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As the field of microbiome research progresses, it is becoming increasingly clear that the microbes residing in and on the body play vital roles in the regulation of host physiology and metabolism. Perhaps most notably, the gut microbiota has been identified as a major modulator of the host metabolic, immune, and nervous systems via the secretion of metabolites that can enter the circulation and interact with our tissues.
In a recent review published in the journal Genome Medicine entitled “Metabolic control by the microbiome”, Cox et al review some of the most well-established currently characterized microbiome-host interactions to help inform the development of microbiota-based therapeutics and diagnostics. Here, we will summarize their findings and outline the implications for the development of novel microbiome-centered technologies.
The two major areas in which the microbiome can influence the host are via the modulation of
Here we will focus on the interplay between the microbiome and systemic metabolism.
Systemic metabolism encompasses the metabolic inputs and outputs into all the cells and tissues of the body. These processes are tightly coordinated to ensure that each organ meets its metabolic demands. Emerging research implicates the microbiota’s ability to modulate these interactions at two primary levels: energy balance and metabolite balance.
Energy balance is determined by both energy intake and energy expenditure, both of which can be influenced by the microbiome according to recent animal studies.
The microbiome can modulate energy intake via two distinct mechanisms, one direct and one indirect:
With regards to the digestion of macronutrients, research has demonstrated that the composition of the gut microbiome dictates the extent to which calories from food are absorbed versus excreted. In fact, comparisons between the gut microbe communities of lean and obese individuals have suggested that differences in these communities significantly contribute to energy harvesting. One microbe implicated in mediating these differences is Akkermansia muciniphila, which resides in the mucus layer and helps to control gut permeability. Indeed, research indicates that lean individuals have disproportionately more Akkermansia relative to those with obesity. Additionally, dimethylglycine—a metabolite produced by certain bacteria—has been shown to enhance energy extraction from food and thereby contribute to weight gain.
Meanwhile, the indirect influence of the microbiome on energy intake via the modulation of hunger and satiety is being increasingly probed as a mechanism by which gut bacteria influence body fatness. For example, the microbial metabolites known as short chain fatty acids (SCFAs) have been shown to trigger the endogenous secretion of gastric peptides that signal satiety such as
SCFAs are produced by commensal bacteria upon their fermentation of complex carbohydrates. The literature indicates that not only do the enteroendocrine cells of the intestines express receptors for these SCFAs but, upon binding of SCFAs to these receptors, the secretion of PYY and GLP-1 is triggered. This negative feedback loop is believed to serve an adaptive role in regulation of the physiology in response to environmental variables such as nutrient availability. Other molecules aside from SCFAs are also implicated in modulation of gastric hormone secretion. For instance, E. coli has been shown to produce a molecule that mimics melanocyte-stimulating hormone, triggering PYY release and stimulating POMC neurons in the brain. These neurons are responsible for regulating body weight by suppressing appetite in the presence of energy surplus and enhancing appetite during times of energy deficit.
Energy expenditure is facilitated by both stimulation of energy-consuming growth pathways (anabolism) as well as the burning of energy to support activity levels and basal metabolic needs (catabolism). The link between catabolism and the gut biome is believed to exist primarily via modulation of non-shivering thermogenesis (NST). NST is a form of heat production within the body that occurs within special fat cells known as brown and beige adipocytes. These cells appear brown or beige, respectively, because of their higher levels of mitochondria relative to white fat. Whereas brown fat has a distinct cellular lineage and cannot be developed as an adult, beige fat can be intentionally cultivated. Beiging of white fat, particularly subcutaneous white fat, occurs in response to cold exposure, thereby increasing the metabolic capacity of this once relatively dormant fat-storage tissue. NST helps to generate body heat in response to cold exposure and, in doing so, increases whole body energy expenditure.
Research studying the relationship between the microbiota and NST has been conflicting. Early studies found that germ-free mice had increased levels of beige fat and improved insulin sensitivity, while later studies found the opposite—that depletion of the microbiome impaired energy expenditure and heat production. Thus, more research, particularly in humans, is needed to understand how microbiota composition may be leveraged to boost NST and energy expenditure to improve metabolic health.
