Akkermansia muciniphila Reduces Peritonitis and Improves Intestinal Tissue Wound Healing after a Colonic Transmural Defect by a MyD88-Dependent Mechanism

Abstract

Anastomotic leakage is a major complication following colorectal surgery leading to peritonitis, complications, and mortality. Akkermansia muciniphila has shown beneficial effects on the gut barrier function. Whether A. muciniphila reduces peritonitis and mortality during colonic leakage is unknown. Whether A. muciniphila can directly modulate the expression of genes in the colonic mucosa in humans has never been studied. We investigated the effects of a pretreatment (14 days) with live A. muciniphila prior to surgical colonic perforation on peritonitis, mortality, and wound healing. We used mice with an inducible intestinal-epithelial-cell-specific deletion of MyD88 (IEC-MyD88 KO) to investigate the role of the innate immune system in this context. In a proof-of-concept pilot study, healthy humans were exposed to A. muciniphila for 2 h and colonic biopsies taken before and after colonic instillation for transcriptomic analysis. Seven days after colonic perforation, A.-muciniphila-treated mice had significantly lower mortality and severity of peritonitis. This effect was associated with significant improvements of wound histological healing scores, higher production of IL22, but no changes in the mucus layer thickness or genes involved in cell renewal, proliferation, or differentiation. All these effects were abolished in IEC-MyD88 KO mice. Finally, human subjects exposed to A. muciniphila exhibited an increased level of the bacterium at the mucus level 2 h after instillation and significant changes in the expression of different genes involved in the regulation of cell cycling, gene transcription, immunity, and inflammation in their colonic mucosa. A. muciniphila improves wound healing during transmural colonic wall defect through mechanisms possibly involving IL22 signaling and requiring MyD88 in the intestinal cells. In healthy humans, colonic administration of A. muciniphila is well tolerated and changes the expression of genes involved in the immune pathways.

Human α-Defensin 51–9 and Human β-Defensin 2 Improve Metabolic Parameters and Gut Barrier Function in Mice Fed a Western-Style Diet

“…By using an organoid cell-culture model, we demonstrated that HD5 1–9 and hBD2 induce HDPs through the Myd88 signaling pathway in vitro. Recent studies revealed that bacterial-mediated regulation of HDP expression occurs in a TLR/Myd88-dependent manner [ 71 , 72 ]. Thus, microbiota-free, TLR- or Myd88-deficient mice exhibited decreased Defa5 mRNA expression, which was recovered by treating with Lactobacillus lactis or TLR agonists [ 73 ].…”

Role of gut microbiota in infectious and inflammatory diseases

“…IL-22 production is also associated with epithelial regeneration and repair. Akkermansia muciniphila , a common human gut bacterium, has been shown to induce IL-22 production by ILC3 cells ( Bachmann et al, 2022 ; Zheng et al, 2023 ). Interferon gamma (IFN-γ) production is a typical response of Th1 cells and is associated with protective immunity against intracellular pathogens.…”

Pasteurized Akkermansia muciniphila improves irritable bowel syndrome-like symptoms and related behavioral disorders in mice

“… 11 In addition, it is already known that A. muciniphila interaction with the host involves TLR2-signaling pathways 19 , 43 and modulation of IL-10 and IL-22 cytokines. 44 , 45 Thus, a moderately induced colonic expression of IL-22 by pasteurized A. muciniphila would restore, at least in part, colonic sensitivity and normal animal behavior in our two IBS-like mouse models.…”