AUTHOR=Ren Yuan , Zhang Yao , Cheng Yanan , Qin Hao , Zhao Hui 

TITLE=Genetic liability of gut microbiota for idiopathic pulmonary fibrosis and lung function: a two-sample Mendelian randomization study

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2024.1348685

DOI=10.3389/fcimb.2024.1348685

ISSN=2235-2988

ABSTRACT=<sec><title>Background</title><p>The microbiota-gut-lung axis has elucidated a potential association between gut microbiota and idiopathic pulmonary fibrosis (IPF). However, there is a paucity of population-level studies with providing robust evidence for establishing causality. This two-sample Mendelian randomization (MR) analysis aimed to investigate the causal relationship between the gut microbiota and IPF as well as lung function.</p></sec><sec><title>Materials and methods</title><p>Adhering to Mendel’s principle of inheritance, this MR analysis utilized summary-level data from respective genome-wide association studies (GWAS) involving 211 gut microbial taxa, IPF, and lung function indicators such as FEV<sub>1</sub>, FVC, and FEV<sub>1</sub>/FVC. A bidirectional two-sample MR design was employed, utilizing multiple MR analysis methods, including inverse variance-weighted (IVW), weighted median, MR-Egger, and weighted mode. Multivariable MR (MVMR) was used to uncover mediating factors connecting the exposure and outcome. Additionally, comprehensive sensitivity analyses were conducted to ensure the robustness of the results.</p></sec><sec><title>Results</title><p>The MR results confirmed four taxa were found causally associated with the risk of IPF. <italic>Order Bifidobacteriales</italic> (OR=0.773, 95% CI: 0.610–0.979, p=0.033), <italic>Family Bifidobacteriaceae</italic> (OR=0.773, 95% CI: 0.610–0.979, p=0.033), and <italic>Genus RuminococcaceaeUCG009</italic> (OR=0.793, 95% CI: 0.652–0.965, p=0.020) exerted protective effects on IPF, while <italic>Genus Coprococcus2</italic> (OR=1.349, 95% CI: 1.021–1.783, p=0.035) promote the development of IPF. Several taxa were causally associated with lung function, with those in <italic>Class Deltaproteobacteria, Order Desulfovibrionales, Family Desulfovibrionaceae, Class Verrucomicrobiae</italic>, <italic>Order Verrucomicrobiales</italic> and <italic>Family Verrucomicrobiaceae</italic> being the most prominent beneficial microbiota, while those in <italic>Family Lachnospiraceae, Genus Oscillospira</italic>, and <italic>Genus Parasutterella</italic> were associated with impaired lung function. As for the reverse analysis, MR results confirmed the effects of FEV<sub>1</sub> and FVC on the increased abundance of six taxa (<italic>Phylum Actinobacteria, Class Actinobacteria, Order Bifidobacteriales, Family Bifidobacteriaceae, Genus Bifidobacterium</italic>, and <italic>Genus Ruminiclostridium9</italic>) with a boosted level of evidence. MVMR suggested monounsaturated fatty acids, total fatty acids, saturated fatty acids, and ratio of omega-6 fatty acids to total fatty acids as potential mediating factors in the genetic association between gut microbiota and IPF.</p></sec><sec><title>Conclusion</title><p>The current study suggested the casual effects of the specific gut microbes on the risk of IPF and lung function. In turn, lung function also exerted a positive role in some gut microbes. A reasonable dietary intake of lipid substances has a certain protective effect against the occurrence and progression of IPF. This study provides novel insights into the potential role of gut microbiota in IPF and indicates a possible gut microbiota-mediated mechanism for the prevention of IPF.</p></sec>