Treating Obesity with Bugs, Not Drugs

Microbiome therapies may provide an adjunct to weight loss

When it comes to obesity, patients and researchers alike often have more questions than answers. How does metabolism vary among individuals? Why do some people have an easier time losing weight than others? Which factors—genetic, diet, lifestyle, environmental exposures, microbiome—exert the strongest influence over type 2 diabetes risk?

The Hormonal Orchestra of Metabolism

Weight and metabolism are governed by a multitude of factors, including several types of hormones. Insulin mobilizes glucose from the blood, ghrelin stimulates hunger, and leptin promotes satiety. Each of these hormones is released by specialized cells in various parts of the body.

Hormones have a particularly strong impact on metabolism because of their ability to exit the bloodstream and act directly on host tissues. For example, the binding of insulin to its target receptors in fat, muscle, and liver tissue turns off glucose production when blood sugar levels are high.

In this manner, the body's "set point" for weight is tightly regulated, akin to a thermostat setting with very little wiggle room. A change in energy intake is usually accompanied by a compensatory change in energy expenditure, allowing the body to maintain equilibrium.

However, recent research suggests that this set point might be more malleable than previously thought, influenced significantly by both genetic factors and the gut microbiome.

Panacea in a Pill?

A class of drugs known as GLP-1 receptor agonists mimic the action of a hormone called glucagon-like peptide-1 (GLP-1), which helps people feel full after they eat. Eating prompts cells in the small intestine to produce GLP-1, which then directs the pancreas to release insulin.

The challenge with natural GLP-1 is its short half-life of about two minutes due to rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4). However, pharmaceutical advancements have led to the development of longer-acting GLP-1 agonists. Semaglutide, approved by the FDA in 2017 for type 2 diabetes and in 2021 under the brand name Wegovy for chronic weight management, boasts a half-life of about one week, allowing for once-weekly dosing.

Clinical trials have shown that patients can lose an average of 15% of their body weight when using semaglutide in conjunction with lifestyle modifications. More recently, a novel medication called tirzepatide (brand name Mounjaro) has gained attention. Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist. Approved by the FDA in May 2022 for type 2 diabetes, tirzepatide was shown to result in an average -20.9% reduction in body weight for the group receiving once-weekly, subcutaneous tirzepatide at the highest dose of 15mg.

While these medications offer promising results, concerns remain regarding side effects and long-term safety. Common adverse effects include gastrointestinal symptoms like nausea, vomiting, and diarrhea. Research is ongoing into rare but serious risks such as pancreatitis and medullary thyroid carcinoma. Moreover, the high cost of these medications and issues with accessibility raise questions about their practicality as a widespread solution to obesity.

A Gut Instinct

If our goal is to alter metabolism by modulating levels of endocrine hormones, another attractive target is the microbiome. The gut microbiome, composed of trillions of bacteria, is a major determinant of levels of insulin, GLP-1, peptide YY (PYY), ghrelin, and leptin.

In murine models, antibiotic-induced microbiome manipulation affects gut GLP-1 signaling. In humans, consumption of dietary fiber can stimulate the growth of beneficial commensals such as Bifidobacteria and Akkermansia muciniphila, which ferment fiber into short-chain fatty acids (SCFAs) like acetate and butyrate. These SCFAs stimulate the production of GLP-1 and PYY, both of which enhance insulin secretion and promote feelings of fullness.

Taking prebiotics such as inulin and oligofructose has been shown to significantly increase circulating plasma levels of GLP-1 after meals in human trials and also help promote satiety, reducing total energy intake by as much as 10%. In this manner, the gut microbiota exerts a profound influence over food intake and appetite regulation.

Recent studies have also explored the use of probiotics and fecal microbiota transplantation (FMT) as potential therapies for obesity. For instance, transferring the microbiota from lean donors to individuals with metabolic syndrome has shown improvements in insulin sensitivity. Additionally, specific strains of bacteria are being investigated for their anti-obesity effects.

For example, Akkermansia muciniphila, a mucin-degrading bacterium, has been associated with improved metabolic health. Supplementation with this strain has been shown to decrease insulin resistance, hypercholesterolemia, and body weight in overweight and obese individuals (albeit by a modest 2.27% in an exploratory study).

Another area of interest is the development of postbiotics—non-viable bacterial products or metabolic byproducts from microbial fermentation that confer health benefits to the host. Postbiotics may offer a safer and more controlled approach compared to live bacteria.

Dr. Ruth Ley, director of the Department of Microbiome Science at the Max Planck Institute for Biology, emphasizes that these studies highlight the shortcomings of the "calories in, calories out" model of energy balance. We can’t simply blame weight gain on a lack of exercise or overeating because our gut microbes play a significant role in how we harvest energy from food. Understanding the microbiome opens up new avenues for personalized nutrition and therapies.

A New Way Forward

While microbiome therapies hold promise, there are challenges to overcome. Individual variations in microbiome composition mean that treatments may need to be personalized. Moreover, the long-term effects of manipulating the microbiome are not fully understood.

Regulatory pathways for microbiome-based therapeutics are still being established. Ensuring the safety, efficacy, and quality control of these treatments is paramount. Additionally, factors such as diet, environment, and genetics all interact with the microbiome, complicating the development of standardized treatments.

The fight against obesity is multifaceted. While pharmacotherapy with agents like GLP-1 receptor agonists offers significant benefits, addressing obesity solely with medication overlooks the underlying complexities of metabolism and energy balance.

Microbiome therapies present an exciting frontier in obesity treatment. By modulating the gut microbiota through diet, prebiotics, probiotics, or postbiotics, we may influence hormone levels and metabolic pathways in a more natural and sustainable manner.

As research progresses, a combination of approaches—lifestyle modifications, pharmacotherapy, and microbiome interventions—may provide the most effective strategy for combating obesity. Understanding the intricate relationship between our bodies and the trillions of microbes we host is crucial in developing holistic and personalized treatments.