Infants with cystic fibrosis have altered fecal functional capacities with potential clinical and metabolic consequences

Abstract

Background 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. 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. Results To 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. Conclusions Our 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.

What Do We Know about the Microbiome in Cystic Fibrosis? Is There a Role for Probiotics and Prebiotics?

“…One key features of the CF gut microbiome is decreased species diversity [ 7 , 12 , 52 , 53 , 54 ] ( Figure 1 ). In addition, paediatric studies have demonstrated that the CF gut microbiome diversifies and matures at a significantly slower rate than that of a healthy child [ 54 , 55 , 56 ]. Compositionally, the CF gut microbiome also differs from that of the healthy gut.…”

“…Recent advancements in metagenomic methods have enhanced the ability to characterise the functionality of the gut microbiota, thereby elucidating the physiological consequences of dysbiosis. It has been demonstrated that the CF gut microbiome displays an increased capacity to metabolise nutrients, antioxidants, and short-chain fatty acids (SCFAs), as well as a relatively decreased propensity to synthesise fatty acids [ 7 , 56 , 59 ].…”

“…While simply adding more dietary fibre to existing CF diets is tantalizing, interventional dietary trials have demonstrated that increasing dietary fibre intake does not necessarily translate to increased SCFA production or improvements in disease outcomes [ 220 , 270 ]. This is pertinent to members of the CF population, who are likely to have altered SCFA-generating pathways [ 7 , 56 , 60 ]. High-quality randomized trials with well-defined dietary components are essential to provide justification for modulating microbiome–host effects through diet.…”

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

“…Infants and young children with CF are dramatically affected and typically require intensive medical attention from birth, with nutritional and growth deficits due to pancreatic insufficiency and progressive lung disease 20,21 . Dramatic alteration of gut microbiota composition is a hallmark of both infants and adults with CF, correlating with linear growth inhibition and increased fecal fat content and markers of intestinal inflammation [22][23][24][25][26][27][28] . Notable compositional differences in the microbiota found across studies between control and CF individuals from both infant and adult cohorts include increased Proteobacteria and diminished levels of Bacteroidetes which manifest following birth and do not resolve 22,23,26,27,29 .…”

Can Bioactive Food Substances Contribute to Cystic Fibrosis-Related Cardiovascular Disease Prevention?

“…Studies showed that the intestinal microbiota of pwCF differs from that of their healthy peers. Furthermore, researchers concluded that the intestinal microbiome of the patients affected by CF diversifies and matures with more difficulty compared to the healthy children [ 66 , 74 ]. Nielsen et al concluded in their study that a CF child, even at fifteen years old, does not achieve the same microbiome richness as a healthy one-year-old child [ 75 ].…”