Microbiota–Muscle/–Immune Interactions in Rhesus Macaque under Simulated Weightlessness Revealed by Integrated Multi-Omics Analysis

Abstract BackgroundLong-term exposure to microgravity during spaceflight has adverse effects on human health including muscle atrophy, impaired immune function, and alterations in gut microbiome profile. Gut microorganisms influence a wide range of host biological processes, but their interactions with skeletal muscle and the immune system under microgravity are not known. MethodsRhesus macaques (Macaca mulatta) were subjected to -6° head-down tilted bed rest (HDBR) for 6 weeks. Fecal samples, skeletal muscle tissue, and peripheral blood mononuclear cells (PBMCs) were collected for metagenomic, metabolomic, and transcriptomic analyses respectively and further integrated for a multi-omics analysis.ResultsHDBR resulted in significantly altered taxon abundance in 1 class, 5 orders, 11 families, 55 genera, and 122 species of microbes. We also identified the significantly changed metabolites in atrophied muscles, including some crucial metabolites (such as L-alanine and L-carnitine) and hub metabolites (such as pyridoxamine and epinephrine) involved in energy metabolism. Transcriptomic analysis of PBMCs revealed genes related to leukocyte activation, differentiation, and interleukin-2 production that were differentially expressed as a result of HDBR exposure. By integrating multi-omics analysis, we identified 3 bacterial genera (Klebsiella, Kluyvera, and Bifidobacterium) that were closely associated with immune dysfunction and 5 (including Oligella, Sporosarcina, Citrobacter, Weissella, and Myroide) that were associated with abnormal metabolism of amino acids in atrophied muscles induced by HDBR. Of note, the reduced abundance of butyrate-producing colon bacteria Eubacterium, Roseburia and their cross-feeding bacteria Bifidobacteria may contribute to both the impaired immune function and muscle atrophy caused by HDBR.ConclusionsWe first reported the HDBR-associated changes in gut microbiota composition, metabolomics of skeletal muscle and transcripts of PBMCs in non-human primate. Particularly, we revealed the underlying microbiota-muscle and microbiota-immune interactions during simulated microgravity, implicating that modulation of gut microbiota may represent a new strategy in enhancing crewmembers’ health and safety during long-term space expeditions.