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

Abstract

The healthy human infant gut microbiome undergoes stereotypical changes in taxonomic composition between birth and maturation to an adult-like stable state. During this time, extensive communication between microbiota and the host immune system contributes to health status later in life. Although there are many reported associations between microbiota compositional alterations and disease in adults, less is known about how microbiome development is altered in pediatric diseases. One pediatric disease linked to altered gut microbiota composition is cystic fibrosis (CF), a multi-organ genetic disease involving impaired chloride secretion across epithelia and heightened inflammation both in the gut and at other body sites. Here, we use shotgun metagenomics to profile the strain-level composition and developmental dynamics of the infant fecal microbiota from several CF and non-CF longitudinal cohorts spanning from birth to greater than 36 months of life. We identify a set of keystone species whose prevalence and abundance reproducibly define microbiota development in early life in non-CF infants, but are missing or decreased in relative abundance in infants with CF. The consequences of these CF-specific differences in gut microbiota composition and dynamics are a delayed pattern of microbiota maturation, persistent entrenchment in a transitional developmental phase, and subsequent failure to attain an adult-like stable microbiota. We also detect the increased relative abundance of oral-derived bacteria and higher levels of fungi in CF, features that are associated with decreased gut bacterial density in inflammatory bowel diseases. Our results define key differences in the gut microbiota during ontogeny in CF and suggest the potential for directed therapies to overcome developmental delays in microbiota maturation.

Longitudinal Profiling of the Intestinal Microbiome in Children with Cystic Fibrosis Treated with Elexacaftor-Tezacaftor-Ivacaftor

“…From shotgun metagenomic sequencing on 114 stool samples, we compared measures of microbiome taxonomy and diversity. In contrast to previously published CF microbiome datasets of infants (8, 22), our dataset of older children was dominated by the phylum Firmicutes with minimal Proteobacteria (Fig. 2A and Supplementary Dataset 1).…”

“…A consistent finding is that high levels of the phylum Proteobacteria, specifically the species Escherichia coli , define the infant CF intestinal microbiome (12, 22). The abundance of Proteobacteria decreases with age in young children with CF (14, 22). In our dataset of older children with CF, Proteobacteria comprised a minority of the identified bacteria (Fig.…”

“…The gastrointestinal microbiome influences whole-body physiology. CF intestinal microbiome abnormalities begin in infancy, diverging from healthy controls soon after birth (8,14,15,(21)(22)(23). Intriguingly, the microbiome of patients with CF resembles that of patients with IBD, a group with a characteristically perturbed intestinal microbiome (12,45,60).…”

“…Intriguingly, the microbiome of patients with CF resembles that of patients with IBD, a group with a characteristically perturbed intestinal microbiome (12,45,60). Considerable prior research has characterized the development of the CF intestinal microbiome in infants (8,(13)(14)(15)(21)(22)(23). Less information exists about the CF intestinal microbiome in children and adolescents (13,24,26,(61)(62)(63)(64)(65).…”

“…In infants with CF, delayed intestinal microbiome maturation has been shown to influence linear growth and immune programming (8,21). Among the most striking differences compared to healthy controls is the abundance of Proteobacteria, specifically Escherichia coli, and concomitant decrease in Bacteroidetes in infants with CF (8,12,(22)(23)(24). Furthermore, during acute CF pulmonary exacerbations, the intestinal microbiome is distinguishable from periods of respiratory stability (15,21,25).…”