434/424419 (95.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e370148/386319 (95.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34286/38100 (90.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e389175/404926 (96.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15259/19493 (78.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19985/424419 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16171/386319 (4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3814/38100 (10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15751/404926 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4234/19493 (21.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16695 (3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14797 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1898 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15323 (3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1372 (6.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLong-term illness\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e295328/431973 (68.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e272573/393101 (69.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22755/38872 (58.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e284390/411843 (69.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10938/20130 (54.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e136645/431973 (31.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e120528/393101 (30.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16117/38872 (41.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e127453/411843 (31.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9192/20130 (45.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9141 (2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8015 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1126 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8406 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e735 (3.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTownsend index tertile\u003c/b\u003e\u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBottom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e147783 (33.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e139373 (34.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8410 (21.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e142542 (33.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5241 (25.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntermediate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e146570 (33.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e135535 (33.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11035 (27.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e140470 (33.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6100 (29.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTop\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e146761 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e126208 (31.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20553 (51.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e137237 (32.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9524 (45.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTownsend index tertile\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-1.4 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.5 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0 (3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-1.4 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.4 (3.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eData are n (%), unless otherwise specified. SD, standard deviation.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003eAlcohol intake was defined as low (once or twice a week, one to three times a month, special occasions only, never) and high (daily or almost daily, three or four times a week).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003ePhysical activity was categorized as at or above 150 minutes of walking or moderate activity per week or 75 minutes of vigorous activity or not.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sup\u003eTownsend index tertile was dichotomized as bottom (\u0026le; -3.18), intermediate (-3.18 ~ -0.7), and top (\u0026gt; -0.7).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe separate and joint effects of social isolation and loneliness on incident IBS, and the interaction between social isolation and loneliness in the risk of IBS were assessed in a multivariable Cox proportional hazard regression model and presented as hazard ratios (HR) with 95% confidence intervals (CI). Three models were generated: Model 1 adjusted for age (continuous) and sex. Model 2 further adjusted for ethnicity, BMI (continuous), education level, and TDI (continuous). Model 3 further adjusted for currently smoking, alcohol drinking, physical activity, and healthy diet. Among the three models, model 3 was considered as the best fit model for the lowest score of the Akaike information criterion (AIC) and Bayesian information criterion (BIC) and was thus chosen for subsequent analyses (Table S3).\u003c/p\u003e \u003cp\u003eWe further performed some subgroup analyses stratified by age (\u0026lt;\u0026thinsp;50, 50\u0026ndash;59, or 60 and older), sex (male or female), ethnicity (White or non-White), BMI (\u0026lt;\u0026thinsp;18.5, 18.5\u0026ndash;24.9, 25-29.9, or \u0026gt;\u0026thinsp;29.9), education level (college or non-college), current smoker (yes or no), alcohol intake (low or high), and TDI (bottom, intermediate, or top). Using likelihood ratio tests, we compared Cox models with and without an interaction term of strata factor and exposure to determine the interaction effects.\u003c/p\u003e \u003cp\u003eWe also performed several sensitivity analyses to validate the separate and joint effects of social isolation and loneliness on incident IBS, and the interaction between social isolation and loneliness in the risk of IBS: (1) the analysis excluding participants who developed IBS in the first three years; (2) the analysis excluded participants who missing any data on covariates; (3) the analysis after multiple imputations by chained equations of missing values (see in Supplementary Materials); (4) the analysis additionally adjusted for depressed mood and long-term illness; (5) the analysis excluding those died during the follow-up period; (6) the analyses based on Fine-Gray sub-distribution hazard model to account for the potential impact of mortality as a competing event.