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T-cells specifically bind antigens to induce adaptive immune responses using highly specific molecular recognition, and a diverse T-cell repertoire with expansion of antigen-specific clones can indicate robust immune responses after infection or vaccination. For patients with inflammatory bowel disease (IBD), a spectrum of chronic intestinal inflammatory diseases usually requiring immunomodulatory treatment, the T-cell response has not been well characterized. Understanding the patient factors that result in strong vaccination responses is critical to guiding vaccination schedules and identifying mechanisms of T-cell responses in IBD and other immune-mediated conditions. Here we used T-cell receptor sequencing to show that T-cell responses in an IBD cohort were influenced by demographic and immune factors, relative to a control cohort of health care workers (HCWs). Subjects were sampled at the time of SARS-CoV-2 vaccination, and longitudinally afterwards; TCR Vβ gene repertoires were sequenced and analyzed for COVID-19-specific clones. We observed significant differences in the overall strength of the T-cell response by age and vaccine type. We further stratified the T-cell response into Class-I- and Class-II-specific responses, showing that Ad26.COV2.S vector vaccine induced Class-I-biased T-cell responses, whereas mRNA vaccine types led to different responses, with mRNA-1273 vaccine inducing a more Class-I-deficient T-cell response compared to BNT162b2. Finally, we showed that these T-cell patterns were consistent with antibody levels from the same patients. Our results account for the surprising success of vaccination in nominally immuno-compromised IBD patients, while suggesting that a subset of IBD patients prone to deficiencies in T-cell response may warrant enhanced booster protocols.

ObjectiveIBD is characterised by dysbiosis, but it remains unclear to what extent dysbiosis develops in unaffected at-risk individuals. To address this, we investigated age-related patterns of faecal and serum markers of dysbiosis in high-risk multiplex IBD families (two or more affected first-degree relatives).DesignFaecal and serum samples were collected from multiplex IBD and control families (95 IBD, 292 unaffected, 51 controls). Findings were validated in independent cohorts of 616 and 1173 subjects including patients with IBD, infants born to mothers with IBD and controls. 16S rRNA gene sequencing and global untargeted metabolomics profiling of faeces and serum were performed.ResultsMicrobial and metabolomic parameters of dysbiosis progressively decreased from infancy until age 8. This microbial maturation process was slower in infants born to mothers with IBD. After age 15, dysbiosis steadily increased in unaffected relatives throughout adulthood. Dysbiosis was accompanied by marked shifts in the faecal metabolome and, to a lesser extent, the serum metabolome. Faecal and serum metabolomics dysbiosis indices were validated in an independent cohort. Dysbiosis was associated with elevated antimicrobial serologies but not with faecal calprotectin. Dysbiosis metrics differentiated IBD from non-IBD comparably to serologies, with a model combining calprotectin, faecal metabolomics dysbiosis index and serology score demonstrating highest accuracy.ConclusionThese findings support that dysbiosis exists as a pre-disease state detectable by faecal and serum biomarkers for IBD risk prediction. Given the expansion of disease-modifying agents and non-invasive imaging, the indices developed here may facilitate earlier diagnoses and improved management in at-risk individuals.

Abstract Background Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn’s disease (CD), have complex pathologies requiring precise diagnostic tools. We evaluated the clinical utility of anti-integrin αvβ6 antibodies in diagnosing UC, focusing on differences between a U.S. cohort (self-reported White) and a Japanese cohort, and additionally assessed whether combining anti-αvβ6 with anti-EPCR improved diagnostic performance. Methods Serum anti-αvβ6 antibody levels were measured in 1138 participants (514 in the U.S. cohort, 624 in the Japanese cohort), including 1093 IBD cases and 45 healthy control subjects. Positivity rates and titers were compared between cohorts, and associations with clinical subphenotypes and anti-EPCR were examined. Results Anti-αvβ6 positivity was significantly higher in UC patients (85.4%) than in CD patients (16.4%) or control subjects (0%). Within UC, high positivity was observed across all disease extents, with only minor cohort differences. Longer disease duration was associated with lower positivity in both cohorts. In CD, the U.S. cohort showed higher positivity (23.4%) than the Japanese cohort (10.1%), particularly in colonic CD. Absence of ileal involvement, strictures, or perianal disease was associated with higher positivity. Anti-αvβ6 and anti-EPCR levels were strongly correlated, but their expression patterns differed in primary sclerosing cholangitis–associated IBD. Combining anti-αvβ6 and anti-EPCR improved UC diagnostic accuracy (area under the curve, 0.98; 95% confidence interval, 0.95-1.00) over either antibody alone (P = .00264). Conclusions Anti-αvβ6 is a valuable biomarker for UC diagnosis. However, this study demonstrated differences in its behavior between U.S. and Japanese cohorts, particularly in CD. Cohort-informed interpretation and combined antibody testing may improve diagnostic precision and disease stratification in IBD. Lay Summary This study reveals that anti-integrin αvβ6 antibodies are highly sensitive and specific biomarkers for ulcerative colitis. It highlights differences between U.S. (self-reported White) and Japanese cohorts, especially in Crohn’s disease, and demonstrates that combining anti-αvβ6 with anti-EPCR enhances diagnostic accuracy.

