The Gut-Lung Axis in Cystic Fibrosis

Abstract

Cystic Fibrosis (CF) is a heritable, multi-organ disease that impacts all tissues that normally express CFTR protein. While importance of the airway microbiota has long been recognized, the intestinal microbiota has only recently been recognized as an important player in both intestinal and lung health outcomes for persons with CF (pwCF). Here, we summarize current literature related to the gut-lung axis in CF, with a particular focus on three key ideas: Mechanisms through which microbes influence the gut-lung axis, drivers of microbiota alterations, and the potential for intestinal microbiota remediation.

Intestinal Bacteroides Modulates Systemic Inflammation and the Microbial Ecology in a Mouse Model of CF: Evidence for Propionate and other Short Chain Fatty Acids Reducing Systemic Inflammatory Cytokines

“…We did not detect any differences in the levels of calprotectin, a frequently used marker of intestinal inflammation, in the stool from mice +/-Bacteroides. While studies have shown that gut microbiome composition is associated with lung health outcomes, evidence is mixed as to whether intestinal calprotectin is correlated with systemic outcomes (Price & O'Toole, 2021). The results reported here support the idea that while calprotectin may be a useful marker for local inflammation, it may not be as useful for assessing inflammation outside of the gut or for a tool to explore the gut-lung axis in mice.…”

“…The intestinal microbial composition has been linked to negative lung health outcomes in several CF clinical studies (Antosca et al, 2019;Bruzzese et al, 2014;Bruzzese et al, 2004;Burke et al, 2017;Coffey et al, 2019;de Freitas et al, 2018;Hayden et al, 2020;Hoen et al, 2015;Madan et al, 2012;Price & O'Toole, 2021). A recent study by Meeker et al found that microbial colonization of germ-free CF mice (CFTR S489X) in part drives abnormal immune development (Meeker et al, 2020), demonstrating that dysbiosis in the CF intestine may be one driver of increased inflammation in pwCF.…”

“…The human gut microbiome is comprised of diverse microorganisms that influence a broad range of host health outcomes, including normal immune development and function (Budden et al, 2017). Cross-talk between the gut and the lung has been referred to as the "gut-lung axis", and this connection between gut and lung has been proposed to play a role in a number of airway diseases, including CF (Price & O'Toole, 2021). Both infants and adults with CF have a dysbiotic gut microbiome (Antosca et al, 2019;Burke et al, 2017;Fouhy et al, 2017;Hayden et al, 2020;Hoffman et al, 2014;Kristensen et al, 2020), and there is a significant correlation between gut microbiome beta-diversity for infants and children with CF and the risk of airway exacerbation in this population (Antosca et al, 2019;Hoen et al, 2015).…”

Insights from shotgun metagenomics into bacterial species and metabolic pathways associated with NAFLD in obese youth

“…B. thetaiotamicron has been shown to reduce diet-induced body weight gain and adiposity in mice and was shown to be in lower abundance in obese human subjects compared to healthy (23). O. splanchnicus, a species within the family Odoribacteriaceae which was shown to be elevated in the NAFLD-negative group, has been associated with reduced incidence of NAFLD (24), cystic brosis (25), and in ammatory bowel disease (26) in previous studies. This species was identi ed as a major driver in PCA and its bacterial family was identi ed via ANCOM analysis.…”

Immunoglobulin A Mucosal Immunity and Altered Respiratory Epithelium in Cystic Fibrosis

“…The lung-gut axis is the possible influence of the gut microbiota on the course of the lung disease (and vice-versa) and was recently reviewed in CF by Price et al [ 131 ]. For example, gut microbiome modifications were associated in children with exacerbations and with Pseudomonas colonization [ 132 ].…”