As human microbiome studies proliferate, scientists are uncovering ways in which it can influence inflammation, chronic diseases, and even obesity. These findings are leading to promising clinical applications, such as the successful use of fecal microbiota transplantation (FMT) in treating Clostridioides difficile infection (CDI). However, there's so much more to learn, said Sahil Khanna, MBBS, MS, a professor of medicine and gastroenterologist at Mayo Clinic.
At this year's Obesity Medicine (OMA) 2024 conference, Khanna spoke about the potential role of the gut microbiome in obesity treatment. With the increasing prevalence of metabolic disorders across the world — predicted to affect more than 1 billion people by 2030 — research about gut microbiota imbalances may hold clues to diagnosis and treatment.
Khanna leads Mayo Clinic's clinical and research program on FMT for CDI and collaborates with other researchers in studying the role of the gut microbiome in other conditions. Based on what he's seen so far, he believes targeting gut microbiota composition can be a potential treatment option for obesity.
In this interview, which has been condensed and edited for clarity, Khanna discussed recent research and the potential for the future.
Uncovering the Microbiome's Link With Obesity
What first interested you in the relationship between the gut microbiome and obesity?
When we think about what microbes do, the first thing that comes to mind is that they help with digestion and energy metabolism. More recently, we've seen a correlation between the loss of gut microbiome diversity and the obesity pandemic across this country and across the world.
With more obesity in Western populations than in Eastern populations, how much of that has to do with the gut microbiome?
Recent studies have shown that as you change your diet to Western patterns, the microbiome changes. The question that comes to mind is, how much of that microbiome change promotes a worsening diet or worsening obesity?
Personally, I became interested in these links from the scientific perspective based on recent developments with CDI and FMT within the past 5 years. Colleen Kelly, MD, a gastroenterologist at Brigham and Women's Hospital and Harvard Medical School, Boston, and colleagues have noted the effectiveness of FMT for CDI, and researchers have begun to wonder about the relevance for obesity.
What has been the most intriguing research question to date?
Are there specific groups or consortia of bacteria — not individual bacterium — that can somehow be modulated to improve metabolism? That seems to be the most important question right now.
After that, what kind of adjunct therapies should be done? If we study microbiome changes in obesity, we should study it to its full potential. Simply conducting FMT in obesity without considering the specifics is shortsighted. For therapeutics to really work, we need to know more about a defined group or consortia of bacteria to put together FMT from selected donors.
FMT on its own is also likely shortsighted and should be considered alongside changes in lifestyle, medications, endocrine therapy, surgical therapy, and so on. We need to understand where in the entire line of obesity management we can fit in microbiome modulation.
Based on research so far, what do we know about the association between obesity and the gut-brain axis?
With piecemeal observations across several studies, we know there are a lot of different mediations that happen with the gut microbiota or microorganisms at the local level in the intestine. The microbiome, which includes the combined genetic material of those microorganisms, contains immune reactions within the lining of the intestine. The metabolome, with the functional properties of the gut microbiota, is also very complex. There are then downstream effects at the local and central levels that lead to energy expenditure or a decrease in the absorption of caloric content, which are subtle but can add up over time.
The second part is that microbes have mediators that affect the motility of the intestine, which is an important factor in the hunger and satiety center in the gut. Then there are central mediators where microbes affect hunger and satiety in the brain itself. We've seen in alcohol-associated liver disease, for instance, that changing the microbiome can affect the craving for alcohol, so can we do the same for sugar or high-fat foods?
We know that many foods we get addicted to — such as sugar or fat — provide an instant dopamine hit, which prompts us to take a second bite of that cookie. It's hard to resist the dopamine, especially when you have that cookie in front of you. So how much of that is mediated by the microbiome or can be changed by modulating the microbiome?
In other disorders, we understand that the gut-brain axis is involved with gastrointestinal functions, such as irritable bowel syndrome with dyspepsia and bloating. The question that is going to be answered in the near future is whether part of what we see in metabolic disorders is linked to the gut-brain axis and how much is being modulated by the microbiome.
How might the microbiome impact obesity itself?
We don't know the whole picture, but we see the pieces — with central appetite, energy absorption, fat storage, chronic inflammation, and the circadian rhythm. With all of these put together, we learn more and more.
The most we know about is the effect of diet and the gut microbiome, which we understand in a simplistic and transient manner. For instance, a diet high in fiber and traditional prebiotics tends to have a more diverse microbiome and redundancy in function, so there's no overpowering effect from a particular bacteria taxa or species leading to an adverse event.
What our grandmothers told us about eating more fruits, vegetables, and fiber really has been shown to have a positive impact on the gut microbiome. After a decade of research on energy metabolism and diet, that's where we're at right now — eat more fiber, which will make you feel better and improve your metabolism.
The Potential of Microbiome Therapeutics
Which microbiome-based treatment options are being researched for obesity?
In studies done in germ-free mice, taking stool from genetically obese mice and putting it into mice that weren't genetically obese, those mice became obese just through the effects of the microbiome. It's fascinating, but is the other way around possible? We're trying to solve obesity, not leanness, so that's the question that needs to be answered.
In humans, can we take microbiome therapeutics of some sort — whether a single live bacterial agent or genetically modified consortia of microbes derived from human donors or computational biology or whole gut microbiome minimally modified from human beings — and then change the metabolism of people?
Essentially, there are several considerations, and I don't think we'll see a standalone therapeutic of doing FMT from a lean donor to an individual with obesity. We need to consider adjunct therapeutics, such as how glucagon-like peptide 1 receptor agonists affect the microbiome and the costs and adverse events associated with them. Could the microbiome provide an off-ramp rather than taking the medications for life?
We don't yet have those data from some of the most revolutionary discoveries happening in the management of obesity in modern medicine.
What other developments have been occurring around FMT research in this area?
The US Food and Drug Administration allows FMT for CDI, but for anything else, it can only be done under research settings.
However, there are scores of clinical trials studying FMT related to metabolic syndrome, metabolic dysfunction–associated steatotic liver disease (MASLD), metabolic dysfunction–associated steatohepatitis, irritable bowel syndrome, Crohn's disease, ulcerative colitis, and more, along with links to microbiome restoration.
At this time, we're not close to prescribing FMT for individual patients, but providers who are interested in learning more should look at the latest on ClinicalTrials.gov. In more than two dozen current studies focused on obesity and FMT, investigators are looking at questions around fiber supplementation, post bariatric surgery, and insulin resistance, so we're going to see more and more data coming out soon.
Unrealistic Expectations and Future Efforts
Are there misconceptions about the microbiome that you'd like to address?
The biggest one is that people feel compelled to get their microbiome tested, and then they go on a spiral of trying to treat excess bacterium either through a probiotic or by asking their doctor to give them an antibiotic.
I tell patients that those tests aren't actionable at this time, and I'm not able to provide any clinical guidance. Even if companies say they can do a detailed microbiome analysis, the biggest misconception is that we can do something about it. I discourage patients from getting those tests. They don't give clinically actionable results.
What are the next research steps or questions you have?
Personally, I'm focused on the microbiome in CDI and continuing to explore clinical trials for therapeutics in that realm. I collaborate with researchers who are studying microbiomes in people with MASLD and others at Mayo who are studying the role of microbiomes in patients who have obesity and dividing their phenotypes into different classes, such as the hungry brain or hungry gut. I'm eager to see the differences.
Carolyn Crist is a health and medical journalist who reports on the latest studies for Medscape Medical News, MDedge, and WebMD.