Controlled Access. Restriction lift date: 2035-05-31
Unravelling the role of the microbiota-gut-brain axis in irritable bowel syndrome and its psychiatric comorbidities
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Date
2024
Authors
Wilmes, Lars
Journal Title
Journal ISSN
Volume Title
Publisher
University College Cork
Published Version
Abstract
Irritable bowel syndrome is a stress-related disorder of gut-brain interaction, characterised by altered bowel movements and visceral hypersensitivity, with a profound impact on quality of life. These symptoms occur in the absence of structural abnormalities or validated biomarkers. While the treatment options under consideration for irritable bowel syndrome have expanded, a significant proportion of patients fail to respond to conventional pharmacological interventions. This challenge is compounded by a subpopulation of patients with psychiatric comorbidities, including anxiety and depression, who tend to exhibit increased symptom severity and psychiatric difficulties that are harder to treat. The microbiota-gut-brain axis has emerged as a promising target for intervention, as supported by both preclinical and clinical studies. However, it remains unclear whether irritable bowel syndrome patients with psychiatric comorbidities possess distinct gut microbiota profiles compared to those without such comorbidities, potentially leading to different outcomes and requiring more precise treatment options.
Using a well-validated animal model, we initially aimed to determine whether distinct gut microbiota profiles are causally linked to irritable bowel syndrome phenotypes with or without psychiatric comorbidities. In our preclinical studies, we showed that rats exposed to maternal separation could be clustered into subgroups, each representing different phenotypes: one group exhibited primarily visceral hypersensitivity, another displayed negative valence behaviour, a third had a comorbid phenotype, while a fourth group was resilient. Importantly, these subgroups showed distinct gut microbiota configurations corresponding to their specific phenotypes. Following this discovery, we conducted faecal microbiota transplants from these clusters into naïve rats, providing direct evidence that the microbiota plays a causal role in driving aspects of these phenotypes.
To assess the clinical relevance of these findings, we isolated gut microbiota from three human populations: healthy individuals, irritable bowel syndrome patients, and irritable bowel syndrome patients with psychiatric comorbidities. After analysing the gut microbiota profiles, we transplanted these bacteria into naïve animals. Interestingly, while the microbiota from both IBS groups increased visceral hypersensitivity, only minor behavioural changes related to psychiatric disorders were observed in the recipient animals.
Finally, we tested a novel next-generation psychobiotic, identified from patients with depression, in an animal model. Specifically, we investigated whether its psychobiotic properties exerted disease-specific effects and whether its efficacy surpassed that of traditional probiotics. However, neither the novel psychobiotic nor the traditionally selected probiotic significantly impacted gastrointestinal physiology or behaviour, highlighting the continuing challenges in translating psychobiotics between bench and bedside.
Our findings underscore the critical role of the gut microbiota in driving distinct behavioural phenotypes and the potential in stratification of IBS subgroups based on the presence of psychiatric comorbidities. While the translation of these preclinical findings into effective treatments remains challenging, this suggests that targeted gut microbiota interventions may offer more precise cluster-specific therapeutic benefits. This may ultimately pave the way for more nuanced approaches in clinical IBS management where this is currently a large unmet medical need.
Description
Controlled Access
Keywords
Microbiota-gut-brain axis , Irritable bowel syndrome , Psychiatric disorders , Stress
Citation
Wilmes, L. 2024. Unravelling the role of the microbiota-gut-brain axis in irritable bowel syndrome and its psychiatric comorbidities. PhD Thesis, University College Cork.