Plant Proteins That "Imitate Fiber" Reprogram Gut Microbes to Favor Healthy Metabolites
核心洞察
Two Ludwig Princeton studies reveal that indigestible plant proteins, termed "proteins imitating fiber" (Prif), shift gut microbial metabolism away from harmful tyrosine-derived phenols toward healthful phenylalanine-derived metabolites.
Isotope-tracing experiments show beneficial phenols come almost entirely from dietary plant proteins, while harmful phenols arise from bacterial consumption of the host's own gut mucus lining.
A companion Nature Metabolism study demonstrates that mammalian metabolism independently produces many indole and phenol metabolites, challenging the assumption that these compounds originate solely from gut bacteria.
Plant-based diets reshape the gut microbiome to boost production of healthful metabolites while suppressing harmful ones, according to a pair of studies led by Ludwig Princeton's Jenna AbuSalim and Director Joshua Rabinowitz. One study, published in the current issue of the Proceedings of the National Academy of Sciences, reveals that plant fibers and indigestible plant proteins reprogram microbial metabolism to favor beneficial phenol metabolites. The other, published in Nature Metabolism in June, demonstrates that many physiologically important metabolites generally attributed to intestinal microbes are in fact produced abundantly by mammalian metabolism as well.
"There's growing interest across medical disciplines in manipulating the human microbiome or using its metabolic products themselves for therapy," said Rabinowitz. "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."
Divergent Health Effects of Phenol Metabolites
The PNAS study explored how plant-based foods affect levels of phenol metabolites, which are produced by the bacterial digestion of the amino acids tyrosine and phenylalanine. These phenols have sharply divergent health effects. One set—phenylpropionate (搜索) and hippuric acid, made from the bacterial processing of phenylalanine—supports gut health and healthy body weight. The other—p-cresol sulfate (搜索) and phenol sulfate, derived from tyrosine—is associated with worse outcomes for cancer (搜索) patients and systemic toxicity in patients with kidney disease (搜索).
"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.
The Overlooked Role of Indigestible Plant Proteins
While the benefits of plant fibers are well known, indigestible proteins from plants have so far been largely overlooked. AbuSalim, Rabinowitz and colleagues report that such proteins are processed by gut microbes, reshaping microbiome composition and host metabolism. They further act in concert with indigestible plant fiber to rewire the metabolic programs of gut bacteria in a manner that favors the production of "good" phenols.
By labeling proteins with stable (non-radioactive) isotopes and tracking their digestion in the mouse gut, the researchers discovered that the "bad" phenols are made by the bacterial consumption of host proteins, such as those in the mucus lining the gut, while the good phenols are made almost exclusively from the indigestible dietary proteins (Prif). Fiber suppresses bacterial catabolism of the gut mucus lining, decreasing production of the bad phenols. Prif enhances the amount of dietary protein reaching gut microbes and thus the production of the good phenols.
"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.
"Food packaging may eventually list Prif right below fiber," said Rabinowitz.
Challenging a Microbiome Assumption
The Nature Metabolism study explored the sources of phenol metabolites and indole metabolites, which are derived from the amino acid tryptophan. Like phenols, indoles are being actively investigated for their therapeutic potential. Indole metabolites have been implicated in diseases ranging from inflammatory bowel disease (搜索) to neurodegenerative disorders to cancer (搜索), where they have been found to influence cancer metastasis and anti-tumor immune responses.
Both phenols and indoles were generally believed to be produced solely by gut bacteria, an assumption AbuSalim and Rabinowitz and colleagues put to the test. There has been much interest in developing dietary or probiotic-based strategies to boost the levels of healthy indole metabolites, but if mammalian metabolism contributes most to their circulating levels, alternative approaches need to be considered.
Isotope-tracing studies in mice, rats and human cells revealed that mammalian metabolism is capable of producing many indole and phenol metabolites, including several physiologically important ones like indole-3-lactate (搜索) and indole-3-acetate (搜索). In mice, circulating levels of the metabolites remained robust following treatment with antibiotics, which disrupt the microbiome. This was reflected also in samples from patients, including cancer (搜索) patients, on antibiotics. Meanwhile, metabolites produced exclusively by microbes, such as indole-3-propionate (搜索) and p-cresol sulfate (搜索), decreased following antibiotic treatment.
Implications for Precision Nutrition and Therapy
Taken together, the findings of the two studies make important contributions to understanding the source and production of phenol and indole metabolites and have implications for the design of tools and strategies to manipulate their levels for therapy. The results show that the same metabolite can sometimes come from more than one source, and its concentration in the bloodstream may reflect a combination of diet, microbial activity, and metabolism in the body's own tissues. A probiotic may be useful when a compound is made primarily by microbes, while a host-produced metabolite may require an entirely different approach.
"Beyond that," said Rabinowitz, "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."