Intestinal Bacteroides Modulates Systemic Inflammation and the Microbial Ecology in a Mouse Model of CF: Evidence for Propionate and other Short Chain Fatty Acids Reducing Systemic Inflammatory Cytokines

Abstract

Persons with cystic fibrosis, starting in early life, have 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 (SCFA) propionate. We demonstrate here that 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. Bacteroides isolates also produce low levels of butyrate; this SCFA is positively correlated with inhibition of the inflammatory response. Finally, the introduction of Bacteroides-supplemented stool from infants with CF into the gut of CftrF508del mice results in an increase in propionate in the stool as well as the reduction in several systemic pro-inflammatory cytokines. Bacteroides supplementation also reduced the fecal relative abundance of E. coli, indicating a potential interaction between these two microbes, consistent with previous clinical studies. Together, our data indicate the important role of Bacteroides and Bacteroides-derived propionate in the context of the developing microbiome in infants and children with CF, which could help explain the observed gut-lung axis in CF.

Predicting Clinical Outcomes in Infants With Cystic Fibrosis From Stool Microbiota using Random Forest Algorithms

“…This study used longitudinal stool and clinical data collections to train a model that can predict respiratory outcomes for children with CF from stool samples. Overall, the relative abundance of stool microbiota at the genus level in children with CF weakly predicts age, consistent with studies showing intestinal microbiome dysbiosis and altered age of maturation in this population 1,2,4,6,8,9,11,20,21,26,28 . Specifically, weak predictive power in cwCF compared to the general population suggests that the CF infant microbiome may mature at different rates than in infants without CF.…”

“…Again, our model was able to correlate stool microbial composition with the High NLR group (i.e., the highest systemic inflammation) with relatively low error. Interestingly, we and others have shown that Bacteroides is depleted in the gut of infants and cwCF 1,2,6,21,26 . While the levels of Bacteroides is low compared to healthy controls for all our samples 7 , we observed that the High NLR group had the highest relative abundance of Bacteroides (Figure 4C).…”

“…Because previous literature has shown that the microbes in the gut can alter systemic inflammatory profiles 6,10,13,14,16,18,26,28,29 , we sought to apply this machine learning predictive pipeline to markers of systemic inflammation. Again, our model was able to correlate stool microbial composition with the High NLR group (i.e., the highest systemic inflammation) with relatively low error.…”

Persistent delay in maturation of the developing gut microbiota in infants with cystic fibrosis

“…Regardless of the underlying mechanism(s), there is accumulating evidence that alterations in the gut microbiota in CF are linked to disease at distal sites 33 . For example, reduced fecal levels of short chain fatty acid-producing gut microbes are separately associated with diminished growth and inflammation 26,34 . Communication between the gut microbiota and the lung may also influence disease progression in CF through the systemic diffusion (or lack of diffusion) of microbially produced metabolites, or through influencing inflammation or immune cells 33 .…”

Marine prebiotics mediate decolonization of Pseudomonas aeruginosa from gut by inhibiting secreted virulence factor interactions with mucins and enriching Bacteroides population

“…Fucose utilization by intestinal commensal like Bacteroides was not analyzed and the level of fecal short-chain fatty acids (SCFAs) such as acetate, propionate and butyrate were not evaluated in the fucoidan-supplemented mice [19,77]. Although we did not evaluate the role of metabolites produced by fucoidans enriched microbiota in improving the gut homeostasis, emerging evidence tends to support the hypothesis that Bacteroides and Bacteroides-derived propionate is beneficial to individuals with cystic fibrosis [78]. By using an in vitro fermentation model Liu et al demonstrated that among the individuals with strong utilization of sulfated polysaccharides, gut microbiota possessed either more Parabacteroides or more Bacteroides, consequently more beneficial metabolites [79].…”