\u003c/p\u003e \u003cp\u003eAll analyses were conducted using SAS version 9.4. The \u003cem\u003eP\u003c/em\u003e values for all the statistical analyses were two-sided, with a significance level of 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characteristics\u003c/h2\u003e \u003cp\u003eThe cohort included a total of 441114 participants, and among these, 236195 were females and 204919 were males, with a mean age of 56.5 years. In this study, 39998 (9.1%) participants were socially isolated, and 20865 (4.7%) had feelings of loneliness. Baseline characteristics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Participants with a higher level of social isolation or loneliness were more likely to be male, more deprived, lower education level, lower alcohol intake, current smoker, a higher percentage of obesity, have a poor diet, have lower physical activity, have a depressed mood, and be lone-term illness.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSocial isolation, loneliness, and incident IBS\u003c/h3\u003e\n\u003cp\u003eThe incidence pattern of IBS for social isolation and loneliness is presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. During a mean follow-up of 14.6 years (standard deviation: 2.7), 9593 participants were diagnosed with IBS. Incident cases among the non-isolated and isolated, and no loneliness and loneliness participants were 8582, 1011, 8943, and 650, respectively, and the corresponding incident cases per 100000 persons-years were 143.9, 175.5, 143.4, and 214.3, respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIBS incidence during the follow-up.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eSocial isolation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eLoneliness\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-isolated\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIsolated\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo loneliness\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLoneliness\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerson-years at risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6539801\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5963740\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e576062\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6236430\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e303371\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncident cases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9593\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8582\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8943\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e650\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncident cases per 100000 person-years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e146.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e143.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e175.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e143.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e214.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eIBS, irritable bowel syndrome.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCompared to non-socially isolated participants, socially isolated participants had a significantly higher risk of IBS (HR 1.15, 95% CI 1.08\u0026ndash;1.23), after adjusting for age, sex, ethnicity, BMI, education level, TDI, currently smoking, alcohol drinking, physical activity, and healthy diet (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Similarly, individuals in the loneliness group were more susceptible to IBS than individuals in the no-loneliness group (HR 1.45, 95% CI 1.33\u0026ndash;1.57) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Meanwhile, with the accelerating levels of social isolation and loneliness, participants showed a progressively higher tendency to develop IBS (\u003cem\u003eP\u003c/em\u003e \u003csub\u003etrend\u003c/sub\u003e \u0026lt; 0.0001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThere was significant association between social isolation and the risk of developing IBS among individuals without loneliness (HR 1.13, 95% CI 1.05\u0026ndash;1.22), but not among individuals with loneliness (HR 1.02, 95% CI 0.85\u0026ndash;1.23), when stratified by loneliness status (Table S4). However, the association between loneliness and incident IBS was significant regardless of social isolation level (HR 1.46, 95% CI 1.33\u0026ndash;1.60 vs. HR 1.31, 95% CI 1.10\u0026ndash;1.55) (Table S4).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup and sensitivity analyses\u003c/h2\u003e \u003cp\u003eThe separate and joint association between social isolation, loneliness, and incident IBS was robust in the subgroup analyses, stratified by age, sex, ethnicity, BMI, education, smoking status, alcohol intake, and TDI (Table S5-S7). No significant interaction was found between these covariates and social isolation or loneliness in the risk of developing IBS (all \u003cem\u003eP\u003c/em\u003e \u003csub\u003einteraction\u003c/sub\u003e \u0026gt; 0.05).\u003c/p\u003e \u003cp\u003eSeveral sensitivity analyses were performed to test the robustness. The separate and joint effects on the association between social isolation, loneliness, and incident IBS, and the interaction between social isolation and loneliness in the risk of IBS remained significant in the analysis performed by excluding participants who developed IBS in the first 3 years of follow-up (Table S8 and S9), the analysis performed by excluding participants with missing data on social isolation, loneliness, and covariates (Table S10 and S11), the analysis based on the multiple imputed datasets (Table S12 and S13), the analysis further adjusted for depressed mood, and long-term illness (Table S14 and S15), the analysis performed by excluding participants who died during the follow-up period (Table S16 and S17), and the analysis based on Fine-Gray sub-distribution hazard model to account for the potential impact of mortality as a competing event (Table S18).