Meet your new patients.
You can’t see them, but trillions — maybe quadrillions — of them travel in and out of your practice every day. They’re hungry, mysterious, community-oriented, and small. Very, very small.
They’re the microbes occupying your current patients’ guts.
Someday soon, you’ll prescribe medicine not just for humans but also for these microbes.
“I am convinced in the future our medicine cabinets are going to have not just medications like a statin for treating us, but [also] pills that treat and inhibit an enzyme in our microbes and elicit a health benefit in some chronic disease,” said Stanley Hazen, MD, PhD, co-section head of Preventive Cardiology & Rehabilitation and director of the Center for Microbiome & Human Health at Cleveland Clinic, Cleveland, Ohio.
These trillions of microbes use our food to generate substances called metabolites that can protect or harm our health, with consequences reaching far beyond our gastrointestinal tracts.
Research has linked microbial metabolites to diabetes, cardiovascular disease, liver disease, obesity, high blood pressure, neurological disorders, depression, cancer, and more. Gastroenterologist Christopher Damman, MD, a clinical associate professor at the University of Washington Medical Center, Seattle, calls it a “growing theme” in microbiome science.
Now scientists are developing treatments targeting gut microbial pathways, designed to eliminate the bad metabolites and boost the good metabolites.
One close to human therapeutic intervention is an oral treatment from Dr. Hazen’s lab targeting the metabolite trimethylamine N-oxide (TMAO), a predictor of and contributor to both cardiovascular disease and chronic kidney disease. The drug, which blocks TMAO formation, is nearing clinical trials, Dr. Hazen said.
The advantage is safety. By targeting the microbe instead of, say, an enzyme, the host (your patient) must absorb little if any drug.
Implications for the future of medicine are huge. “Gut microbial pathways contribute to diabetes, obesity, virtually everything,” Dr. Hazen said. “Therapies that target gut microbiome processes will probably even be used for psychiatric disorders within, I’ll say, 10 or 20 years.”
The Science
About 100 trillion strains of bacteria live in our guts. As humans have evolved, so have they.
Between 70% and 90% come from the phyla Firmicutes and Bacteroidetes, with person-to-person variation shaped by genetics, environment, and lifestyle.
“Everyone’s microbiome is subtly different,” said Dr. Hazen. “So the combination of what they’re making is different. All these different biologically active compounds are influencing us in subtly different ways.”
How it works: When you eat, your microbes eat, breaking down food into metabolites that interact with the thin layer of epithelial cells lining your gut. Some can be absorbed through the lining and into your bloodstream, a phenomenon known as “leaky gut.” Once in your blood, they can trigger irritation and inflammation, potentially leading to a wide variety of health issues, from gas and bloating to autoimmune conditions and mood disorders.
“On the other side of the epithelial lining, you have some of the largest concentrations of immune cells,” said Narendra Kumar, PhD, associate professor of pharmaceutical sciences at Texas A&M University, College Station, Texas.
Metabolites can influence how these immune cells work, possibly explaining why each person’s immune system behaves distinctively.
Of the 1000-plus metabolites linked to the gut microbiome, scientists have identified several that matter.
Short-chain fatty acids. When we eat fiber, colon bacteria ferment it into the beneficial short-chain fatty acids acetate, propionate, and butyrate. These bind to receptors in muscle, liver, and fat tissue, affecting the secretion of gut hormones and peptides related to appetite, inflammation, energy expenditure, and fat oxidation.
Butyrate has been linked to health benefits. It supports the integrity of the gut’s lining, stifling pathogenic gut bacteria, fighting cancer-promoting inflammation, and protecting against obesity and diabetes. It can function as a prebiotic, helping beneficial bacteria thrive. And recent studies linked an abundance of butyrate-producing bacteria with reduced bone fracture risk and hospitalization for infectious disease.
TMAO and phenylacetylglutamine. When we eat foods rich in animal proteins — think eggs, milk, fish, and especially red meat — some gut bacteria convert nutrients like choline and L-carnitine into TMAO and phenylalanine into phenylacetylglutamine. Research conducted by Dr. Hazen’s lab and replicated by others has linked both metabolites to heart problems.
In a landmark study from Dr. Hazen’s group, healthy adults who went on to develop coronary artery disease had significantly higher plasma TMAO levels than those who did not wind up with the condition. The association remained strong, even after controlling for risk factors like age, sex, smoking, high blood pressure, and high cholesterol.
In preclinical studies, elevated TMAO enhanced cardiovascular disease. TMAO-producing microbes also accentuated cardiovascular disease phenotypes in mouse models, while blocking these pathways inhibited the phenotypes.
Research suggests TMAO may harm cardiomyocytes (cells that contract and relax the heart) in dozens of ways, such as activating the expression of proteins to promote hypertrophy and fibrosis, decreasing mitochondrial function, and disrupting calcium signaling.
Another study linked phenylacetylglutamine levels to cardiac event risk in patients with heart failure. Recent mechanistic investigations suggest the metabolite alters signaling in a beta-adrenergic receptor involved in our fight-or-flight response, said Hazen.
“It’s like a rheostat on the light switch, a dimmer switch, and it’s what’s called a negative allosteric modulator,” he said. “It’s the first time that this type of behavior has ever been shown to be present for a gut microbial metabolite and a host receptor.”
Tryptophan metabolites. Microbes in your colon can convert the amino acid tryptophan, also found in animal-based foods, into neurotransmitters like serotonin and melatonin.
“The enteric nervous system, the nervous system around the gut, is immense,” said James Versalovic, MD, PhD, professor of pathology and immunology at Baylor College of Medicine, Houston. “The gut-brain axis has become a very fertile area of research.”
Lesser-known tryptophan metabolites — like indole, tryptamine, and indoleethanol — have been linked to benefits like fortifying the gut barrier, promoting the release of glucagon-like peptide 1 to reduce appetite, and protecting the liver from hepatitis. However, indole can also spur the production of indoxyl sulfate, a toxin linked to chronic kidney disease.
Bile acid byproducts. Your gut bugs also feast on (and transform) bile acids before they reabsorb and travel back to the liver.
Research is gaining traction on these secondary bile acids, which can affect inflammation and immune function in helpful and harmful ways.
One area of interest is how microbes break down hormones in bile. A recent study from Harvard showed that gut microbes convert corticoid hormones in bile into progestins, which could affect postpartum depression risk. And researchers are exploring the estrobolome — a gut microbial community dedicated to breaking down estrogen into its active form so it can be reabsorbed.
“Depending on the bacteria that you have, more or less can be recirculated back into your blood,” said Beatriz Peñalver Bernabé, PhD, an assistant professor of biomedical engineering and urology at the University of Illinois Chicago. “So you may be producing the same amount of estrogen, but depending on the bacteria you have, the real free estrogen that can bind to your cells may be very different.”
The gut microbiome can also regulate testosterone, with studies showing microbial differences in men with high testosterone vs those with less.