Re-shaping the Gut, Re-shaping the Body?: Gut Microbiota and its Influence on Obesity

Obesity is a public-health challenge with complex causes beyond simple caloric imbalance. Emerging evidence points towards the gut microbial ecosystem - known as the gut microbiota - as a biological factor influencing energy homeostasis, metabolism and inflammation. The interactions between diet, environment and microbiota may in part help explain why many individuals may struggle to either lose weight or maintain weight loss. Recent advances in our understanding of gut microbiota-obesity links outline plausible mechanisms and therapeutic oopportunities when tackling the issue of weight fluctuations.

Experimental Observations

Various germ-free mouse experiments have been conducted that established that the presence or absence of gut microbes have significantly influenced fat storage and energy metabolism. Where mice devoid of microbiota resist diet-induced obesity compared with conventional mice. Germ-free mice and conventional mice were put on high-fat diets (HFDs) and observed. HFD induced visible changes in their microbiota such as a weaker intenstinal barrier, more lipopolysaccharides in blood circulation which are not only a long chain fatty

acid and harder to break down but also cause systemic inflammation leading to insulin resistance/obesity.

Microbiota transfer experiments between obese and lean mice have gained sufficient evidence towards the role our gut could be playing in regards to our weight. These experiments involved leptin, a hormone produced mainly by fat cells that signals to the brain to regulate long-term energy balance, suppress appetite, and decrease fat consumption. A donor mouse that is obese (genetically ob/ob and leptin deficient), would be compared to a germ-free mouse and researchers would transplant the gut microbiota of the ob/ob mice into the germ-free mice, continuing to keep their diets and lifestyles identical and consistent. Within two weeks, the mice that had received the obese microbiota gained 60% more total body fat than those that received lean microbiota, even though the same amount of food was being consumed. It was seen that obese-donor microbiota had a higher ratio of firmicutes to bacteroidetes, which are two dominant bacterial phyla in the human gut. This imbalance leads to greater energy harvesting from indigestible carbohydrates, leading to higher levels of fatty acids and evidence of increase energy extraction and fat growth.

These experimentations have led to further investigation where diet came into play - obese and/ or lean microbiota was fed into germ-fre epice and they were fed different diets; between high-fat/high-sugar, and low-fat/high-fiber). This resulted in the high-fat, low-fiber diet to cause the obese-donor microbiota to induce obesity much faster and more severely than the high-fiber diet where the effect was mostly prevented. The high-fiber diet helps gut microbiota by providing food for beneficial bacteria to ferment, which produces short-chain fatty acids (SCFAs) like acetate. These SCFAs have numerous health benefits, such as reducing inflammation and improving metabolic health. Fiber also increases the diversity and abundance of beneficial microbes.

Some other mechanisms linking gut microbiota to obesity include:

Gut Barrier Integrity, Endotoxemia & Inflammation

• An altered microbiota may compromise gut‐epithelial integrity, leading to increased translocation of microbial products such as lipopolysaccharide (LPS) into circulation (so-called “metabolic endotoxaemia”). This can trigger low‐grade systemic inflammation, alter insulin signalling, and favour adipose tissue dysfunction.

Microbiota as Bioreactors for Bioactive Compounds

• The gut microbiota‐host interface generates various metabolites beyond SCFAs (e.g., secondary bile acids, indoles, branched‐chain amino acids) which can influence adipose tissue, liver metabolism, and systemic energy balance.

Therapeutic Implications: Modulating Gut Microbiota in Obesity

Dietary Interventions, Prebiotics & Probiotics

• Increasing dietary fibre, prebiotic supplementation, and probiotic administration aim to shift the gut microbiota toward a more favourable configuration. The Yale piece recommends more fibre, probiotics and prebiotics in diet to increase “good bacteria”. Clinical studies show interventions like inulin-propionate ester can modulate the microbiota, metabolites and improve insulin sensitivity.

Exercise and Lifestyle

• Exercise not only increases energy expenditure but also appears to favourably alter gut microbiota composition.

Fecal Microbiota Transplantation (FMT)

• There is growing interest in FMT (transferring gut flora from healthy donors) as a way to restore microbial balance in dysbiotic hosts. While still experimental, current studies and tests have proven effective.

Microbial Metabolite Therapeutics

• Some metabolites derived from gut microbes (or modulation of their receptors) may become drug candidates. For example, SCFA receptor agonists or modulators of bile acid signalling are being explored.

The gut microbiota emerges as a key player in obesity and metabolic disease, mediating influences on energy harvest, gut barrier integrity, inflammation and host hormonal/metabolic pathways. While preclinical evidence is strong, translation into effective human therapies remains in the works. Modulating the gut microbiota via diet, prebiotics/probiotics, exercise, and potentially FMT or metabolite-based therapies holds promise as an supplement to conventional obesity management. Ultimately, personalized microbiome‐based interventions may form part of future multi-modal strategies to prevent and treat obesity.

References

Geng, J., Ni, Q., Sun, W., Li, L., & Feng, X. (2022). The links between gut microbiota and obesity and obesity-related diseases. Biomedicine & Pharmacotherapy, 147, Article 112678. https://doi.org/10.1016/j.biopha.2022.112678 

Liu, R., Hong, J., Xu, X., Feng, Q., Zhang, D., Gu, Y., Shi, J., Zhao, S., Liu, W., Wang, X., Xia, H., Liu, Z., Cui, B., Liang, P., Xi, L., Jin, J., Ying, X., Wang, X., & Ning, G. (2021). Gut microbiota in obesity. World Journal of Gastroenterology, 27(25), 3310-3325. doi: 10.3748/wjg.v27.i25.3837

Van Hul, M., & Cani, P. D. (2023). Gut microbiota and metabolic disorders: How the gut–brain axis impacts obesity. Nature Reviews Endocrinology, 19, 83-98. https://doi.org/10.1038/s41574-022-00794-0

Yale School of Medicine. (2023, March 9). Treating obesity with gut microbiota. Yale Medicine News. https://medicine.yale.edu/news-article/treating-obesity-with-gut-microbiota/

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