The Gut–Lung Axis: What’s below the Diaphragm Is Also Important

The gut microbiota play a critical role in mammalian host immune cell development (1). Although commensal microbes in the gut are known to be critical for maintaining local immune homeostasis, there is increasing recognition that disruption to normal gut microbiota alters immunity in distant sites such as the lung in what has become known as the gut–lung axis (2, 3). For example, evidence in the literature suggests that the biodiversity of intestinal microbiota in infancy inversely correlates with risk of allergic airway disease in children (4, 5), whereas in adults there appears to be a correlation between chronic obstructive pulmonary disease and inflammatory bowel disease, although the biology underlying this link remains ill defined (6). Despite accumulating evidence from epidemiological observations, experimental work on the gut–lung axis is just beginning.

In this issue of the Journal, Zhang and colleagues (pp. 680–694) report on the role of the gut–lung axis in a murine model of zinc oxide nanoparticle (ZnONP)-induced lung injury (7). The authors show that intratracheal administration of ZnONP was followed by the development of acute lung injury (ALI) and that depletion of gut microbiota with enteral antibiotics before ZnONP exposure increased the severity of the injury. Intriguingly, restoration of the microbiota in antibiotic-treated mice by fecal microbial transplantation (FMT) attenuated ZnONP-ALI, providing evidence that the gut–lung axis may play a critical role in ZnONP-induced lung inflammation. The authors then investigated the potential mechanistic role of bacterial metabolic products in the gut–lung axis. Interrogation of short-chain fatty acids (SCFAs) in plasma, which are metabolic products of gut flora, revealed significant decreases in propionic acid in this injury model; correspondingly, supplementation with sodium propionate ameliorated ALI caused by ZnONP. Finally, the authors provide in vitro data suggesting that propionic acid signaling through GPR43 (G-coupled protein receptor 43) on macrophages protects against oxidative stress and modulates cytokine production, positioning SCFA as a potential link between gut microbiota and lung mucosal inflammation.

The gut–lung axis in ALI is an emerging concept that remains poorly understood. Evidence in the literature suggests that gut microbiota may play a protective role in infectious models of lung injury (8, 9). Ichinohe and colleagues previously showed that depletion of gut microbiota with an antibiotic cocktail resulted in impaired viral clearance in a murine model of influenza infection (9). Microbiota depletion, specifically of neomycin-sensitive bacteria, impaired the proper activation of inflammasomes, dendritic cell migration, and T cell priming in the lung. In another study, Schuijt and colleagues reported that depletion of gut microbiota increased bacterial dissemination, inflammation, and mortality in mice infected with Streptococcus pneumoniae, and this increased susceptibility was reverted by FMT (8). However, the precise cellular or chemical messenger that links the gut to the lung in these infectious lung injury models remains elusive.

SCFAs, as metabolites of gut microbiota, have been implicated as potential chemical messengers in the gut–lung axis. SCFAs regulate immune responses through engagement with GPRs, including GPR41, GPR43, and GPR109A (3, 10). Depending on the downstream signaling, these receptors promote inflammation or exert an antiinflammatory effect. Interestingly, results from Zhang and colleagues position propionic acid, an endogenous metabolite that is primarily gut derived, as a potential regulator of sterile lung injury through antiinflammatory effects of GPR43 signaling.

Both sterile and infectious lung injuries suggest restoration of normal gut microbiota as beneficial. However, their mechanisms appear distinct. In this study, propionic acid and FMT dampened inflammation. In infectious models with respiratory viruses, however, gut microbiota were required for optimal innate and adaptive immune responses (11). In contrast, O’Dwyer and colleagues observed improved survival and increased lung regulatory T cells expressing forhead box P3 (Foxp3⁺ Tregs) in germ-free mice compared with conventional mice after bleomycin injury (12). Thus, the gut–lung axis is a complex, bidirectional process where modulation by gut microbiota is highly context dependent and may lead to divergent outcomes.

One limitation in this study is that ALI from ZnONP exposure impacts a narrowly defined population, and the protective role of propionic acid in other models is unknown. Another important limitation to consider is that the lung microbiota were likely affected by antibiotics in this study. There is accumulating evidence in the literature that implicates the importance of lung microbiota in clinical outcomes in acute and chronic lung diseases (12, 13). How antibiotics influenced lung microbiota in this model was not assessed. Nevertheless, this study adds novel insights to an ever-growing body of literature around the gut–lung axis, highlighting the importance of the gut in lung health.