Abstract

BackgroundInfants with cystic fibrosis (CF) suffer from gastrointestinal (GI) complications, including pancreatic insufficiency and intestinal inflammation, which have been associated with impaired nutrition and growth. Recent evidence identified altered fecal microbiota taxonomic compositions in infants with CF relative to healthy infants that were characterized by differences in the abundances of taxa associated with GI health and nutrition. Furthermore, these taxonomic differences were more pronounced in low length infants with CF, suggesting a potential link to linear growth failure. We hypothesized that these differences would entail shifts in the microbiome’s functional capacities that could contribute to inflammation and nutritional failure in infants with CF.ResultsTo test this hypothesis, we compared fecal microbial metagenomic content between healthy infants and infants with CF, supplemented with an analysis of fecal metabolomes in infants with CF. We identified notable differences in CF fecal microbial functional capacities, including metabolic and environmental response functions, compared to healthy infants that intensified during the first year of life. A machine learning-based longitudinal metagenomic age analysis of healthy and CF fecal metagenomic functional profiles further demonstrated that these differences are characterized by a CF-associated delay in the development of these functional capacities. Moreover, we found metagenomic differences in functions related to metabolism among infants with CF that were associated with diet and antibiotic exposure, and identified several taxa as potential drivers of these functional differences. An integrated metagenomic and metabolomic analysis further revealed that abundances of several fecal GI metabolites important for nutrient absorption, including three bile acids, correlated with specific microbes in infants with CF.ConclusionsOur results highlight several metagenomic and metabolomic factors, including bile acids and other microbial metabolites, that may impact nutrition, growth, and GI health in infants with CF. These factors could serve as promising avenues for novel microbiome-based therapeutics to improve health outcomes in these infants.

Highlights

  • Infants with cystic fibrosis (CF) suffer from gastrointestinal (GI) complications, including pancreatic insufficiency and intestinal inflammation, which have been associated with impaired nutrition and growth

  • CF-associated differences in metabolic gene abundances and their associated functions could contribute to the growth failure that is common among infants with CF, which we recently showed to be associated with the infant CF taxonomic dysbiosis [27]

  • While we did not detect any significant associations between differences in specific functional capacities during the first year of life and linear growth failure, our analysis identified other predicted functional impairments and metabolomic differences among infants with CF that could potentially contribute to early nutritional outcomes that we did not measure

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Summary

Introduction

Infants with cystic fibrosis (CF) suffer from gastrointestinal (GI) complications, including pancreatic insufficiency and intestinal inflammation, which have been associated with impaired nutrition and growth. Recent evidence identified altered fecal microbiota taxonomic compositions in infants with CF relative to healthy infants that were characterized by differences in the abundances of taxa associated with GI health and nutrition These taxonomic differences were more pronounced in low length infants with CF, suggesting a potential link to linear growth failure. Fecal microbiome studies have shown that the CF and non-CF GI microbiomes differ in both taxonomic composition [17, 49] and functional capacities encoded by the microbiota [21] This CF dysbiosis manifests early in childhood [42], with abnormal bacterial species and functional gene abundances that are associated with increased fecal measures of inflammation and dietary fat malabsorption [28, 35].

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