AhR/IL-22 pathway as new target for the treatment of post-infectious irritable bowel syndrome symptoms, 2022, Maëva et al

Discussion in ''Conditions related to ME/CFS' news and research' started by Andy, Feb 1, 2022.

  1. Andy

    Andy Committee Member

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    ABSTRACT

    Alterations in brain/gut/microbiota axis are linked to Irritable Bowel Syndrome (IBS) physiopathology. Upon gastrointestinal infection, chronic abdominal pain and anxio-depressive comorbidities may persist despite pathogen clearance leading to Post-Infectious IBS (PI-IBS). This study assesses the influence of tryptophan metabolism, and particularly the microbiota-induced AhR expression, on intestinal homeostasis disturbance following gastroenteritis resolution, and evaluates the efficacy of IL-22 cytokine vectorization on PI-IBS symptoms.

    The Citrobacter rodentium infection model in C57BL6/J mice was used to mimic Enterobacteria gastroenteritis. Intestinal homeostasis was evaluated as low-grade inflammation, permeability, mucosa-associated microbiota composition, and colonic sensitivity. Cognitive performances and emotional state of animals were assessed using several tests. Tryptophan metabolism was analyzed by targeted metabolomics. AhR activity was evaluated using a luciferase reporter assay method. One Lactococcus lactis strain carrying an eukaryotic expression plasmid for murine IL-22 (L. lactisIL−22) was used to induce IL-22 production in mouse colonic mucosa. C. rodentium-infected mice exhibited persistent colonic hypersensitivity and cognitive impairments and anxiety-like behaviors after pathogen clearance. These post-infectious disorders were associated with low-grade inflammation, increased intestinal permeability, decrease of Lactobacillaceae abundance associated with the colonic layer, and increase of short-chain fatty acids (SCFAs). During post-infection period, the indole pathway and AhR activity were decreased due to a reduction of tryptophol production. Treatment with L. lactisIL−22 restored gut permeability and normalized colonic sensitivity, restored cognitive performances and decreased anxiety-like behaviors. Data from the video-tracking system suggested an upgrade of welfare for mice receiving the L.lactisIL−22 strain.

    Our findings revealed that AhR/IL-22 signaling pathway is altered in a preclinical PI-IBS model. IL-22 delivering alleviate PI-IBS symptoms as colonic hypersensitivity, cognitive impairments, and anxiety-like behaviors by acting on intestinal mucosa integrity. Thus, therapeutic strategies targeting this pathway could be developed to treat IBS patients suffering from chronic abdominal pain and associated well-being disorders.

    Open access, https://www.tandfonline.com/doi/full/10.1080/19490976.2021.2022997
     
  2. Hutan

    Hutan Moderator Staff Member

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    I'm finding it a bit confusing. On the one hand, low short-chain fatty acids seems to be a problem and associated with post-infectious disorders, on the other, as here, higher levels of short-chain fatty acids are a problem. Just what is being measured for SCFA's is not always clear.
     
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  3. Andy

    Andy Committee Member

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    Perhaps their model doesn't accurately model real life consequences?
     
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  4. Hutan

    Hutan Moderator Staff Member

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    Yeah, maybe, but there are references elsewhere to high levels of short chain fatty acids in the gut being a problem. One possible cause is malabsorption. If that's the case, then both the low levels and high levels of SCFAs in faeces could indicate low levels in the gut epithelium, with the downstream consequences of a permeable gut, immunological issues...

    I'm a bit interested in this, as when my daughter was hospitalised with suspected appendicitis but what turned out to be the disease that seemed to precipitate the three of us in the family developing ME/CFS, one of the tests that was abnormal was short chain fatty acids in the faeces. The levels were very high. Something odd was going on.

    It feels as though there are clues around the place that might add up to something, but time and energy is needed to put all the bits together.
     
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