Plant-based diets are linked to better gut, immune, metabolic and cardiovascular health, in part because fiber nourishes a diverse community of gut bacteria. But what happens when those microbes run short of fiber? Two new studies led by Princeton researchers at the Ludwig Princeton branch — Jenna AbuSalim and Director Joshua Rabinowitz — offer a striking answer: gut bacteria may start consuming the proteins in the protective mucus lining of the gut, and the compounds they produce in the process can be harmful.
In the first study, published in the current issue of the Proceedings of the National Academy of Sciences, the team examined phenol metabolites — compounds gut bacteria create when they digest the amino acids tyrosine and phenylalanine. The two pathways have very different health consequences: phenylpropionate and hippuric acid (from phenylalanine) are associated with gut health and healthy body weight, while p-cresol sulfate and phenol sulfate (from tyrosine) have been linked to worse outcomes in cancer patients and systemic toxicity in people with kidney disease.
Using stable isotope labeling, the researchers followed the digestion of proteins in the mouse gut. The "bad" phenols were produced when bacteria consumed host proteins — including proteins in the gut's mucus lining. The "good" phenols, by contrast, came almost entirely from indigestible plant proteins, which the team calls "Proteins Imitating Fiber," or Prif. Fiber reduced the bacterial breakdown of the mucus lining, lowering the production of harmful phenols; Prif increased the dietary protein reaching gut microbes, giving them more material to make the beneficial compounds.
"We think Prifs represent an emerging class of dietary nutrients that shape the composition of the gut microbiome and could have a far-reaching influence on metabolic health," AbuSalim said. "Food packaging may eventually list Prif right below fiber," added Rabinowitz.
The second study, published in Nature Metabolism in June, challenged another common assumption: that phenol and indole metabolites are produced only by gut bacteria. Using isotope tracing in mice, rats and human cells, the researchers found that mammalian metabolism can produce many of these compounds on its own, including indole-3-lactate and indole-3-acetate. In mice, circulating levels stayed high even after antibiotics disrupted the microbiome, and the same pattern appeared in samples from patients taking antibiotics. Only metabolites made exclusively by microbes — such as indole-3-propionate and p-cresol sulfate — declined after antibiotic treatment.
Together, the two studies clarify where these metabolites come from and how they are produced, which could shape therapies designed to raise or lower specific compounds. They also add detail to how diet interacts with the microbiome. "A clearer picture of how different foods interact with the microbiome to modulate the production of bacterial metabolites will help sharpen the guidance nutritionists and doctors can give to people for disease prevention and therapy," Rabinowitz said.