Similar to energy balance, maintenance of metabolite balance is also crucial to ensure that all organ systems have access to the nutrients and building blocks that they need for optimal function. Namely, the production and consumption of the three major macronutrients are key for the health of the whole body:
It has been reported frequently in the literature that germ-free mice exhibit a blunted blood glucose response to carbohydrate-containing meals. Despite the reliability of this observation, the mechanism underlying this phenomenon is not yet totally understood. However, recent research has begun to provide some hints. For example, imidazole propionate—a metabolite produced by certain bacteria from the amino acid histidine—has been shown to inhibit insulin signaling and is associated with type 2 diabetes. The microbiome has also been shown to regulate the expression of genes involved in glucose metabolism and insulin signaling. More recently, it has been demonstrated that the microbiota plays a role in the neuronal regulation of glucose balance. Namely, the microbially-produced SCFA acetate was shown to activate the parasympathetic nervous system and promote glucose-stimulated insulin secretion in rodent models. Meanwhile, the SCFA propionate resulted in the opposite: sympathetic activation and insulin resistance. In humans, decreases in the blood levels of propionate have been observed with weight loss, which supports the notion that propionate may be inversely proportional with metabolic health.
Essential amino acids are amino acids that cannot be synthesized by our human cells and are thus essential dietary nutrients, and the microbiome is known to play an important role in dietary amino acid metabolism. For example, microbes in the gut are known to breakdown dietary tryptophan into metabolites like indoles, tryptamine, and kynurenine. Tryptamine induces the release of serotonin and stimulates gastrointestinal motility, while kynurenine plays various roles in the regulation of inflammation, metabolism, and neuronal functioning. Moreover, the amino acids phenylalanine and tyrosine can be broken down by gut microbes into active metabolites that influence intestinal permeability and immune cell function.
It has been observed that germ-free mice are largely resistant to obesity in response to a high-fat, high-sugar diet and excrete larger amounts of lipids in their stool. In humans, it has been exhibited that key bacterial species is able to convert dietary cholesterol into a poorly absorbed sterol, and that this species is associated with lower serum cholesterol levels. Additionally, the consumption of saturated fats has been shown to increase inflammation in fat tissue in a microbiome-dependent manner. Recent research has shown that microbes in the gut regulate gut-adjacent immune cell secretion of the cytokine IL-22 which modulates the expression of lipid transporters in intestinal cells. Meanwhile, SCFAs have also been shown to upregulate IL-22 secretion. These are but a few examples of the extensive crosstalk between gut microbes and host physiology and metabolism that have the potential to be leveraged in both health and disease.
Figure 1. Crosstalk between the host and microbiome [1]
Perhaps the most important reason for characterizing the interactions outlined above is to facilitate the development of new clinical approaches in the treatment of complex chronic diseases like type 2 diabetes. Microbiome-based therapeutics are among the most exciting cutting-edge therapies due to their projected low toxicity and non-invasive nature. Although the only microbiome-centered clinical intervention is fecal matter transplant (FMT) for the treatment of C. difficile infection, new approaches are being developed at an increasing rate namely in the areas of:
One such example is the administration of an Akkermansia muciniphila postbiotic in a recent clinical trial, where preliminary results suggest that administration of inactivated A. muciniphila was capable of improving insulin sensitivity and reducing blood cholesterol. In rodents, A. muciniphilawas also shown to secrete a factor that promotes thermogenesis and GLP-1 release from enteroendocrine cells.
Overall, continued research focusing on the characterization of both 1) microbiome signatures across different disease states and 2) the active metabolites produced by key species will facilitate the development of targeted therapeutic interventions for a wide range of pathologies.
Written by: Dr. Alexis Cowan
[1] Cox TO, Lundgren P, Nath K, Thaiss CA. Metabolic control by the microbiome. Genome Med. 2022 Jul 29;14(1):80. doi: 10.1186/s13073-022-01092-0. PMID: 35906678; PMCID: PMC9338551.
