Metagenomic evidence for taxonomic dysbiosis and functional imbalance in the gastrointestinal tracts of children with cystic fibrosis

Abstract

Cystic fibrosis (CF) results in inflammation, malabsorption of fats and other nutrients, and obstruction in the gastrointestinal (GI) tract, yet the mechanisms linking these disease manifestations to microbiome composition remain largely unexplored. Here we used metagenomic analysis to systematically characterize fecal microbiomes of children with and without CF, demonstrating marked CF-associated taxonomic dysbiosis and functional imbalance. We further showed that these taxonomic and functional shifts were especially pronounced in young children with CF and diminished with age. Importantly, the resulting dysbiotic microbiomes had significantly altered capacities for lipid metabolism, including decreased capacity for overall fatty acid biosynthesis and increased capacity for degrading anti-inflammatory short-chain fatty acids. Notably, these functional differences correlated with fecal measures of fat malabsorption and inflammation. Combined, these results suggest that enteric fat abundance selects for pro-inflammatory GI microbiota in young children with CF, offering novel strategies for improving the health of children with CF-associated fat malabsorption.

The CF gastrointestinal microbiome: Structure and clinical impact

“…These dysbioses were particularly marked among people who with the most severe CFTR dysfunction, such as those homozygous for the F508del CFTR mutation. Hoffman et al showed that these effects were already present in young children with CF, and even in the absence of recent antibiotic treatment; this dysbiosis was significantly associated with fecal measures of both fat malabsorption and inflammation, suggesting a relationship between the microbiota and GI dysfunction in CF supported by observations from additional studies of microbiota, probiotics, and GI dysfunction, to be described below.…”

“…GI dysbiosis has also been linked to a number of common diseases of the liver, including non‐alcoholic fatty liver disease, non‐alcoholic steatohepatitis, alcoholic liver disease, and cirrhosis . For example, the dysbiosis that arises as a result of increased luminal fat, as is the case in CF, results in enrichment of bacteria that convert primary bile acids into hepatotoxic secondary bile acids, as well as in increased gut permeability and, therefore, greater liver exposure to gut‐derived endotoxins . However, GI dysbiosis has also been shown to be associated with a range of diseases beyond the GI tract, often those in which chronic inflammation or metabolic dysregulation is implicated in pathogenesis .…”

“…Manor et al found that fecal dysbiosis in young children with CF resulted in enrichment in bacterial genes for degrading lipids (which are abundant due to malabsorption) relative to children without CF. Conversely, the same metagenomic analysis showed that CF fecal microbiota are predicted to be relatively deficient for synthesizing specific microbial‐derived small molecules, known as short‐chain fatty acids (SCFAs), which are important for regulating epithelial cell health and mucosal immune responses in the GI tract.…”

“…In turn, the GI physicochemical environment, which is decidedly altered in people with CF, shapes both the constituency and behavior of the GI microbiota. Recent evidence shows that CF GI microbiota are indeed different from people without CF, potentially with pathological consequences within and beyond the CF GI tract . In this article, we will review the recent literature on the CF GI microbiome and its clinical impact, as well as how we might use these recent discoveries to prevent a host of CF disease manifestations.…”

Lessons from the lower airway microbiome in early CF

“…Future studies are clearly needed to examine longitudinal changes and the impact of antibiotics. In addition, recent publications suggest that the gastrointestinal microbiota may also be important in CF, with influences on nutritional status, systemic inflammation and airway pathogen acquisition 19 20. Understanding the impact of antibiotics, novel therapies, environmental exposures and nutrition on CF microbiota may lead to improved clinical outcomes.…”