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this large-scale prospective cohort study of more than 400000 participants in the UKB, we discovered that social isolation and loneliness were separately and jointly associated with a higher risk of developing IBS. The increased risk was not explained by the differences in age, sex, socioeconomic background, and lifestyle risk factors. And there was no interaction between social isolation and loneliness with respect to the risk of IBS. This study, to the best of our knowledge, is the first large-scale cohort study to confirm the relationship between social isolation, loneliness, and the incident IBS.\u003c/p\u003e \u003cp\u003eSeveral prospective cohort studies indicated that the gut-brain axis is bidirectional, through which the development of IBS could contribute to mental illness and vice versa [\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Recently, Anna et al. conducted a cohort study including 798 participants and reported that anxiety and resilience were associated with IBS [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Jasmine et al. performed a meta-analysis and indicated that stress and psychological disorders were associated with abdominal pain-related disorders of gut-brain interaction [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. However, to our knowledge, no study to date has examined the association of social isolation and loneliness with IBS. In this study, we discovered that social isolation and loneliness were separately and jointly associated with a higher risk of developing IBS, which underscore the valuable role of social interaction in the primary prevention of IBS and fostering social connection could effectively alleviate the risk of developing IBS. Systematic and effective strategies across individuals and society should be implemented to relieve the burden of social isolation and loneliness. For example, psychological therapy, social-skill training, and communication technology promotion are essential for individuals to enhance social connection [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], meanwhile, organizing community activities and establishing clubs are effective choices across society level [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this cohort, we did not find the significant interaction of social isolation, loneliness, and IBS risk. Nevertheless, we discovered that the association between loneliness and the incident IBS remained significant regardless the level of social isolation, while the relationship of social isolation and IBS risk was only confirmed significant across no-loneliness individuals. Similar conclusion was also drawn on the relationship between social isolation, loneliness and the risk of heart failure and type 2 diabetes mellitus [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], which indicated that subjective feeling of loneliness played a more important role than objective level of social connection. Loneliness is a subjective feeling mostly derived from social isolation, and could potentially contribute to stress and depression, which directly cause healthy burdens [\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Therefore, in addition to merely enhance social connection, psychological therapy is also indispensable for individuals with negative emotions.\u003c/p\u003e \u003cp\u003eSeveral potential mechanisms have been proposed to explain the association between social isolation, loneliness, and incident IBS. First, social isolation and loneliness activate hypothalamic-pituitary-adrenocortical axis and sympathetic nervous system, which triggers gut dysbiosis and further increase the risk of developing IBS [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Second, social isolated and lonely individuals show higher expression of genes related to proinflammatory cytokine signaling and prostaglandin synthesis, as well as a higher C-reactive protein and lipid levels [\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Pro-inflammatory immune response is critical to the risk of developing IBS. Third, social isolated or lonely individuals are more prompt to have negative emotions such as stress, anger, anxiety, and depression [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], and unhealthy lifestyles like alcohol abuse, physical inactivity, and smoking [\u003cspan additionalcitationids=\"CR41\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e], thus leading to increased risk of IBS.\u003c/p\u003e \u003cp\u003eOur results showed the association between social isolation, loneliness and incident IBS through a population-based cohort study from the UKB, which allowed for real world impact demonstration. Furthermore, this study explored the separate and joint effects of social isolation and loneliness, and the interaction between social isolation and loneliness in the risk of IBS, accounting for more convincing conclusions. In addition, the large sample size and long follow-up duration supplied strong statistical power to determine the association between social isolation, loneliness, and incident IBS.\u003c/p\u003e \u003cp\u003eAdmittedly, this study also has some limitations. First, it is noteworthy that some subclinical symptoms of undiagnosed IBS could contribute to changes in life styles like diet, alcohol abuse, sleep habits, and smoking, which biased the relationship between social isolation, loneliness, and incident IBS by reverse causality. However, we performed some sensitivity analyses such as excluding individuals diagnosed with IBS within 3 years, and draw the consistent conclusion, which indicated that this association was hardly caused by reverse causation. Second, lacking consideration for changes in social isolation and loneliness during the follow-up period means that there was no data for the duration and stability of social isolation and loneliness. Future cohort study with repeated measurements of social isolation and loneliness is necessary to test the cumulative risk of developing IBS among social isolated and lonely individuals. Third, the predominantly White ethnicity in the UKB cohort makes it hard to generalize the association to a broader population. Future study focus on other ethics is needed. Forth, since the non-randomized observational data was used, it was hard to exclude residual confounding, even though we have tried our best to adjust for various potential confounders. Fifth, the total response rate of the UKB was only 5.5%, therefore, selection bias should not be ignored [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e], although previous study has confirmed the consistent results between from the UKB and the representative UK samples [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study demonstrates a significant association between social isolation, loneliness, and the risk of developing IBS. These findings suggested that interventions to enhance objective and subjective social connection should be considered as important prevention strategies for IBS management.