The human gut microbiome and blood biochemistry connection

“Ultimately, the effects on branched-chain amino acids may have important implications for the mTOR pathway and insulin resistance,” he said, noting that it’s an emerging field with in vitro and in vivo animal model data as well as human data.

On the topic of microbial modulation of cardiovascular disease, Dr. Versalovic cites the work of Stanley Hazen, MD, PhD, and colleagues of the Cleveland Clinic Lerner Research Institute on trimethylamine (TMA) and trimethylamine N-oxide (TMAO). In a review article, Brown and Hazen write that the TMAO pathway “is a meta-organismal metabolic pathway whereby nutrients that are present in high fat foods . . . can be metabolized by several distinct gut microbial enzyme complexes (CutC/D, CntA/B, YeaW/X) to generate the primary gut microbial metabolite TMA” (Brown JM, et al. Nat Rev Microbiol. 2018;16[3]:171–181). Other reviews, they write, highlight the clinical relevance and therapeutic potential of the TMAO pathway in cardiovascular disease.

Red meat, eggs, saltwater crustaceans and fish, and dairy products have relatively high amounts of choline and L-carnitine that can be converted by bacteria in the gut through well-defined biochemical pathways, Dr. Versalovic said. CutC/D is the enzyme that converts choline to TMA. A separate pathway, CntA, converts L-carnitine to TMA. TMA is then metabolized in the liver by flavin monooxygenases to TMAO. “These findings appear to be clearly relevant” and are yielding a new biomarker (or new biomarkers) for human cardiovascular disease, Dr. Versalovic said. Dr. Hazen’s group and others have now fully documented the connection, he said, between increases in TMAO and elevated risk for atherosclerosis, plaque development in blood cells, heart failure, increase in foam cell macrophage formation due to upregulation of scavenger receptors, and increase in platelet aggregation and hyperreactivity.

TMAO is licensed and used as a clinical test to evaluate this additional biomarker for measuring cardiovascular disease risk, and there are preclinical trials to inhibit TMAO pathways in the microbiome to reduce the risk of CVD, Dr. Versalovic said.

In their 2021 review of how gut microbiota contributes to heart failure, Zhang, et al., write that TMAO “is closely associated with the poor survival of HF patients, which helps clinicians to screen out high-risk groups and pay more attention to their follow-up monitoring as well as enhance HF-related treatments.” The problem, they add, is the lack of diversity in the existing clinical research subjects, who are mainly Caucasian, and additional cohort studies enrolling patients of other races are needed (Zhang Y, et al. Transl Res. 2021;228:109–125).

Drug discovery and development are ongoing, with the aim of inhibiting TMAO “based on this new paradigm for atherosclerosis and relevance to type 2 diabetes,” Dr. Versalovic said. TMA lyase is the enzyme most commonly found in the microbiome that is linked to TMA production. It is present in a variety of bacterial species that lead to conversion of dietary choline to TMA (Steinke I, et al. Front Physiol. 2020;11:567899).

Dimethyl-1-butanol (DMB), a compound found in red wine and in higher amounts in balsamic vinegar and grapeseed and olive oils, “is a powerful inhibitor of the bacterial TMA lyase in the gut microbiome,” Dr. Versalovic said. DMB and other derivative compounds are being developed to target the CutC/D pathway in the microbiome to try to reduce cardiometabolic disease risk long term (Wang Z, et al. Cell. 2015;163[7]:1585–1595).

Berberine, a plant alkaloid found in some food products and supplements, has been documented to block the conversion of choline to TMA (Ma SR, et al. Signal Transduct Target Ther. 2022;7:207).

The human microbiome over a lifetime is exposed to thousands of xenobiotics—any substance or chemical compound that is foreign to the body or ecosystem, such as pesticides, printing ink, food additives, and drugs. “Think of residual plastic in your water,” Dr. Versalovic said.

While antimicrobial agents are most commonly associated with an impact on the microbiome, the focus in his talk was drugs for which it was unclear, until recently, whether there was an impact on or by the microbiome. Corticosteroid metabolism by human gut microbes, specifically Clostridium scindens, can convert glucocorticoids into androgens. Human microbes will convert C-21 corticosteroids to androgens and other metabolites (Ridlon JM, et al. J Lipid Res. 2013;54[9]:2437–2449). “This may be relevant to patients who are medicated for chronic autoimmune and other conditions that require the use of corticosteroids over time,” he said.

“We’re now beginning to understand the different metabolic pathways in the human microbiome that may affect drug metabolism.”

Since human microbes can modify drugs and medications through various biochemical pathways, such as acetylation and β-glucuronidation, leading to activation or inactivation of drugs or toxic metabolite production, the implications for pharmacology and patients are important. “I could see a future where we’re examining both bacterial genes and human genes and assessing whether drugs are going to work in different sets of patients,” Dr. Versalovic said. “And we as a pathology community are going to have to be front and center in helping our clinical colleagues navigate this very complex genetic landscape.” The number of genes in the human genome is far lower than the 2 million in the human microbiome. “One hundred-fold more bacterial genes may be residing within you.”

“This is a massive genetic and biochemical microbial landscape in the human body,” he said, “and we’re obviously going to need high-throughput, latest-generation sequencing technologies and mass spectrometry to be able to discern signal from noise.” He’s optimistic: “This is a manageable problem and health care challenge for the next decade.” Pathologists can help lead the way, he said, in providing new diagnostic and patient-monitoring strategies based on a “holistic world view of human pathology and the microbiome.”

Amy Carpenter Aquino is CAP TODAY senior editor.