Altered Stool Microbiota of Infants with Cystic Fibrosis Shows a Reduction in Genera Associated with Immune Programming from Birth

Abstract

Previous work from our group indicated an association between the gastrointestinal microbiota of infants with cystic fibrosis (CF) and airway disease in this population. Here we report that stool microbiota of infants with CF demonstrates an altered but largely unchanging within-individual bacterial diversity (alpha diversity) over the first year of life, in contrast to the infants without CF (control cohort), which showed the expected increase in alpha diversity over the first year. The beta diversity, or between-sample diversity, of these two cohorts was significantly different over the first year of life and was statistically significantly associated with airway exacerbations, confirming our earlier findings. Compared with control infants, infants with CF had reduced levels of Bacteroides, a bacterial genus associated with immune modulation, as early as 6 weeks of life, and this significant reduction of Bacteroides spp. in the cohort with CF persisted over the entire first year of life. Only two other genera were significantly different across the first year of life: Roseburia was significantly reduced and Veillonella was significantly increased. Other genera showed differences between the two cohorts but only at selected time points. In vitro studies demonstrated that exposure of the apical face of polarized intestinal cell lines to Bacteroides species supernatants significantly reduced production of interleukin 8 (IL-8), suggesting a mechanism whereby changes in the intestinal microbiota could impact inflammation in CF. This work further establishes an association between gastrointestinal microbiota, inflammation, and airway disease in infants with CF and presents a potential opportunity for therapeutic interventions beginning in early life. IMPORTANCE There is growing evidence for a link between gastrointestinal bacterial communities and airway disease progression in CF. We demonstrate that infants with CF ≤1 year of age show a distinct stool microbiota versus that of control infants of a comparable age. We detected associations between the gut microbiome and airway exacerbation events in the cohort of infants with CF, and in vitro studies provided one possible mechanism for this observation. These data clarify that current therapeutics do not establish in infants with CF a gastrointestinal microbiota like that in healthy infants, and we suggest that interventions that direct the gastrointestinal microbiota closer to a healthy state may provide systemic benefits to these patients during a critical window of immune programming that might have implications for lifelong health.

The Cross-Talk Between Gut Microbiota and Lungs in Common Lung Diseases

“…Increasing evidence shows a link between gastrointestinal microbiota and progression of lung disease in cystic fibrosis (Schippa et al, 2013;Li and Somerset, 2014;Nielsen et al, 2016;Rogers et al, 2016;Burke et al, 2017;Fouhy et al, 2017) (Figure 4). In infants with cystic fibrosis, alpha diversity was not increased over the first year of life as expected in control cohort, while the beta diversity of these two cohorts was significantly different, associating with airway exacerbations (Antosca et al, 2019). Compared with controls, levels of Bacteroides, a bacterial genus related with immune modulation, were decreased over the first year of life.…”

“…Compared with controls, levels of Bacteroides, a bacterial genus related with immune modulation, were decreased over the first year of life. Bacteroides species supernatants could reduce the generation of IL-8 from intestinal cell lines, indicating the alteration in the gut microbiota influences the inflammation in cystic fibrosis (Antosca et al, 2019). During this critical window of immune programing, interventions targeting to establish a healthy state of gastrointestinal microbiota in infants with cystic fibrosis may be beneficial for lifelong health (Antosca et al, 2019).…”

The intestinal virome in children with cystic fibrosis differs from healthy controls

“…Dysfunction of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) results in an altered intestinal milieu with proposed mechanisms including: (i) reduced bicarbonate secretion and low intestinal pH, (ii) thick and inspissated mucus, (iii) a lack of endogenous pancreatic enzymes, (iv) delayed intestinal transit and (v) possibly impaired innate immunity [1,2]. These mechanisms along with treatment and diet regimens [3] likely result in intestinal bacterial dysbiosis and inflammation, which have repeatedly been reported in CF [4][5][6][7][8][9][10][11][12].…”

“…Intestinal inflammation in CF may have significant clinical relevance due to its link with growth and nutrition [9,13,14]. In children with CF compared to healthy controls (HC), intestinal bacterial profiles are often characterised by an increased abundance of Proteobacteria (Escherichia coli, Shigella, Enterobacter) and a decreased abundance of Bacteroidetes (Bacteroides, Alistipes) and Firmicutes (Faecalibacterium prausnitzii) [4,6,8,12]. It has been suggested that in children with CF, enteric fat abundance (increased as a result of diet regimens and a lack of endogenous pancreatic enzymes) selects for pro-inflammatory gut microbiota [6].…”

Age and environmental exposures influence the fecal bacteriome of young children with cystic fibrosis

“…Infants with CF demonstrate early pathology including progressive lung disease, recurrent sinorespiratory infections and gastrointestinal complications 1 . Emerging evidence suggests that one contributor to early CF disease is the establishment of persistent shifts in intestinal and respiratory microbial populations that can affect clinical outcomes or symptoms (dysbiosis) compared with infants without CF 2‐16 . Within CF there can also be a gradient of dysbiosis associated with worsened outcomes, as progressive intestinal dysbiosis distinguishes between CF infants with normal and poor linear growth 17 .…”