Lay Summary T-cell and antibody responses to severe acute respiratory syndrome coronavirus 2 vaccination in inflammatory bowel disease patients are poorly correlated. T-cell responses are preserved by most biologic therapies, but augmented by anti-tumor necrosis factor (anti-TNF) treatment. While anti-TNF therapy blunts the antibody response, cellular immunity after vaccination is robust.

Background The safety of a third dose of SARS-CoV-2 mRNA vaccination in patients with inflammatory bowel disease is unknown. Methods We compared symptoms following a third SARS-CoV-2 mRNA vaccine dose with symptoms after the second dose in IBD. Results The study group included 594 patients (70% female, 58% BNT162b2). Overall, 41% reported symptoms after a third dose. Symptom frequency and severity were lower after the third dose relative to the second dose for every organ system, except for gastrointestinal symptoms which were marginally worse. Conclusion The frequency and severity of symptoms after a third mRNA vaccine dose are generally similar or milder than after a second dose for most organ systems. Lay Summary The postvaccination symptom profile in patients with IBD is unknown after a third mRNA COVID vaccine dose. In a cohort of 594 subjects with IBD, we demonstrated that 41% experienced any symptoms after a third dose, the vast majority of which were mild and lasted less than 2 days. Symptoms after third dose were less frequently reported than after the second dose.

Abstract Background Vaccine hesitancy is prevalent among people with IBD, in part due to insufficient evidence regarding comparative safety of vaccines in this population. Methods We conducted a nationwide comparative study of postvaccination symptoms among those with IBD and health care workers (HCWs) without IBD. Symptom frequency, severity, and duration were measured. Continuous and categorical data were analyzed using Wilcoxon rank-sum and Fisher’s exact test. Regression analysis was used to adjust for confounding variables. Results We had 2910 and 2746 subjects who completed a survey after dose 1 (D1) and dose 2 (D2) respectively (D1: HCW = 933, IBD = 1977; D2: HCW = 884, IBD = 1862). Mean age was 43 years, 67% were female, and 23% were nonwhite; 73% received BNT162b2 (Pfizer) including almost all HCWs and 60% of IBD patients. Most postvaccine symptoms were mild and lasted ≤2 days after both doses in both groups. Health care workers experienced more postvaccination symptoms overall than IBD patients after each dose (D1: 57% vs 35%, P < .001; D2: 73% vs 50%, P < .001). Gastrointestinal symptoms were noted in IBD more frequently after D1 (5.5% vs 3%, P = .003) but not after D2 (10% vs 13%, P = .07). Inflammatory bowel disease subjects who received mRNA-1273 (Moderna) reported more overall symptoms compared with BNT162b2 (57% vs 46%, P < .001) including gastrointestinal symptoms (12% vs 8%, P = .002) after D2. Conclusions People with IBD had fewer postvaccination symptoms following the first 2 doses of SARS-CoV-2 mRNA vaccines than HCWs. Among those with symptoms, most symptoms were mild and of short duration. Lay Summary Those with inflammatory bowel disease (IBD) reported fewer postvaccination symptoms relative to non-IBD health care workers. Local and systemic symptoms were generally mild and lasted less than 2 days in both populations. The data are reassuring with considerable vaccine hesitancy.