AhR/IL-22 pathway as new target for the treatment of post-infectious irritable bowel syndrome symptoms

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. lactis IL−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. lactis IL−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.lactis IL−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.

Antihyperalgesic properties of gut microbiota: Parabacteroides distasonis as a new probiotic strategy to alleviate chronic abdominal pain

“…As previously reported, 43 infection with C rodentium induces CHS after pathogen clearance by increasing intracolonic pressure to colorectal distension in male mice (P , 0.05 at 60 mm Hg and P , 0.01 at 80 mm Hg) (Figs. 5A and B).…”

“…A "leaky gut" is a hallmark of the DSS-induced CHS model, and we previously demonstrated that intestinal barrier integrity is also impaired in both infectious and postinfectious phases of this model. 43 Of interest, no effect of the F1-2 strain on CHS was observed in the NMS model, in which we previously observed only a slight increase in colonic permeability, but to a much lesser extent than in the 2 previous models. 38 Because translocation of bacteria or their metabolites beyond the gastrointestinal tract is one of the hallmarks of the intestinal hyperpermeability, 60 we confirmed in our study that there is an increase of intracolonic bacteria, reveled by 16S RNAscope staining, in the DSS-treated mice but not in the sensitized NMS mice.…”

Lactococcus lactis engineered to deliver hCAP18 cDNA alleviates DNBS-induced colitis in C57BL/6 mice by promoting IL17A and IL10 cytokine expression

“…hCAP18 synthetic cDNA optimized for L. lactis expression was cloned into a pSEC plasmid as described in 70 to create pSEC:hCAP18; this was then transformed in L. lactis NZ9000 to create the recombinant strain LL-pSEC:hCAP18, in which the induction of hCAP18 was nisin-dependent. hCAP18 synthetic cDNA optimized for expression in mice was cloned into the proBi-H1 plasmid to create proBi-H1:hCAP18; this plasmid vector contained the repA and repC origin of replication, the chloramphenicol resistance gene, and the expression cassette from pcDNA3 (Invitrogen) as published before 71 . The resulting vector was 3.7 kb long.…”

Chlorogenic Acid Ameliorates Post‐Infectious Irritable Bowel Syndrome by Regulating Extracellular Vesicles of Gut Microbes

“…[5] The composition and abundance of the gut microbiota in patients with PI-IBS are significantly different, and the levels of short-chain fatty acids (SCFAs), which exhibit inhibitory activity against pathogenic bacteria, are also reduced due to inflammatory immune responses. [6] The complex microbiota of the human gut affects host health, both directly and indirectly. The host provides a growth environment for the gut microbiota, which participates in maintaining host homeostasis by regulating intestinal development, nutrient digestion, and immune status, as well as affecting brain activity through the enteric nervous system.…”

“…[ 5 ] The composition and abundance of the gut microbiota in patients with PI‐IBS are significantly different, and the levels of short‐chain fatty acids (SCFAs), which exhibit inhibitory activity against pathogenic bacteria, are also reduced due to inflammatory immune responses. [ 6 ]…”