Sept. 23, 2024 -- Someday soon, your medicine cabinet will have pills not just for you, but also for the microbes in your gut.
These pills will "treat and inhibit an enzyme in our microbes and elicit a health benefit in some chronic disease," said cardiologist Stanley Hazen, MD, PhD, co-head of the Preventive Cardiology and Rehabilitation, Heart, Vascular and Thoracic Institute and director of the Center for Microbiome and Human Health at Cleveland Clinic.
How can he be so sure?
Because evidence is mounting that the gut microbiome influences just about every major human disease. These trillions of microbes use our food to make substances called metabolites that can protect or harm our health, with consequences reaching far beyond our digestive 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 use in humans is an oral treatment from 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, Hazen said.
The advantage is safety. By targeting the microbe instead of, say, an enzyme, the host (you) must absorb little if any drug.
Implications for the future of medicine are huge. "Gut microbial pathways contribute to diabetes, obesity, virtually everything," 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, but the mix varies, depending on your genes, environment, and lifestyle.
"Everyone's microbiome is subtly different," said 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, an associate professor of pharmaceutical sciences at Texas A&M University, College Station.
Metabolites can influence how these immune cells work – which could explain why each person's immune system behaves differently.
Of the 1,000-plus metabolites linked to the gut microbiome, scientists have flagged several that matter.
- Short-chain fatty acids. When we eat fiber, colon bacteria ferment it into beneficial short-chain fatty acids. These bind to receptors in muscle, liver, and fat tissue, affecting gut hormones and peptides related to appetite, inflammation, energy expenditure, and fat burning.
One of these fatty acids, called butyrate, has been linked to health benefits. It strengthens the gut's lining, stifling bad 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. When we eat foods rich in animal proteins – especially red meat – some gut bacteria convert nutrients like choline and L-carnitine into TMAO. Research done by Hazen's lab and copied by others has linked the metabolite to heart problems.
In a landmark study from Hazen's group, healthy adults who went on to get coronary artery disease had significantly higher TMAO levels than those who did not wind up with the condition. The link remained strong, even after controlling forrisk factors like age, sex, smoking, high blood pressure, and high cholesterol. In mouse studies, higher TMAO enhanced cardiovascular disease.
Research suggests TMAO may harm cells that contract and relax the heart in dozens of ways, such as activating proteins to promote thickening and scarring, and decreasing the function of mitochondria (the powerhouse of the cell).
- Tryptophan metabolites. Microbes in your colon can convert the amino acid tryptophan, also found in animal-based foods, into chemical messengers like serotonin and melatonin.
"The enteric nervous system, the nervous system around the gut, is immense," said James Versalovic, MD, PhD, a professor of pathology and immunology at Baylor College of Medicine, Houston. "The gut-brain axis has become a very fertile area of research."
Other tryptophan metabolites – like indole, tryptamine, and indoleethanol – have been linked to benefits like fortifying the gut barrier, promoting the release of the hormone glucagon-like peptide 1 (GLP-1) to reduce appetite, and protecting the liver from hepatitis. But 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’re reabsorbed 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 turn a type of hormone known as corticoids into progestins, substances linked to postpartum depression risk.
And researchers are exploring the estrobolome – a collection of gut bacteria that break down estrogen. These bacteria impact estrogen levels, which in turn can influence things like weight and mood.
"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.
What You Can Do Now
Advances in the field of microbiome research – and the related "gut health" wellness craze – have spawned all kinds of new microbiome-based products, like over-the-counter probiotic supplements and at-home test kits, which let you send a stool sample for analysis to reveal microbiome health and personalized diet recommendations.
But the science behind these tests is still evolving, said Damman. "The clinical inferences and applications are still pretty limited."
For most people, the first step to fostering healthier microbial metabolites is much simpler: Diversify your diet.
"A lot of folks are missing that diversity," Damman said. "Eat foods and experiment with foods that you might not eat all the time," especially fruits, vegetables, nuts, seeds, and beans.
Another strategy: Eat foods with probiotic bacteria. "I view it as an insurance policy," said Versalovic, "fortifying my gut with probiotics, with daily yogurt, for example, at breakfast."
Fermented foods like kimchi and kombucha can also increase microbial diversity and can even contain health-promoting postbiotics, research shows.
As for probiotic supplements, the jury's still out.
Certain strains of probiotic bacteria may be beneficial for some, like those with diarrhea, Crohn's disease, and irritable bowel syndrome, according to World Gastroenterology Organisation guidelines.
As with other interventions, individual responses can vary. A Stanford study showed that some people with metabolic syndrome improved when taking a probiotic, while others didn't. Both groups had key differences in gut bacteria and diet.
For best results, such microbiome-based interventions will need to be personalized, experts say. And the technology to do that is coming sooner than you might think.
Microbiome's Medical Future: 'We Are on the Cusp of a New Era'
In just a few years, artificial intelligence (AI) models could predict the makeup of your gut based on data such as your diet and household characteristics, Kumar said.
Advancements in metabolomics and bioinformatics could soon help doctors and patients personalize their treatment approaches, said Damman.
One focus will be on fortifying the gut with whatever it lacks.
"In those individuals where certain microbes are missing, (a) how could we add them back potentially in a rational, science-driven way, and (b) maybe some of those factors that the microbes are producing out the other ends, you could give directly," said Damman.
For example, multiple companies make butyrate as a dietary supplement, although the research is too early to support widespread use. Another option could be eating something that spurs butyrate production. One small study found that a fiber supplement made to increase butyrate levels in the colon reduced people’s systolic blood pressure by an average of six points.
Another option could be synbiotics, products that combine bacteria and what they feed on.
"If you just give a diet-based therapy, it is not going to work as much. Because what if that diet needs certain bacteria to have these beneficial metabolites?" said Ashutosh Mangalam, PhD, an associate professor of pathology at the University of Iowa Carver College of Medicine, Iowa City.
Gut microbial metabolites could also affect disease screening and intervention. What if gut microbe sequencing could predict a pregnant person's risk of developing depression, something now assessed through simple questionnaires?
"Imagine that your doctor says, 'OK, give me a poop sample,' " Bernabé said. "Then they phenotype it, and then they put it in your electronic medical record, and they say, 'Well, you have high likelihood of having a mood disorder down the line in your pregnancy. Why don't we directly refer you to a provider now so you can follow up?' "
Research is already underway to understand how metabolites might be linked to pregnancy outcomes, complex regional pain syndrome, and anxiety. Researchers are also investigating whether supplementing our diets with things like prebiotic fibers, apple polyphenols, or tomato paste might influence metabolites. And fecal transplants that shift the gut microbiome and metabolites could have potential in diseases like unexplained atherosclerosis, post-COVID syndrome, and hidradenitis suppurativa(a skin condition that causes small, painful lumps).
Hazen's discovery linking TMAO with heart risk has already changed clinical practice. A blood TMAO test can help identify patients at risk who may not have traditional risk factors. "Millions have been done," Hazen said.
Meanwhile, his drug targeting the TMAO pathway inches closer to clinical trials.
"In an animal model, we elicit improvement in heart failure, renal disease, atherosclerosis, thrombosis, aortic aneurysm, and obesity," Hazen said. The first clinical trials will focus on renal disease.
As with any drug, the road to approval takes time. And success is not guaranteed.
But Hazen for one is optimistic.
"We are on the cusp of a new era," he said. "Like when humans first discovered insulin and glucagon were hormones that impact sugar metabolism. We now recognize myriad new 'hormones' in the form of gut microbiome metabolites that impact our physiology and susceptibility to diseases."
