The Gut-Lung Axis in Critical Illness: Microbiome Composition as a Pr edictor of Mortality at Day 28 in Mechanically Ventilated Patients
Authors: Zhou Piaopiao , Zou Zhiqiang , Wu Wenwei , Zhang Hui , Wang Shuling , Tu Xiaoyan , Huang Weibin , Chen Cunrong , Zhu Shuaijun , Weng Qinyong , Zheng Shixiang 
Published: August 2023

Abstract
Background The gut-lung axis is a crucial interface in the complex interplay between microbial communities and their human hosts. Despite being two of the most important microbial populations in the human body, there is still a significant knowledge gap regarding the distinct variations between lung and gut microbiota and how they affect clinical outcomes in critically ill patients.Methods A retrospective observational cohort study was conducted in the intensive care unit (ICU) of an affiliated university hospital. Sequential specimens were collected from two anatomical sites, namely the respiratory and intestinal tracts, at two time points: within 48 hours and on day 7 after intubation. These specimens underwent comprehensive analysis to characterize microbial profiles and assess concentrations of fecal short-chain fatty acids (SCFAs) using 16S ribosomal RNA (rRNA) gene sequencing. Lung and gut microbial diversity, along with indicator species, served as the primary predictors in this investigation. The primary outcome of interest was survival status at 28 days after mechanical ventilation.Results A total of 247 specimens, comprising 123 bronchoalveolar lavage and 124 fecal samples, were meticulously collected from 62 critically ill patients in the intensive care unit (ICU). Our analysis revealed significant differences in the composition of respiratory and intestinal microflora between the deceased and survivor groups. Specifically, the alpha diversity of respiratory and intestinal microorganisms was significantly reduced in the deceased group with prolonged mechanical ventilation compared to the survivor group (p < 0.05). Furthermore, there were significant disparities in respiratory and intestinal β-diversity observed among the surviving and deceased groups (p < 0.05). Interestingly, Enterobacteriaceae exhibited enrichment in the respiratory tract (p < 0.05), while Enterococcaceae were enriched in the intestine (p < 0.05) in the deceased group. Notably, lower concentrations of short-chain fatty acids (SCFAs) were detected in the fecal samples from patients who succumbed. Leveraging a multivariate Cox regression analysis, we established robust associations between lung microbial diversity and Enterococcaceae abundance in the intestine with a risk ratio for mortality at day-28 adjusted for confounding factors (aHR = 0.773; CI:95%: [0.652 ~ 0.916], p = 0.003; and aHR = 1 .022; CI:95%: [1 .008 − 1 .037], p = O.OO2). These findings underscored potential clinical significance of microbial profiling to predict critical outcomes among ICU patients.Conclusion Following mechanical ventilation in critically ill patients within the ICU, we observed a significant decline in respiratory microbial diversity, accompanied by an imbalance in the intestinal flora, resulting in the predominant proliferation of Enterococcaceae. This dysbiotic shift holds predictive value for adverse clinical outcomes. Furthermore, the levels of short-chain fatty acids (SCFAs) serve as an indicator of the balance between commensal and pathogenic flora within the gut, signifying its protective role against respiratory diseases. Such insights could pave the way for future strategies aimed at mitigating adverse outcomes in critically ill patients.