Intestinal <i>Bacteroides</i> modulates inflammation, systemic cytokines, and microbial ecology via propionate in a mouse model of cystic fibrosis

Abstract

Persons with cystic fibrosis (CF), starting in early life, show intestinal microbiome dysbiosis characterized in part by a decreased relative abundance of the genus <i>Bacteroides. Bacteroides</i> is a major producer of the intestinal short chain fatty acid propionate. We demonstrate here that cystic fibrosis transmembrane conductance regulator-defective (CFTR-/-) Caco-2 intestinal epithelial cells are responsive to the anti-inflammatory effects of propionate. Furthermore, <i>Bacteroides</i> isolates inhibit the IL-1β-induced inflammatory response of CFTR-/- Caco-2 intestinal epithelial cells and do so in a propionate-dependent manner. The introduction of <i>Bacteroides-</i>supplemented stool from infants with cystic fibrosis into the gut of <i>Cftr^F508del</i> mice results in higher propionate in the stool as well as the reduction in several systemic pro-inflammatory cytokines. <i>Bacteroides</i> supplementation also reduced the fecal relative abundance of <i>Escherichia coli</i>, indicating a potential interaction between these two microbes, consistent with previous clinical studies. For a <i>Bacteroides</i> propionate mutant in the mouse model, pro-inflammatory cytokine KC is higher in the airway and serum compared with the wild-type (WT) strain, with no significant difference in the absolute abundance of these two strains. Taken together, our data indicate the potential multiple roles of <i>Bacteroides</i>-derived propionate in the modulation of systemic and airway inflammation and mediating the intestinal ecology of infants and children with CF. The roles of <i>Bacteroides</i> and the propionate it produces may help explain the observed gut-lung axis in CF and could guide the development of probiotics to mitigate systemic and airway inflammation for persons with CF.IMPORTANCEThe composition of the gut microbiome in persons with CF is correlated with lung health outcomes, a phenomenon referred to as the gut-lung axis. Here, we demonstrate that the intestinal microbe <i>Bacteroides</i> decreases inflammation through the production of the short-chain fatty acid propionate. Supplementing the levels of <i>Bacteroides</i> in an animal model of CF is associated with reduced systemic inflammation and reduction in the relative abundance of the opportunistically pathogenic group <i>Escherichia</i>/<i>Shigella</i> in the gut. Taken together, these data demonstrate a key role for <i>Bacteroides</i> and microbially produced propionate in modulating inflammation, gut microbial ecology, and the gut-lung axis in cystic fibrosis. These data support the role of <i>Bacteroides</i> as a potential probiotic in CF.