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 than others? Which factors (genetic, diet, lifestyle, environmental exposures, microbiome) exert the strongest influence over type 2 diabetes risk?
Weight and metabolism are governed by a number of different 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 migrate out of the bloodstream and act on host tissues directly. The binding of insulin to its target receptors in fat, muscle, and liver tissue, for example, 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 an equilibrium.
Panacea in a Pill?
A class of drugs known as GLP-1 receptor agonists, or GLP-1s, mimic the action of a hormone called glucagon-like peptide 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 problem with GLP-1? With a natural half-life of about 90 seconds, it doesn’t last too long in the human body. However, some research from animal models suggests that this may not be a problem, as long-term benefits seem to persist even after discontinuation of therapy.
The first GLP-1 receptor agonist was introduced to the market in 2005. Derived from the saliva of a Gila monster, exenatide resembles human GLP-1 and is sometimes used as an adjunct therapy to diet and exercise for patients diagnosed with type 2 diabetes (T2D).
Over the years, various GLP-1 receptor agonists have been shown to exert beneficial effects in terms of cardiovascular parameters, blood pressure reduction, and weight loss in patients with type 2 diabetes resistant to first-line metformin therapy.
Off-label usage of the drugs for weight loss purposes has spurned some concerns, however. Robust long-term safety data on GLP-1 agonist drugs remains elusive, and many scientists and healthcare professionals worry about side effects. The drugs may cause pain hypersensitivity, and efficacy over time is another point of contention.
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 primarily of trillions of bacteria, is a major determinant of levels of insulin, glucagon-like peptide-1, peptide YY, 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, which ferment fiber into short-chain fatty acids (SCFAs) such as acetate and butyrate. These SCFAs stimulate production of glucagon-like peptide-1 and peptide YY, both of which stimulate insulin secretion.
Taking prebiotics such as inulin and oligofructose (OFS) has been shown to significantly increase circulating plasma levels of GLP-1 after meals in human trials and also helps 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.
Ruth Ley, director of the Microbiome Science at the Max Planck Institute for Developmental 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 microbes and the compounds they produce alter our metabolism.
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