Lonely minds, inflamed guts: metabolic and circulating protein pathways linking social isolation and loneliness to inflammatory bowel disease

Abstract Mounting evidence suggests that psychosocial stressors, such as social isolation and loneliness, contribute to gastrointestinal disorders by disrupting gut-brain interactions. We aim to investigate the associations of social isolation, loneliness, and their related alterations in metabolism and circulating proteins with the risk of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD). 275,157 adults from the UK Biobank were analyzed, including metabolomic data from 68,362 participants and proteomic profiling from 29,339 participants. The exposures included social isolation, loneliness, and their related metabolites and circulating proteins, with incident IBD as the outcome. Cox regression and two-sample Mendelian randomization (TSMR) analysis were utilized to examine the associations. Over a mean follow-up of 13.49 years, this cohort study identified 1565 incident IBD cases, comprising 1063 UC cases and 492 CD cases. Social isolation and loneliness showed significant associations with an elevated risk of IBD (social isolation: hazard ratio [HR] most isolated : 1.31, 95%CI: 1.01-1.70; loneliness: 1.29, 95%CI: 1.04-1.60). Social isolation and loneliness jointly increased the risk of IBD by 85%, with an HR of 1.85 (95% CI: 1.02-3.36). TSMR analyses further indicated that more sports or gym activity reduced IBD and CD risk, more religious activity lowered UC risk, while fewer leisure/social activities increased UC risk. For the metabolomic analysis, eight and five metabolites were identified to be associated with social isolation and loneliness, respectively. Additionally, 22 circulating proteins consistently associated with both loneliness and social isolation were identified, predominantly enriched in cytokine-related pathways. The derived protein scores were positively associated with an increased risk of IBD. This study demonstrates social isolation and loneliness significantly raise IBD risk, with related metabolite and circulating proteins shedding light on underlying biological mechanisms.