Eating more plants is widely associated with better health, but scientists are still uncovering the exact biological mechanisms behind these benefits. New research suggests that dietary fiber is only part of the story. Certain plant proteins that resist digestion may also play a surprisingly important role in shaping gut bacteria and determining whether they produce beneficial or potentially harmful substances.
Plant-based diets support digestive health, immune function, metabolism, and cardiovascular health. One reason for these widespread systemic benefits is that nutrient-dense plants help maintain a diverse community of microorganisms living in the human intestines, collectively known as the gut microbiome. Many of these resident bacteria are highly beneficial, assisting the human body by breaking down food components that our own digestive systems cannot process independently.
Fiber is particularly important in this ecosystem because it provides primary nourishment for gut microbes. Plants also contain various phytochemicals, which are natural substances that often give fruits and vegetables their vibrant colors and help protect the plants from environmental threats in nature. These bioactive compounds can also contribute significantly to human health. Yet, researchers have only recently begun to understand the complicated chemical interactions that occur when gut bacteria digest complex plant foods.
Two pivotal studies led by Jenna AbuSalim and Joshua Rabinowitz, director of the Princeton Branch of the Ludwig Institute for Cancer Research, provide crucial new insights into these processes. One study, published in the Proceedings of the National Academy of Sciences, demonstrates how plant fiber and certain specialized proteins influence gut bacteria to favor the production of beneficial compounds over potentially harmful ones. The other study, published in Nature Metabolism, challenges the longstanding scientific belief that many important chemical compounds circulating in the human body originate exclusively from intestinal microbes.
"There’s growing interest across medical disciplines in manipulating the human microbiome or using its metabolic products themselves for therapy," said Rabinowitz, who is also a professor in the Department of Chemistry and the Lewis-Sigler Institute for Integrative Genomics at Princeton University, as well as a member of the Rutgers Cancer Institute. "Diet holds great promise for controlling the microbiome and its outputs. But to devise effective therapeutic interventions, we need to understand what aspects of the diet control which microbial outputs."
How Plant Foods Change the Chemicals Your Gut Produces
In the PNAS study, researchers closely examined a group of substances called phenol metabolites. Metabolites are chemical byproducts formed when the body or its resident microorganisms break down and process various nutrients. Some of these metabolites are essential for normal biological functions, while others can contribute to significant health problems when they accumulate in high concentrations.
The phenol metabolites investigated by the research team are produced when gut bacteria process two specific amino acids: tyrosine and phenylalanine. Although amino acids serve as the foundational building blocks of proteins, the ultimate compounds they produce via microbial action can have vastly different effects on human health.
Two distinct metabolites derived from phenylalanine—specifically phenylpropionate and hippuric acid—are closely associated with maintaining a healthy body weight and overall better gut health. In stark contrast, two compounds derived from tyrosine, known as p-cresol sulfate and phenol sulfate, have been linked directly to worse clinical outcomes in cancer patients and harmful effects throughout the body in individuals suffering from kidney disease.
The researchers wanted to understand whether different individual components of plant foods could actively influence which of these divergent substances gut microbes choose to produce.
"Our studies showed that both the fiber and indigestible proteins from plants—which we call ‘proteins imitating fiber,’ or Prif—shift the balance of phenol metabolites from the harmful kind made from tyrosine to the healthful variety derived from phenylalanine," said AbuSalim.
An Overlooked Plant Protein Works Alongside Fiber
Although the health benefits of dietary fiber have been studied extensively for decades, scientists have historically paid much less attention to plant proteins that pass through the human digestive system without being fully broken down by natural enzymes.
The researchers discovered that these indigestible proteins, termed Prifs, successfully reach the lower gut microbiome and serve as alternative structural material for bacterial metabolism. In doing so, they actively influence which microbial species thrive in the intestines and which specific chemical compounds are subsequently produced.
Importantly, these proteins do not work in isolation. They cooperate synergistically with plant fiber to change how gut bacteria process incoming nutrients, effectively shifting their metabolic activity away from destructive pathways and toward the production of beneficial phenol metabolites.
This discovery suggests that the nutritional value of plant foods may depend on far more than their familiar concentrations of fiber, vitamins, and minerals. The exact amount and type of protein that escapes human digestion could also help determine how a specific meal influences the health and composition of the gut microbiome.
When Gut Bacteria Run Low on Fiber, They May Feed on Your Gut’s Protective Mucus
One of the most intriguing findings of the research concerns where gut bacteria obtain the raw materials used to produce harmful metabolites when their preferred nutrients run low.
To investigate this phenomenon, the researchers labeled proteins with stable, non-radioactive isotopes. This advanced scientific technique allowed them to track precisely where the proteins traveled and how they were processed inside the digestive systems of mice. This method gives molecules a detectable chemical signature without rendering them radioactive or disrupting their natural behavior.
The controlled experiments revealed a striking and important difference between the biological sources of beneficial versus harmful phenols.
