Gut microbiome–metabolome interactions during varied low-carbohydrate food consumption

Low-carbohydrate (LC) foods have been associated with weight loss, insulin resistance, and reduced inflammation. Gut microbes may drive these effects by changing the host’s immune and metabolic state, yet the optimal replacement strategies (e.g., protein vs. fat) and the biochemical impacts are still uncertain. Thus, we conducted a randomized cross-over study in canines (n = 35) using a high-carbohydrate food for 4 wk, followed by two 5-wk intervals of LC foods replacing carbohydrates with fat or protein. Feces and blood samples collected after each interval underwent metabolome profiling, as well as shotgun metagenomic and metatranscriptomic sequencing from feces. We observed strong associations between food and overall fecal and serum chemical and gut microbial composition. Bifidobacterium spp. were significantly reduced during consumption of either LC food, whereas many species from Firmicutes increased. In addition to broad taxonomic changes, we also found that several microbially associated metabolites (tryptophan derivatives, secondary bile acids, and short-chain fatty acid fermentation) shifted in abundance in response to differing LC foods. Broadly, we also identified a strong trend toward decreased amino acids in the feces of dogs fed LC foods, particularly the high fat food. Coupled with decreased fecal dipeptide levels and increased fecal ammonia, these findings indicate a broad metabolic shift within the gut microbiome, potentially toward protein catabolism. Together, the data suggest that diverse carbohydrate replacement strategies induce extensive gut reprogramming, with some changes dependent on whether carbohydrate energy was replaced with fat or protein.