Plant-based diets support health in several ways, including benefits for the gut, immune system, metabolism, and cardiovascular system. Part of that effect comes from fostering a diverse population of bacteria in the intestines. Scientists have long known that dietary fiber contributes to these benefits because gut microbes help break it down. Plants also contain colorful “phytochemicals” that help protect them from environmental threats and can influence human health. Even so, researchers are still working to understand exactly how gut bacteria process the many components of plant foods and how those interactions produce beneficial effects.
Two studies led by Ludwig Princeton’s Jenna AbuSalim and director Joshua Rabinowitz offer new insights into that process. One appears in the current edition of the Proceedings of the National Academy of Scienceswhile the other was published in nature metabolism in June. The first study found that plant fiber and certain plant proteins can change microbial metabolism in ways that increase beneficial metabolites and reduce harmful ones. The second demonstrated that several biologically important metabolites normally attributed to gut microbes can also be produced in substantial quantities by mammalian metabolism.
“There is growing interest across medical disciplines in manipulating the human microbiome or using its own metabolic products for therapy,” Rabinowitz said. “Diet holds great promise for controlling the microbiome and its products. But to design effective therapeutic interventions, we need to understand which aspects of diet control which microbial products.”
How plant foods change gut metabolites
In it PNAS In the study, Rabinowitz, AbuSalim and their colleagues examined how plant-based foods influence phenol metabolites. Gut bacteria create these compounds when they digest the amino acids tyrosine and phenylalanine, but the resulting metabolites can have very different health effects.
Phenylpropionate and hippuric acid are produced when bacteria process phenylalanine and are associated with gut health and healthy body weight. In contrast, p-cresol sulfate and phenol sulfate come from tyrosine and have been linked to worse outcomes in cancer patients, as well as systemic toxicity in people with kidney disease.
“Our studies showed that both fiber and nondigestible plant proteins, which we call ‘fiber-mimicking proteins’ or Prif, shift the balance of phenol metabolites from the harmful type made from tyrosine to the healthy variety derived from phenylalanine,” AbuSalim said.
Fiber has long been recognized as an important part of a healthy diet, but indigestible plant proteins have received much less attention. AbuSalim, Rabinowitz, and their colleagues discovered that these proteins are processed by gut microbes and can alter both microbiome composition and host metabolism. Working together with indigestible plant fiber, they can also change the metabolic activity of intestinal bacteria in ways that promote the production of beneficial phenols.
When intestinal bacteria resort to the lining of the intestine
To track where these compounds came from, the researchers labeled proteins with stable (non-radioactive) isotopes and followed their digestion in the mouse intestine. They found that “bad” phenols were produced when bacteria consumed host proteins, including proteins found in the mucosal lining of the intestine. The good phenols, on the other hand, came almost entirely from indigestible proteins in the diet (Prif).
The fiber reduced bacterial breakdown of the mucosal lining of the intestine, which in turn reduced the production of harmful phenols. Prif increased the amount of dietary protein reaching gut microbes, giving them more material to produce beneficial phenols.
“We believe that Prifs represent an emerging class of dietary nutrients that shape the composition of the gut microbiome and could have a powerful influence on metabolic health,” AbuSalim said.
“Food packaging may eventually include Prif just below the fiber,” Rabinowitz said.
Rethinking where gut metabolites come from
He nature metabolism The study focused on the origins of phenol metabolites, as well as indole metabolites, which are produced from the amino acid tryptophan. Like phenols, indoles are being studied for their possible therapeutic value.
Indole metabolites have been linked to a wide range of diseases, including inflammatory bowel disease, neurodegenerative disorders, and cancer. In cancer research, they have been found to affect processes including cancer metastasis and anti-tumor immune responses.
Scientists had generally assumed that phenols and indoles were produced solely by intestinal bacteria. AbuSalim, Rabinowitz and their colleagues decided to test that assumption. Researchers have been especially interested in dietary and probiotic approaches that could increase beneficial indole metabolites. But those strategies may need to be reconsidered if mammalian metabolism, and not microbes, is responsible for much of what circulates in the body.
Using isotope scanning in mice, rats, and human cells, the researchers found that mammalian metabolism can produce many indole and phenol metabolites on its own. These included important compounds such as indole-3-lactate and indole-3-acetate.
In mice, circulating levels of these metabolites remained high even after antibiotic treatment altered the microbiome. A similar pattern appeared in samples from patients taking antibiotics, including cancer patients. At the same time, metabolites produced exclusively by microbes, including indole-3-propionate and p-cresol sulfate, decreased after antibiotic treatment.
New leads for dietary and microbiome therapies
Together, the two studies provide a clearer picture of where phenol and indole metabolites come from and how they are produced. The findings could influence the development of therapies designed to increase or decrease specific metabolites.
They also add important details to scientists’ understanding of how diet interacts with the microbiome. Knowing which foods influence specific microbial products could help researchers design more precise dietary, probiotic or metabolic interventions.
“Beyond that,” Rabinowitz said, “a clearer picture of how different foods interact with the microbiome to modulate the production of bacterial metabolites will help improve the guidance that nutritionists and doctors can provide people for disease prevention and therapy.”
These studies were funded by the Ludwig Institute for Cancer Research, the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, the Princeton Alliance for Collaborative Research and Innovation, and Princeton University.
In addition to his position as Director of the Princeton branch of the Ludwig Institute for Cancer Research, Joshua Rabinowitz is a professor in the Department of Chemistry at the Lewis-Sigler Institute for Integrative Genomics and a member of the Rutgers Cancer Institute.