Hypobaric hypoxia, and dietary protein and fat intakes have been independently associated with an altered gastrointestinal (GI) environment and gut microbiota, but little is known regarding host-gut microbiota interactions at high altitude (HA) and the impact of diet macronutrient composition. This study aimed to determine the effect dietary protein:fat ratio manipulation on the gut microbiota and GI barrier function during weight loss at high altitude (HA), and to identify associations between the gut microbiota and host responses to HA. Following sea level (SL) testing, 17 healthy males were transported to HA (4300m) and randomly assigned to consume provided standard-protein (SP; 1.1g/kg/d, 39% fat) or higher-protein (HP; 2.1g/kg/d, 23% fat) carbohydrate-matched hypocaloric diets for 22d. Fecal microbiota composition and metabolites, GI barrier function, GI symptoms, and acute mountain sickness (AMS) severity were measured. Macronutrient intake did not impact fecal microbiota composition, had only transient effects on microbiota metabolites, and had no effect on increases in small intestinal permeability, GI symptoms, and inflammation observed at HA. AMS severity was also unaffected by diet, but in exploratory analyses was associated with higher SL relative abundance of Prevotella, a known driver of inter-individual variability in human gut microbiota composition, and greater microbiota diversity after AMS onset. Findings suggest that the gut microbiota may contribute to variability in host responses to HA independent of the dietary protein:fat ratio, but should be considered preliminary and hypothesis-generating due to the small sample size and exploratory nature of analyses associating the fecal microbiota and host responses to HA.

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