Digestion-resistant proteins support the healthy metabolite profiles associated with plant-based diets.
Plant-based diets are associated with both positive health outcomes and a diverse gut microbiome. Such diets alter the microbiome's metabolic outputs, including increasing phenylalanine-derived phenols associated with beneficial health outcomes (hippuric acid and 3-phenylpropionate), while decreasing tyrosine-derived phenols considered uremic toxins (phenol sulfate and p-cresol sulfate). The mechanisms linking plant eating to these phenol metabolites are not known. Plant-based foods are fiber and phytochemical rich. They also contain proteins that are resistant to host digestion and thus reach the gut microbiome. Here, we show that fiber and digestion-resistant protein work in concert to shift the phenol profile by altering gut microbiome nutrient supply. Through isotope-tracing studies, we reveal that host secreted proteins are a source for phenol sulfate and p-cresol sulfate, while digestion-resistant dietary protein is the source for hippuric acid and 3-phenylpropionate. Fiber decreases bacterial digestion of host secreted proteins (e.g., mucins) and thus suppresses tyrosine-derived phenol sulfate and p-cresol sulfate, whose levels correlate with the mucin-digesting bacterial family Oscillospiraceae. Digestion-resistant dietary protein increases bacterial access to phenylalanine and thereby boosts phenylalanine-derived hippuric acid and 3-phenylpropionate. Thus, digestion-resistant plant protein modulates microbiome metabolism and, together with fiber, supports healthy metabolite profiles associated with plant-based diets.