The potentially harmful phenols came primarily from gut bacteria breaking down proteins belonging to the host organism, including structural proteins found in the vital mucus layer that coats the inside of the intestines. This protective mucus layer helps separate intestinal microbes from the delicate cells lining the gut wall and forms a critical part of the body’s natural defense systems against infection and inflammation.
Meanwhile, the beneficial phenols were produced almost entirely from indigestible proteins supplied directly by the food consumed.
Fiber helped suppress the bacterial breakdown of the gut’s protective mucus, successfully reducing the production of harmful phenols. The indigestible plant proteins, or Prifs, in turn supplied an alternative source of dietary protein to the gut bacteria, encouraging them to produce healthful compounds instead.
Together, these findings reveal two complementary ways that plant foods can powerfully influence intestinal chemistry. Fiber helps discourage bacteria from consuming vital proteins in the gut’s protective mucus, while Prifs provide an alternative nutrient source that supports the production of healthier metabolites.
"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," said AbuSalim.
The broader implications of this work could eventually extend directly to consumer nutrition labels and official dietary recommendations worldwide.
"Food packaging may eventually list Prif right below fiber," Rabinowitz noted.
A Second Discovery Challenges What Scientists Thought About Gut Bacteria
The companion study published in Nature Metabolism addressed another fundamental question in microbiome science: Are gut bacteria truly responsible for producing all of the metabolites traditionally attributed exclusively to them?
Alongside phenol metabolites, the researchers examined indole metabolites, which are formed from tryptophan, another essential amino acid found abundantly in dietary proteins.
These specific substances have attracted immense scientific interest because they participate directly in biological processes linked to inflammation, immune activity, and various chronic diseases. Researchers have intensively investigated their involvement in inflammatory bowel disease, neurodegenerative disorders, and cancer. Furthermore, some indole metabolites have been found to influence the spread of cancer cells and the immune system’s ability to recognize and attack tumors.
For years, scientists have generally assumed that gut bacteria are the primary or sole source of these compounds in the human body. That widely held belief has strongly encouraged efforts to develop targeted probiotics and specialized dietary interventions designed to increase the production of potentially beneficial indole metabolites.
However, this therapeutic approach depends on a major, unverified assumption: that intestinal microbes are solely responsible for producing most or all of the compounds researchers are attempting to influence.
If the body’s own mammalian cells actually make substantial amounts of these metabolites independently, changing the microbiome through diet or probiotics may not be the most effective way to control their circulating levels.
Your Body Can Make Compounds Once Attributed to Gut Microbes
To investigate this possibility, the research team used sophisticated isotope tracing techniques in mice, rats, and human cells to follow how different metabolites were produced in real time.
The results challenged conventional medical thinking. Mammalian cells proved fully capable of generating numerous phenol and indole metabolites completely independently of intestinal bacteria.
Among these autonomously produced chemicals were indole-3-lactate and indole-3-acetate, two biologically important compounds that were previously considered exclusively the products of microbial metabolism.
The researchers also examined what happened when powerful antibiotics disrupted the normal intestinal microbiome. If certain metabolites depended entirely on the presence of gut bacteria, their concentrations would be expected to decline sharply or disappear entirely when those bacterial populations were depleted.
Yet, many metabolites remained at substantial, stable levels in the blood of antibiotic-treated mice. A remarkably similar pattern appeared in clinical samples from patients receiving antibiotics, including individuals undergoing active cancer treatment.
Other compounds behaved quite differently, confirming that the distinction is real. Levels of indole-3-propionate and p-cresol sulfate, which are produced exclusively by microbes, declined steeply following antibiotic treatment.
These results provided definitive evidence that some metabolites depend entirely on intestinal bacteria, while others can also be manufactured autonomously by the body’s own internal metabolic processes.
This distinction matters significantly because it could fundamentally change how researchers and pharmaceutical developers design treatments intended to increase beneficial metabolites or reduce harmful ones in patients.
What These Discoveries Mean for Nutrition and Future Treatments
Together, these two comprehensive studies offer a significantly more detailed and nuanced understanding of how diet, gut microbes, and the body’s own metabolism constantly interact.
The first study identifies an overlooked category of plant proteins that works cooperatively with fiber to influence bacterial activity, potentially helping shift the metabolic balance away from harmful products. The second study demonstrates that the human body itself can produce many chemical compounds once believed to originate exclusively from gut bacteria.
Both sets of findings carry profound implications for ongoing research into metabolic diseases, digestive health, oncology, and other clinical conditions involving the microbiome.
They also strongly suggest that future attempts to manipulate human gut chemistry through precision diet, probiotics, or other therapeutic approaches will need to account carefully for both microbial activity and the body’s own intrinsic metabolic capabilities.
Much of the current experimental evidence comes from animal models and laboratory cell studies, meaning additional clinical research will be necessary to determine precisely how these newly discovered mechanisms influence long-term health outcomes in humans.
Nevertheless, a better scientific understanding of the complex relationships between different food components and microbial metabolism could eventually make dietary advice far more precise and help researchers identify entirely new therapeutic strategies.
"Beyond that," Rabinowitz concluded, "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."
These studies were generously 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.