Butyrate reduces adherent-invasive E. coli -evoked disruption of epithelial mitochondrial morphology and barrier function: involvement of free fatty acid receptor 3

Abstract

Gut bacteria provide benefits to the host and have been implicated in inflammatory bowel disease (IBD), where adherent-invasive E. coli (AIEC) pathobionts ( e.g ., strain LF82) are associated with Crohn’s disease. E. coli -LF82 causes fragmentation of the epithelial mitochondrial network, leading to increased epithelial permeability. We hypothesized that butyrate would limit the epithelial mitochondrial disruption caused by E. coli -LF82. Human colonic organoids and the T84 epithelial cell line infected with E. coli -LF82 (MOI = 100, 4 h) showed a significant increase in mitochondrial network fission that was reduced by butyrate (10 mM) co-treatment. Butyrate reduced the loss of mitochondrial membrane potential caused by E. coli -LF82 and increased expression of PGC-1 mRNA, the master regulator of mitochondrial biogenesis. Metabolomics revealed that butyrate significantly altered E. coli -LF82 central carbon metabolism leading to diminished glucose uptake and increased succinate secretion. Correlating with preservation of mitochondrial network form/function, butyrate reduced E. coli -LF82 transcytosis across T84-cell monolayers. The use of the G-protein inhibitor, pertussis toxin, implicated GPCR signaling as critical to the effect of butyrate, and the free fatty acid receptor three (FFAR3, GPR41) agonist, AR420626, reproduced butyrate’s effect in terms of ameliorating the loss of barrier function and reducing the mitochondrial fragmentation observed in E. coli -LF82 infected T84-cells and organoids. These data indicate that butyrate helps maintain epithelial mitochondrial form/function when challenged by E. coli -LF82 and that this occurs, at least in part, via FFAR3. Thus, loss of butyrate-producing bacteria in IBD in the context of pathobionts would contribute to loss of epithelial mitochondrial and barrier functions that could evoke disease and/or exaggerate a low-grade inflammation.

Therapeutic Prospects of Mesenchymal Stem Cell and Their Derived Exosomes in the Regulation of the Gut Microbiota in Inflammatory Bowel Disease

“…For example, butyrate can reduce the aggregation of neutrophils, thus ameliorating DSS-induced colitis in mice [85]. Recently, it was shown that butyrate can also ameliorate increased intestinal epithelial permeability induced by AIEC pathobionts (e.g., strain LF82) in UC and maintain the normal morphology and function of epithelial cell mitochondria [86]. Huc-MSCs can upregulate the levels of SCFA-producing bacteria, including Akkermansia, Faecalibaculum, and Clostridia_UCG_014, in the IBD model, which, in turn, promotes T cell homeostasis, thereby alleviating the inflammatory state of the intestinal mucosa [87].…”

Organoids in gastrointestinal diseases: from bench to clinic

“… 179 Furthermore, organoids models are employed for evaluating repurposed drugs originally intended for other diseases and assessing their efficacy against novel diseases. 180 , 181 They also serve as a means to continuously identify new targets and design targeted therapy strategies. 182 , 183 , 184 , 185 Organoids models also facilitate the exploration of alternative treatment approaches for challenging drug targets.…”

“…Therefore, decreased abundance of butyrate‐producing bacteria in IBD would contribute to loss of epithelial mitochondrial and barrier functions, which could further trigger disease and/or exacerbate a low‐grade inflammation. 180 …”