Affiliation:
1. Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, USA
2. Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, USA
3. Department of Psychiatry, Geisel School of Medicine at Dartmouth, Hanove, USA
Abstract
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
Bacteroides. Bacteroides
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,
Bacteroides
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
Bacteroides-
supplemented stool from infants with cystic fibrosis into the gut of
Cftr
F508del
mice results in higher propionate in the stool as well as the reduction in several systemic pro-inflammatory cytokines.
Bacteroides
supplementation also reduced the fecal relative abundance of
Escherichia coli
, indicating a potential interaction between these two microbes, consistent with previous clinical studies. For a
Bacteroides
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
Bacteroides
-derived propionate in the modulation of systemic and airway inflammation and mediating the intestinal ecology of infants and children with CF. The roles of
Bacteroides
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.
IMPORTANCE
The 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
Bacteroides
decreases inflammation through the production of the short-chain fatty acid propionate. Supplementing the levels of
Bacteroides
in an animal model of CF is associated with reduced systemic inflammation and reduction in the relative abundance of the opportunistically pathogenic group
Escherichia
/
Shigella
in the gut. Taken together, these data demonstrate a key role for
Bacteroides
and microbially produced propionate in modulating inflammation, gut microbial ecology, and the gut-lung axis in cystic fibrosis. These data support the role of
Bacteroides
as a potential probiotic in CF.
Funder
Cystic Fibrosis Foundation
HHS | National Institutes of Health
Publisher
American Society for Microbiology