Initial findings linking gut microbiota and obesity: insights from animal models
Even though obesity is the result of a long-term imbalance between energy intake and energy expenditure, lifestyle interventions aimed at restoring that imbalance do not work for everybody. In recent years, increasing evidence has linked obesity to the gut microbiota.
Initial findings in rats two decades ago showed that changes in the gut microbiota caused by fermentable fiber such as inulin-type fructans (e.g., inulin or oligofructose) reduced body weight and adipose mass in rats by involving gut peptides that regulate appetite. Additional findings showed that slim germ-free mice colonized with a normal gut microbiota gained more body fat by 60% and increased their insulin resistance, even though they reduced their food intake. When using a humanized mouse model, researchers showed that mice receiving the microbiota from obese human donors gained more weight as compared to their counterparts receiving the microbiota from a genetically-identical twin pair but which was lean. However, the germ-free model widely used in elucidating the causal role of the microbiota during obesity also has its caveats, as the housing conditions of mice can lead to contradictory results in the context of obesity (see here and here).
The difficulty of translating mouse results into the human context
When data across different human studies were analyzed, the connection between obesity and gut microbiota composition was less strong. While gut microbiota composition is an important contributor of weight gain in mouse models, it may not be the most important factor driving human weight changes. This can be explained by the fact that different factors that should be considered as confounding variables in human microbiome studies (e.g., social environment and social pressure, multiple dietary factors, specific drugs and bariatric surgery) can affect both the composition and diversity of the gut microbiota. So far, there is no clear hallmark of obesity based on the gut microbiota composition and the so called “Firmicutes/Bacteroidetes ratio” is one of the example that should no longer be used.
Weight-loss interventions that affect the gut microbiota
The most widely studied weight-loss interventions that shape the gut microbiota and host hormones include dietary patterns (e.g., Mediterranean diet, fiber-enriched diet and ketogenic diet), fasting, physical activity, some medications (e.g., anti-obesity drugs such as Orlistat and glucose lowering drugs such as Metformin), fecal microbiota transplantation and bariatric surgery.
Diet is the intervention with the strongest impact on the gut microbiota and a Mediterranean diet rich in fiber is the dietary pattern supported by human data with the most evidence to support its use for improving cardiometabolic health. In contrast, the benefits of the ketogenic diet for promoting weight loss that come mostly from mice data are not conclusive. While intermittent fasting is another popular diet used for losing weight, available studies are limited and most of the time of short duration, which limits making general recommendations for weight loss. Therefore, the best method for losing weight is probably based on personalizing dietary advice with the help of a registered dietitian, while the science remains limited on the use of the results of what kind of microbes live in our gut as means of helping with losing weight.
Targeting the human gut microbiota with specific bacteria linked to beneficial effects in the context of obesity such as on insulin resistance and pre-diabetes is also another feasible option. The case of Akkermansia muciniphila is a key example. This bacterium is a normal inhabitant of the human gut. It has been shown that both live bacteria and pasteurized A. muciniphila (i.e., heat-inactivated form) may improve insulin sensitivity, total cholesterol and liver dysfunction and decrease blood inflammatory markers when supplemented for three months to people who met the criteria for metabolic syndrome. Although, no specific effects on body weight were observed in this study.
Instead of administering a few bacteria in low doses in form of a probiotic, consortia of bacteria also offer a potential new treatment for weight management. However, while a few randomized placebo-controlled studies have explored the administration of fecal microbiota transplants in patients with obesity and metabolic syndrome, their efficacy is limited and relies largely not only on donors’ diet and gut microbiota composition, but on the recipient gut microbiota.
The mechanisms by which microbiota-targeted interventions impact host metabolism involve many potential factors such as the production of short-chain fatty acids, endocannabinoids, tryptophan metabolites and bile acids. For instance, both butyrate and propionate stimulate the secretion of gut peptides such as glucagon-like peptide 1 (GLP1), peptide tyrosine tyrosine (PYY) and GLP2. These effects can contribute to reduce food intake, improve glucose metabolism, maintain inflammation at bay and keep anaerobic conditions in the gut lumen. These changes can also prevent the metabolic endotoxemia that accompanies obesity by preventing lipopolysaccharide (LPS) leakage into the bloodstream. Strikingly, specific microbial profiles have been found in the liver, adipose tissue and plasma in people with morbid obesity and diabetes, whereas their relevance to host metabolism remains to be seen.
To sum up, while the first treatment for cardiometabolic disorders is a healthy diet and sufficient exercise, gut microbiota-related interventions have brought new hope despite being a new field of research. One challenge that should be overcome is to move away from simple associations between shifts in the gut microbiota at the taxonomic level and the features of obesity. Instead, also exploring the metabolic capacity of the intestinal microbiota and metabolites produced seems to be more relevant in terms of health outcomes. Trying to avoid the classification of gut microorganisms as “friend” or “foe” can also help in advancing the field, as can measuring confounders that can impact the effects of the gut microbiota on the host metabolism.
Van Hul M, Cani PD. The gut microbiota in obesity and weight management: microbes as friends or foe? Nat Rev Endocrinol. 2023; 19(5):258-71. doi: 10.1038/s41574-022-00794-0.