New Insights Into the Microbiome and Its Metabolites Illuminate Health

Plant-based diets can reshape the gut ecosystem, promoting health through a spectrum of fibers and plant-derived compounds. Yet the precise mechanisms by which intestinal microbes convert dietary ingredients into beneficial—rather than harmful—metabolites have remained difficult to pin down. Two related studies from Ludwig Princeton’s Jenna AbuSalim and Director Joshua Rabinowitz now clarify how diet influences key metabolite pathways, with implications for microbiome-targeted therapies.

In one study, published in Proceedings of the National Academy of Sciences (PNAS), the researchers examined phenol metabolites generated after gut processing of the amino acids tyrosine and phenylalanine. These phenols split into two functional classes: “healthful” phenylpropionate and hippuric acid versus “harmful” p-cresol sulfate and phenol sulfate, compounds associated with worse outcomes in cancer patients and increased toxicity in kidney disease.

The work shows that both plant fiber and indigestible plant proteins—termed “proteins imitating fiber” (Prif)—reprogram microbial metabolism. Specifically, they shift the balance of phenol production away from tyrosine-derived metabolites and toward phenylalanine-derived metabolites. AbuSalim and colleagues link this outcome to coordinated changes in gut microbial composition and activity.

To determine metabolite origins, the team used stable isotope–labeling of proteins and tracked digestion in mouse guts. The experiments indicated that many of the harmful phenols arise largely from bacterial consumption of host proteins, including those present in the gut mucus layer. By contrast, the healthful phenols derive primarily from ingested Prif.

Fiber also plays an inhibitory role by suppressing bacterial catabolism of gut mucus, thereby reducing the substrate available for producing harmful phenols. Meanwhile, Prif increases the flow of dietary protein to microbes, enhancing pathways that generate the beneficial phenol set.

A second study, published in Nature Metabolism in June, challenges the assumption that circulating indole and phenol metabolites come exclusively from microbes. Using isotope tracing across mice, rats, and human cells, the researchers found that mammalian metabolism can generate many physiologically important indole and phenol metabolites, including indole-3-lactate and indole-3-acetate.

These findings carried a crucial antibiotic test: circulating metabolite levels of mammalian-generated products remained stable after microbiome disruption, whereas microbial-specific metabolites declined. The pattern was also observed in patient samples, including individuals receiving antibiotics.

Taken together, the studies refine how diet and host biochemistry jointly determine metabolite profiles. Rabinowitz emphasizes that understanding which dietary inputs control particular microbial outputs will improve nutrition-based guidance and future therapeutic strategies that aim to modulate microbiome-derived—or host-derived—metabolites.