Abstract
Short-chain fatty acids (SCFA) are important dietary and microbiome metabolites that can have roles in gut immunity as well as further afield. We previously observed that gut microbiome alteration via antibiotics led to attenuated lung inflammatory responses. The rationale for this study was to identify gut microbiome factors that regulate lung immune homeostasis. We first investigated key factors within mouse colonic lumen filtrates (CLF) which could elicit direct inflammatory effects in vitro. We identified lipopolysaccharide (LPS) and SCFAs as key CLF ingredients whose levels and inflammatory capacity changed after antibiotic exposure in mice. Specifically, the SCFA propionate appeared to be a key regulator of LPS responses in vitro. Elevated propionate: acetate ratios, as seen in CLF after antibiotic exposure, strongly blunted inflammatory responses in vitro. In vivo, exposure of lungs to high dose propionate, to mimic how prior antibiotic exposure changed SCFA levels, resulted in diminished immune containment of Staphylococcus aureus pneumonia. Finally, we discovered an enrichment of propionate-producing gut bacteria in mice with reduced lung inflammation following lung ischemia reperfusion injury in vivo. Overall, our data show that propionate levels can distinctly modulate lung immune responses in vitro and in vivo and that gut microbiome increased production of propionate is associated with reduced lung inflammation.
Highlights
The human body coexists with a vast commensal microbiome that is increasingly recognized to play important roles in human health, physiology, and disease (Cho and Blaser, 2012; Shreiner et al, 2015; Sender et al, 2016; Alverdy and Krezalek, 2017; Young, 2017)
After previously reporting that antibiotic treatment led to diminished inflammatory changes in the mouse lung following lung ischemia reperfusion (Prakash et al, 2015), we tested whether colon contents of mice contained inflammationinducing factors
The main findings of these studies indicate that levels of microbiome-derived metabolites, propionate, can influence lung immune and inflammatory responses in vivo and in vitro
Summary
The human body coexists with a vast commensal microbiome that is increasingly recognized to play important roles in human health, physiology, and disease (Cho and Blaser, 2012; Shreiner et al, 2015; Sender et al, 2016; Alverdy and Krezalek, 2017; Young, 2017). Gut Propionate Regulates Lung Immunity over the life cycle of the human host (after early postnatal colonization). These symbiotic organisms may serve purposes besides food digestion and vitamin production, such as during immune education and host defense. While it may be conceptually challenging at first to explain how gut commensal microbial communities affect physiological processes in distant organ systems, a few studies have supported this paradigm (Trompette et al, 2014; Vieira et al, 2015, 2016)
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