INFLAMMATORY BOWEL DISEASE (IBD)-ASSOCIATED MICROBIOTA ALTER VISCERAL SENSITIVITY AND BEHAVIOUR IN MICROBIOTA-HUMANIZED MICE.

Background: IBD is characterized by relapsing episodes of inflammation in the gastrointestinal tract. Abdominal pain is common in IBD and often persists in the absence of overt inflammation. The treatment has limited efficacy, in part due to our incomplete understanding of its pathophysiology, and commonly leads to dependency on opioids. Moreover, patients with IBD are more likely to develop psychiatric comorbidities (anxiety and depression), further impairing the disease course and quality of life. The gut microbiota has been shown to modulate pain, mood, and anxiety. Gut microbiota is altered in patients with IBD, however, it is unknown whether it affects pain perception and emotional behaviour. We hypothesized that microbiota from patients with IBD contribute to visceral hypersensitivity and modulate emotional behaviour in a subset of patients.

Methods: Adult germ-free C57BL/6 mice (n=80) of both sexes were colonized with fecal microbiota from patients with IBD (Crohn’s Disease n=5, Ulcerative Colitis n=3) and healthy controls (HC n=4); 4-10 mice were colonized per each human donor. Mice were fed with a human-like (Western) diet. Three weeks post-colonization, the light preference, open field, and tail suspension tests were employed to assess anxiety- and depression-like behaviour. Visceral sensitivity was assessed by measuring visceromotor responses to isovolumetric colorectal distension.

Results: Compared to mice with HC microbiota, mice with IBD microbiota had reduced body weight; however, no differences in colon length were found. Although no differences were found in the open field test, mice with IBD microbiota displayed a reduced preference for the light chamber and increased immobility in the tail suspension test compared to HC mice, suggestive of anxiety- and depression-like behaviour, respectively. Importantly, no differences in overall locomotion were observed, thus ruling out sickness-like behaviour. When subjected to colorectal distension, mice with IBD microbiota had an overall higher visceromotor response (area under the curve) compared to HC mice. Furthermore, we observed mainly an increased response to non-noxious stimuli (100 μL colorectal distension), suggestive of visceral allodynia. There were no differences in colonic compliance between groups suggesting there was no significant colonic inflammation. Neither sex nor the IBD subtype were specifically associated with changes in visceral sensitivity.

Conclusion: Our data demonstrate that microbiota from patients with IBD negatively affects the gut-brain axis by inducing changes in emotionality-related behaviour and triggering visceral hypersensitivity. Uncovering the microbial products and molecular mechanisms underlying these abnormalities will guide the development of novel microbiota-based therapies for patients with IBD.