How tiny microorganisms lead to big changes: the role of the microbiome in obesity

By Ellie Fung

In the midst of the current pandemic, it is easy to forget about the trillion other microbial species that thrive within humans apart from COVID-19. But what if a subset of these microbes has the potential to elevate the severity and fatality of coronavirus infections by contributing to obesity (Sanchis-Gomar et al., 2020)? In the last decade, the human gut microbiome has been pushed to the limelight, for it serves a number of physiological functions and directly influences health of the host. Specifically, recent findings in rodent models and, to a lesser extent, human metagenomic studies have linked obesity to the communities residing in the gastrointestinal tract.

The gut microbiota possesses 100 times more genes that its host (Qin et al., 2010) and thus raises functional diversity of the host, or the number and abundance of different metabolic pathways. In particular, gut bacteria improves energy extraction by breaking down otherwise indigestible complex polysaccharides into short-chain fatty acids (SCFAs) such as butyrate (which acts as a primary energy source for colonic epithelial cells), and propionate and acetate (which contribute to hepatic lipogenesis and gluconeogenesis) (Muscogiuri et al., 2019).

Two phyla, Gram-negative Bacteroidetes and Gram-positive (for the most part) Firmicutes, constitute 90% of the total bacterial species part of the gut microbiota (Castaner et al., 2018). More diverse microbiomes are shown to contribute to greater global metabolic potential, thus improving overall health by performing and regulating physiological and metabolic processes that the host is incapable of (Conteville, Oliveira-Ferreira & Vicente, 2019). In a now famous experiment, one set of germ-free mice were inoculated with the gut microbiota of an obese human twin, leading to increased adiposity of the mice, whereas the second set of mice mice that were inoculated with the microbiota of the second lean twin, remained lean (Ridaura et al., 2013). Thus, microbiome composition may possibly reflect the overall metabolic status of an individual. Dysbiosis, or disturbance of the bacterial community composition (Davis, 2016), is characterised in obese individuals by a lowered bacterial diversity and a higher proportion of Firmicutes at the expense of Bacteroidetes when compared to lean individuals (Sun et al., 2018).

The complex mechanisms behind the relationship between obesity and the gut microbiota are still not fully understood, but it has been proposed that dysbiosis may enhance the biosynthesis of SCFAs and hence excess accumulation of adipose. Obese rodent models demonstrated 50% more Firmicutes and 50% less Bacteroidetes than lean mice, along with a greater abundance of enzymes involved in polysaccharide digestion and fermentation (Ley et al., 2005). In line with this, the obese mice also had higher intestinal concentrations of SCFA and lower faecal energy losses, suggesting a greater efficiency in energy extraction from digestate (Ramakrishna, 2013). In humans, genetic sequencing of faecal samples showed that obese individuals had lower bacterial diversity and almost 90% less Bacteroidetes, and when these individuals lost up to 25% of weight on a low-fat or low-carbohydrate diet, the bacterial composition shifted to be more akin to that of a lean individual’s (Ley et al., 2005). However, it should be noted that faecal microbiota compositions display differences to colonic microbiota compositions and hence may not accurately reflect the reality of the gut microbiota. Findings on the significance of the

Bacteroidetes:Firmicutes ratio in health have also been inconsistent in various studies (Davis, 2016).

Another proposed mechanism is the microbiota’s influence on fat deposition and storage. Lipoprotein lipase released by adipose and muscle tissues increases cellular uptake of circulating triglycerides for storage as adipose or for energy production (Bäckhed et al., 2004). In the obese, elevated Firmicutes levels may be able to change colonic genetic expression by suppressing the release of circulating fasting-induced adiposity factor, an inhibitor of lipoprotein lipases, which would promote triglyceride deposition and white fat storage (Muscogiuri et al., 2019).

Dysbiosis may also disturb intestinal integrity and permeability, increasing absorption of molecules normally barred from entering the bloodstream, a condition coined “leaky gut”. As such, pathogen-associated molecular patterns, such as bacterial lipopolysaccharides (LPS) from the lysis of Gram-negative bacteria, may escape the gut lumen and move into circulation. In one study involving genetically obese mice, elevated levels of circulating LPS were found along with increased intestinal permeability (Ramakrishna, 2013). This is postulated to stimulate activation of toll-like receptor 4 on immune cells, and induce the LPS-triggered release of pro-inflammatory cytokines as well as the development of insulin resistance, both of which are seen in obese humans (Muscogiuri et al., 2019). It should be noted that these mechanisms are still not firmly established, and there is still much debate regarding the specific role of the gut microbiota in human obesity (Sun et al., 2018).

Despite the recognition of the role of the gut microbiota towards overall health and rapid technical advancements in the field, there is still much speculation towards the complex interactions between the gut microbiota and the human host. Most findings are a result of animal studies, but these models do display some physiological and metabolic differences to humans, while human studies may have been influenced by uncontrollable dietary, genetic and environmental factors that could also affect the microbiota (Davis, 2016). Nevertheless, it is still worth keeping in mind that global health is not only susceptible to lockdown-inducing microbes. The community within our gastrointestinal tracts may have a significant part to play in another modern pandemic: obesity.

References:

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Castaner, O., Goday, A., Park, Y., Lee, S., Magkos, F., Shiow, S. T. E. & Schröder, H. (2018) The Gut Microbiome Profile in Obesity: A Systematic Review. International Journal of Endocrinology. 2018 4095789. Available from: doi: 10.1155/2018/4095789.

Conteville, L. C., Oliveira-Ferreira, J. & Vicente, A. C. P. (2019) Gut Microbiome Biomarkers and Functional Diversity Within an Amazonian Semi-Nomadic Hunter–Gatherer Group. Frontiers in Microbiology. 10 1743. Available from: https://www.frontiersin.org/article/10.3389/fmicb.2019.01743.

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Muscogiuri, G., Cantone, E., Cassarano, S., Tuccinardi, D., Barrea, L., Savastano, S. & Colao, A. (2019) Gut microbiota: a new path to treat obesity. International Journal of Obesity Supplements. 9 (1), 10-19. Available from: doi: 10.1038/s41367-019-0011-7.

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Sun, L., Ma, L., Ma, Y., Zhang, F., Zhao, C. & Nie, Y. (2018) Insights into the role of gut microbiota in obesity: pathogenesis, mechanisms, and therapeutic perspectives. Protein & Cell. 9 (5), 397-403. Available from: doi: 10.1007/s13238-018-0546-3.

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