What Makes a Healthy Gut Microbiome?

Everyone talks about the importance of building and preserving a healthy gut microbiome, a gastrointestinal Xanadu touted in particular by the makers of home-based testing kits. But is such a microbial paradise even possible to achieve — and would we know it when we saw it?

Purna Kashyap, MBBS

The answers to those questions are, at least for the moment, out of reach, according to two experts on a recent panel examining the value of direct-to-consumer gut microbiome tests.

At the heart of the problem: Researchers don't always agree on the best methods for quantifying and typing the microorganisms that make up a "normal" microbiome or what they mean to the health of a given person, according to Purna Kashyap, MBBS, a professor of medicine and of physiology at the Mayo Clinic, Rochester, Minnesota.

The human gastrointestinal tract harbors 100 trillion microbes, according to Kashyap, whose laboratory is researching not only the organisms that make up that stunning mass but how they interact with the host genotype, diet, and gastrointestinal function.

Kashyap participated in a recent panel on microbiome testing at the Academy of Nutrition and Dietetics' 2022 Food & Nutrition Conference & Expo in Orlando, Florida.

Although experts on the human microbiome agree that diversity of gut organisms is good, individual microbial mileage may vary. In other words, the types, quantities, and ratios of microorganisms that constitute a healthy microbiome might be defined differently for any given individual, according to Kashyap. Even if healthy relationships between diverse taxa are eventually defined, the best way to quantify them and their ratios in the gut microbiome have yet to be standardized.

Levi Teigen, PhD, RD

One issue is that the ecosystem as a whole rather than any specific bacteria is the most likely difference between a healthy and an unhealthy gut microbiome, according to both Kashyap and his fellow panelist, Levi Teigen, PhD, RD, an assistant professor in the Department of Gastroenterology, Hepatology, and Nutrition at the University of Minnesota, Minneapolis.

In the experimental setting, most of the measuring techniques are based on "proprietary methods that lack validation in large cohorts," Kashyap said. And even if a meaningful definition of a healthy microbiome could be established, the degree to which dietary changes or any other therapies can move the microbiome toward some goal of microbiome diversity is unclear.

"Diet appears to help shape the microbiome community in the long term, but short-term interventions have limited effect on microbiota composition," Kashyap said.

Your Good, My Bad?

Teigen drew the same basic conclusion about the current utility of direct-to-consumer gut microbiome testing. Defining a healthy microbiome or the methods by which it can be targeted, he said, are challenges yet to be met.

"At this point in time, the home-based microbiome tests are not validated in a way that allows for provision of useful information," he told Medscape Medical News.

The intestinal microbiome is a "complex ecosystem," Teigen added. "What we consider to be a healthy microbiome exists on a continuum and its function, or what it does, is heavily influenced by external factors such as the immune system and diet. The composition, or what microbes are there, is only one piece of the puzzle and it doesn't tell us much in isolation."

Two of the commonly used methods to assess the microbiome are amplicon and shotgun sequencing. The amplicon approach, which generally relies on profiling of the 16S rRNA gene, is less expensive and has the advantage of detecting taxa in low abundance. But for sequencing at the species level, amplicon sequencing is less reliable than the shotgun method, Teigen said.

Shotgun sequencing involves genome analysis through small fragments of DNA that are sequenced individually. It can miss taxa present in low abundance and is more costly to perform, but it more useful for identifying species and genes that are functionally relevant, according to Teigen.

Both technologies are commonly used in experimental efforts to characterize and understand the activity of the gut microbiome, but neither can reliably reveal the degree to which microorganisms in the gut are contributing to risk for disease in general or to specific diseases. One of the most important reasons is that the function of microbial strains appears to depend on the interrelationship with other microorganisms that are present.

This overlap becomes confusing quickly, because "there is also functional redundancy so that multiple taxa can perform the same function," Teigen said.

Artificial intelligence (AI) is being avidly pursued to wade through this complexity, according to Kashyap. Recent studies have used AI to determine why postprandial glucose responses (PPGRs) vary in people with similar diets. Clearly, many known variables — such as body fat and recent fiber consumption — and unknown factors affect PPGR, but he that said machine learning is showing promise for combining clinical variables with microbiota profiles to determine how these factors interact.

Kashyap said that he sees several clinical applications in the future, including the potential for direct-to-consumer tests that not only characterize the microbiome but also use patient-specific factors within an algorithm to guide intervention. In the case of abnormal PPGR, the algorithms might guide selection of specific dietary fibers with the greatest potential to alter the gut microbiome in order to improve glucose metabolism.

Despite current limitations, research is active, and Teigen is not alone in predicting that relationships between the microbiome and disease will eventually be understood. The promise is substantial, but he remains circumspect about the degree to which individuals can evaluate their microbiome and make changes to improve health based on what is currently known.

Again, the problem is not just proving a relationship between any specific microbiome profile and health risks or health benefits, but proving that the microbiome can be altered to reduce these risks.

"So far, the functionality of the microbiota is difficult to elucidate," Teigen said.

Kashyap agreed. "Should gut microbiome profiling be used to determine dietary intervention? Not yet," he said.

Kashyap reports financial relationships with Intrinsic Medicine, the IP Group, Novome Biotechnologies, and Pendulum Therapeutics. He and others at Mayo Clinic also have a financial interest in developing tryptamine-producing bacteria for treating gastrointestinal disorders. Teigen reports no potential conflicts of interest.

Presented October 9 at the Academy of Nutrition and Dietetics' 2022 Food & Nutrition Conference & Expo, Orlando, Florida.

Ted Bosworth is a medical journalist in New York City.

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