Clinical Case Summary

A 57 years-old patient with a history of active smoking, moderate body overweight (BMI 29 Kg/mq) and mild systolic hypertension in treatment with Olmesartan complained history of chronic diarrea and abdominal pain since 2006, rarely associated with hematochezia. After replacement of antihypertensive therapy to eliminate a potential confouding factor, he underwent multiple colonoscopies through the years with nonspecific findings until 2017, when moderated discontinuos inflammation with multiple erosions was seen in the transverse colon and in the rectum. Histologic examination described presence of chronic inflammation with cryptic microabscesses and cryptitis suggetive for Crohn's disease, while intestinal ultrasound revealed no small bowel localizations. He was treated with 2.4 daily grams of oral mesalamine with benefit until the end of 2023, when he came up to our clinic complaining resumption of bloody diarrhoea and abdominal pain, with 3-4 liquid stools per day. Addition of topic mesalamine was not of benefit. The patient underwent another colonoscopy which confirmed presence of hyperemic mucosa with diffuse erosions in the rectum, with histology confirming active Inflammatory Bowel Disease. In march 2024, after neurological investigations for recurrent paresthesias and strength deficits, the patient was diagnosed with relapsing-remitting Multiple Sclerosis. After multidisciplinary consultation, negative cardiologic evaluation, chest X-ray and blood screening exams, in October 2024 the patient started the anti sphingosine-1 phosphate Ozanimod, which was well-tolerated at maintenance dose of 0.92 milligrams per day. Three months after, he came back for scheduled follow-up reporting 1 or 2 daily evacuations in absence of abdominal pain and rectal bleeding. Calprotectin levels droped up to 17 ug/g. He also described complete neurological remission and complete absence of drug side effects.

References

1) Feagan BG, Schreiber S, Afzali A, Rieder F, Hyams J, Kollengode K, Pearlman J, Son V, Marta C, Wolf DC, D'Haens GG. Ozanimod as a novel oral small molecule therapy for the treatment of Crohn's disease: The YELLOWSTONE clinical trial program. Contemp Clin Trials. 2022 Nov;122:106958.
2) Pérez-Jeldres T, Alvarez-Lobos M, Rivera-Nieves J. Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis. Drugs. 2021 Jun;81(9):985-1002. Erratum in: Drugs. 2021 Aug;81(12):1451.
3) Harris S, Feagan BG, Hanauer S, Vermeire S, Ghosh S, Yan J, Wu C, Hu Y, Maddux R, Wolf DC, D'Haens G. Ozanimod Differentially Impacts Circulating Lymphocyte Subsets in Patients with Moderately to Severely Active Crohn's Disease. Dig Dis Sci. 2024 Jun;69(6):2044-2054.
4) Sands BE. Positioning Sphingosine-1 Phosphate Receptor Modulators in Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y). 2024 Jul;20(7):417-420.
5) Cree BA, Selmaj KW, Steinman L, Comi G, Bar-Or A, Arnold DL, Hartung HP, Montalbán X, Havrdová EK, Sheffield JK, Minton N, Cheng CY, Silva D, Kappos L, Cohen JA. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial. Mult Scler. 2022 Oct;28(12):1944-1962. doi: 10.1177/13524585221102584. Epub 2022 Jun 28. Erratum in: Mult Scler. 2022.

Introduction

Irritable bowel syndrome (IBS) has a profound impact on health-related quality of life. Increasing evidence suggests psychological factors have a large impact in the development and course of IBS, and in particular quality of life, with large individual heterogeneity. This observational study aims to investigate the influence of personality traits using the Big Five Inventory (BFI) and examine their associations with abdominal pain, general and gastrointestinal-specific anxiety, and quality of life in patients with IBS.

Aims & Methods

Data from a large observational study in patients with IBS (Rome III criteria) was used, in which patients completed questionnaires with regards to personality traits (BFI-44), symptom severity, general anxiety, GI-specific anxiety, and quality of life. Multivariable regression models and a network correlation analysis were used to determine underlying associations.

Results

194 patients were included for analysis (74.7% female, mean age 51.36 years). There was a positive association of neuroticism to GI-specific anxiety (B 7.234, P = 0.040) and general anxiety (B 0.954, P = 0.040) with a strong negative association to mental quality of life (B – 3.576, P = 0.007). In addition, a strong negative association of agreeableness to mental quality of life was found (B – 4.266, P = 0.001). Although there were no significant associations of personality traits to abdominal pain, positive associations were found regarding general anxiety (B 6.304, p < 0.001) and GI-specific anxiety (B 0.034, P <0.001) of abdominal pain. There were no associations found with regards to the other personality traits openness, conscientiousness or extroversion.

Conclusion

IBS patients with a higher level of neuroticism were more likely to experience higher levels of GI-specific and general anxiety. The trait neuroticism and/or agreeableness was more likely to have a significant lower mental quality of life in IBS. These findings emphasize the contribution of personality traits in the pathophysiology and course of IBS, pleading for a more personalized approach in patient management.

