Impact of Dietary Macromolecular Quantity and Quality on Host Assimilation of Microbially Derived Essential Amino Acids

Background Protein is the main structural and functional component of cells making it crucial for the survival of all living organisms. Wild mammalian herbivores and omnivores often consume diets deficient in the amount of protein required to grow and maintain homeostasis. To compensate, mammals likely rely on their gut microbiota to synthesize essential amino acids (AA _ESS ) needed for survival. In this study, we investigated whether deer mice ( Peromyscus maniculatus ) utilized AA _ESS synthesized by their gut-associated microbiota with a series of controlled feeding experiments with either a synthetic or semi-natural diet that varied in the type (quality) and quantity of protein and carbohydrates mice may encounter in the wild. Our study combines genetic sequencing (16S rRNA gene and shotgun metagenomic) with compound-specific carbon isotope (d ¹³ C) analysis to trace the origin of AA _ESS used by mammals to build their skeletal muscle. Results Results show that dietary macromolecular quality, in addition to quantity, plays a substantial role in host assimilation of microbially derived AA _ESS and drives microbial genomic potential for AA _ESS biosynthesis. Mice fed diets limited in dietary protein received greater contributions of AA _ESS of microbial origin, especially branched-chain amino acids (valine, leucine, isoleucine), lysine, and threonine. Gut microbial populations with the genetic potential for AA _ESS biosynthesis were differentially abundant in mice with substantial contributions of microbially derived AA _ESS in their skeletal muscle. Significant microbial contributions of AA _ESS in host muscle were observed in the low (2.5%) protein synthetic diet, while a larger suite of microbial AA _ESS contributed to tissue synthesis in mice fed the semi-natural diet across all protein treatments (2.5–10%). Conclusions Our study highlights the crucial and likely pervasive role the gut microbiome plays in host protein metabolism, especially in wild herbivorous and omnivorous mammals facing dietary protein limitation. Critical interactions between mammals and their associated gut microbiome are often difficult to disentangle. Our work provides a framework for doing so by uniquely combining genetic and isotopic data to advance our understanding of animal physiology and ecology.