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAIC, Akaike information criterion; BMI, Body mass index; BIC, Bayesian information criterion; CI, confidence interval; HR, hazard ratio; IBS, irritable bowel syndrome; ICD, International classification of diseases; SD, standard deviation; TDI, Townsend deprivation index UKB, UK Biobank.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe UKB study was approved by the UK North West Multi-Center Research Ethics Committee (11/NW/0382). All procedures performed in studies were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all participants through electronic signatures at baseline.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearchers can request the data we used from the UK Biobank (www.ukbiobank.ac.uk/).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by High-level Talents special support plan of Zhejiang Province (No. 2023R5239 to Zhe Shen).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTZ: data curation, formal analysis, writing - original draft. ZJ: investigation, visualization. KY: methodology, conceptualization. ZS: supervision, resources, funding acquisition, project administration. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAlmario CV, Sharabi E, Chey WD, et al. Prevalence and Burden of Illness of Rome IV Irritable Bowel Syndrome in the United States: Results From a Nationwide Cross-Sectional Study. Gastroenterology. 2023;165(6):1475\u0026ndash;87. Epub 2023/08/19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSperber AD, Bangdiwala SI, Drossman DA, et al. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study. Gastroenterology. 2021;160(1):99\u0026ndash;e1143. Epub 2020/04/16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFord AC, Sperber AD, Corsetti M, et al. Irritable bowel syndrome. 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Comparison of risk factor associations in UK Biobank against representative, general population based studies with conventional response rates: prospective cohort study and individual participant meta-analysis. BMJ (Clinical Res ed). 2020;368:m131. Epub 2020/02/14.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-public-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pubh","sideBox":"Learn more about [BMC Public Health](http://bmcpublichealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pubh/default.aspx","title":"BMC Public Health","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Social isolation, Loneliness, Irritable bowel syndrome","lastPublishedDoi":"10.21203/rs.3.rs-6465123/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6465123/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe disease burden of irritable bowel syndrome (IBS) is well recognized as the dysfunction of gut-brain axis. We aimed to investigate the association between social isolation, loneliness, and the risk of developing IBS.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA total of 441114 participants not diagnosed with IBS at baseline enrolled in the UK Biobank from 2006 to 2010 were included in this cohort study. The exposures of interest were social isolation and loneliness. The primary endpoint was incident IBS. Cox proportional hazard regression models were used to calculate the hazard ratios (HR) and 95% confidence intervals (CI) of the separate and joint effects of social isolation and loneliness on incident IBS.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThis study documented 9593 IBS cases during a mean follow-up of 14.6 years. Social isolation (HR 1.15, 95% CI 1.08\u0026ndash;1.23) and loneliness (HR 1.45, 95% CI 1.33\u0026ndash;1.57) were significantly associated with an increased risk of developing IBS. With the accelerating levels of social isolation and loneliness, participants showed a progressively higher tendency to develop IBS (\u003cem\u003eP\u003c/em\u003e \u003csub\u003etrend\u003c/sub\u003e \u0026lt; 0.0001). No substantial changes were found in the further subgroup and sensitivity analyses.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eSocial isolation and loneliness were associated with an increased risk of developing IBS. These findings suggested that interventions to enhance objective and subjective social connection should be considered as important prevention strategies for IBS management.\u003c/p\u003e","manuscriptTitle":"Social isolation, loneliness, and incident irritable bowel syndrome: a prospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-22 13:07:26","doi":"10.21203/rs.3.rs-6465123/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-05-22T07:59:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"311279165804091103929961736059675142041","date":"2025-05-20T10:44:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-16T21:07:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"47740063646150343867065320081571096721","date":"2025-05-16T20:35:31+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-15T11:18:37+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-04-21T12:19:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-21T07:35:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-21T07:33:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Public Health","date":"2025-04-16T15:49:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-public-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pubh","sideBox":"Learn more about [BMC Public Health](http://bmcpublichealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pubh/default.aspx","title":"BMC Public Health","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d7208948-5cff-438b-bbfe-c8da0ede0a80","owner":[],"postedDate":"May 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-05-22T13:07:26+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-22 13:07:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6465123","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6465123","identity":"rs-6465123","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}