Introduction

Studies have shown that adults with irritable bowel syndrome (IBS) may be associated with anxiety, mood disorders, chronic headache, and other neuropsychiatric conditions. This growing body of evidence can allude to a possible bidirectional gut-brain connection. While adolescence is the age when both IBS and neuropsychiatric illnesses often first manifest, this population remains under-studied.

Aims & Methods

We aim to assess the association between the presence of irritable bowel syndrome (IBS) and neurologic and psychiatric disorders in a nationwide cohort of adolescents. This cross-sectional study included all adolescents aged 16-21 who underwent mandatory medical evaluations as part of their conscription between 2000-2021. All individuals completed comprehensive medical interviews. Suspected diagnoses prompted referral to board-certified specialists for confirmation and severity grading based on predefined criteria. IBS was diagnosed according to the Rome II-IV criteria by a certified gastroenterologist.
Neurologic disorders included attention-deficit/hyperactivity disorder [ADHD], epilepsy, chronic headache, sleep disorders. Psychiatric disorders included psychotic, personality, general anxiety disorder [GAD], non-combat post-traumatic stress disorder [PTSD], mood, dissociative, and eating disorders. Each diagnosis was classified by severity (mild, moderate, severe). Unadjusted and multivariate-adjusted logistic regression models were fitted to estimate odds ratios (ORs) for associations with IBS. The adjusted models were accounted for age, sex, intelligence score, body mass index (BMI), socioeconomic status (SES), education, country of origin, and any concurrent neuropsychiatric diagnoses.

Results

The study included 1,561,717 adolescents (666,442 [42%] women, mean age 17.4 ± 1.4 years), of whom 7,230 (0.46%) were diagnosed with IBS (4,778 mild; 1,948 moderate; 504 severe). Neurologic disorders were present in 1,661 (23.0%) and 143,348 (9.2%) of those with and without IBS, respectively. The respective numbers of people with psychiatric disorders were 773 (10.7%) and 49,889 (3.2%). In multivariable adjusted models, those with IBS were more likely to have chronic headache (aOR 4.7, 95% CI: 4.4-5.1), GAD (aOR 3.6, 95% CI: 3.2-3.9), eating disorders (aOR 2.6, 95% CI: 1.9-3.5), mood disorders (aOR 2.5, 95% CI: 2.1-3.1), personality disorders (aOR 2.5, 95% CI: 2.1-2.9), and dissociative disorders (aOR 19.1, 95% CI: 12.5-28.9). Patients with severe IBS (n=504) were independently associated with the presence of at least one severe neurologic (aOR 2.9, 95% CI: 1.2-7.1) or psychiatric disorder (aOR 3.8, 95% CI: 2.6-5.4).

Conclusion

In this large nationwide cohort, adolescents with IBS were more likely to have several tested neurologic and psychiatric disorders, compared to those without IBS. Longitudinal studies are needed to explore the directionality and long-term implications of these associations.

Introduction

While the mechanistic background to functional bowel disorders, including irritable bowel syndrome (IBS) is insufficiently understood, there is growing evidence that cytokine imbalance and inflammation may contribute to IBS pathogenesis.

Aims & Methods

We undertook a comprehensive investigation of serum cytokine profiles in individuals with functional bowel disorders (IBS n=164, functional constipation n=6, functional diarrhea n=3) and healthy controls (n=31), mapping their associations with clinical symptoms (GSRS-IBS, HAD), the gut microbiome (whole-metagenome sequencing of fecal samples), colonic mucosal responses (bulk RNA sequencing of sigmoid biopsies), intestinal physiological parameters, and the serum metabolome (liquid chromatography-mass spectrometry). Serum levels of IFN-γ, IL-1β, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α, IL-17A and CXCL10 were measured with Meso Scale Discovery (MSD) multiplex immunoassay kits.

Results

While cytokine levels did not differ significantly between persons with functional bowel disorders and healthy individuals, CXCL10 was reduced in participants with predominant diarrhea (IBS-D and functional diarrhea, p=0.01), whereas IL-12p70 was increased in predominant constipation (IBS-C and functional constipation, p=0.03), compared to healthy controls. Within both the full study cohort and participants with functional bowel disorders, IL-12p70 levels correlated with oroanal transit time (rho 0.20 and 0.19, p=0.007 and 0.01, respectively), and were inversely associated with fecal short-chain fatty acids (p=0.006, 0.01 and 0.03 for acetate, propionate and butyrate, respectively), as well as with the abundance of several butyrate-producing species. By contrast, IL-12p70 levels were positively associated with mucus-resident species (e.g., from the Akkermansia and Victivallis genera), with metabolites potentially derived from the degradation of mucosal carbohydrates, and with a distinct T helper 1 type response in colonic biopsies. Moreover, IL-12p70 levels correlated with anxiety (rho 0.17, p=0.03) in participants with functional bowel disorders.

Conclusion

Systemic cytokine profiles did not discriminate persons with functional bowel disorders from healthy individuals, but participants with predominant constipation and diarrhea exhibited distinct cytokine profiles. Alteration of systemic cytokines, notably IL-12p70, may result from disrupted mucosal barrier integrity and host-microbe homeostasis, and contribute to extraintestinal symptoms in a subset of individuals with functional bowel disorders.