November 10, 2022 8 min read
The relationship between the gut microbiome and the gastrointestinal system is somewhat intuitive given their direct interface with one another. Research in the space has further characterized the important functional interplay between intestinal cells and adjacent microbes.
Perhaps more surprising, however, are the links being discovered between the
microbiota and various other tissues within the body including the brain and the skeletal muscle.
In a recent Frontiers review entitled “Role of brain-gut-muscle axis in human health and energy homeostasis”, Yin et al outline the currently identified mechanisms by which the microbes residing within the gut can alter the function of the brain and muscle. Here we will summarize their findings and their implications.
The gut microbiome is the vast ecosystem of bacteria, fungi, protozoa, and viruses that reside within the gastrointestinal tract. Upwards of 100 trillion bacteria reside in and on our bodies, with roughly 80% of these found in the colon.
These bacteria constitute a diverse array of species that collectively encode over 100x more gene products than our human genome. As a result, these microbes are incredible chemists that have the ability to perform metabolic feats that human cells cannot accomplish. Because of their sheer biomass and their production of
thousands of metabolites that can enter into the host circulation, the gut microbiome is being increasingly recognized as a major player in human health and disease.
Indeed, specific changes in microbiome composition have been associated with metabolic disorders including obesity and diabetes, as well as neuropsychiatric illnesses such as depression, anxiety, and eating disorders. With regards to their influences on metabolic health, research has shown that metabolites produced by the microbiota have the ability to modulate inflammation, insulin secretion, energy production, and glucose levels via a gut-brain-muscle axis.
Muscle is both a metabolic organ, serving as the major site of glucose disposal, as well as an endocrine organ where it secretes factors known as myokines that can elicit changes in mood, learning, and memory by acting directly on the brain or indirectly via modulation of gut function.
Perhaps the most well-studied of the microbial metabolites are the short chain fatty acids (SCFAs):
SCFAs are produced by the fermentation of dietary fibers by key species of bacteria within the gut. Butyrate is readily taken up by colonocytes (i.e. colon cells) which rely on their molecule as a primary fuel source. These SCFAs can also enter into the host circulation where they can interact with various tissues including the brain and small intestine. The interaction of SCFAs with the enteroendocrine cells of the small intestine result in increased secretion of factors including:
These two influence satiety and feeding behavior by sending messages to the brain. Additionally, the blood brain barrier (BBB; i.e. the membrane that protects the brain and mediates the passage of only specific molecules) expresses the transporters needed to take up SCFAs, facilitating the direct interaction between the brain and these molecules. In the BBB, SCFAs up-regulate the expression of proteins needed to maintain the tight junctions of this membrane. Like the breakdown of the tight junctions within the gut leads to “leaky gut”, the breakdown of the tight junctions in the BBB leads to “leaky brain”, which drives up neuroinflammation and neurodegeneration over time. In the brain, SCFAs:
Another group of metabolites associated with the microbiome are the secondary bile acids. Bile acids are molecules created from cholesterol in the liver and serve as an important factors within bile. Any bile acids that aren’t absorbed during the digestion process pass into the colon where they undergo transformation into secondary bile acids by the bacteria therein. Two of the major secondary bile acids are
Bile acids increase gut permeability by disrupting tight junctions and, thus, also negatively impact the brain by increasing BBB permeability. These metabolites also result in the release of GLP-1 and fibroblast growth factor 19 (FGF19) from the intestines. GLP-1 interacts with the brain and vagus nerve to regulate feeding and blood glucose levels, whereas FGF19 creates an anorexic effect by inhibiting the signaling in the brain that promotes feeding.
Bile acids also have immunological effects. UDCA decreases inflammation by modulating microglia within the brain, and TUDCA inhibits the pro-inflammatory pathways in various cell types within the body.
The microbes within the gut readily convert the amino acid tryptophan into a variety of metabolites including:
Each of these impact the central nervous system by binding to a specific receptors known as the aryl hydrocarbon receptor (AhR), and have implications in brain inflammation and neuropsychiatric illnesses. Indeed, microbial tryptophan metabolites have been shown to activate AhR and inhibit inflammatory responses and neurodegeneration.
The maintenance of a health gut barrier is absolutely essential for protecting the body’s inside world from the outside world. Importantly, in addition to the gut and the microbes therein impacting brain function, the brain also directly influences the function and integrity of the gut. Indeed, the brain can modulate gut function and structure and, in doing so, regulate intestinal
There are three primary routes by which the brain and gut communicate:
In the nervous system, key cells in the medulla of the brain trigger the release of norepinephrine in response to physical and psychological stress which results in inhibition of intestinal motility and changes to electrolyte balance within the gut.
In the immune system, stress-induced modulation of cytokine secretion from immune cells affects the intestinal barrier. Reductions in secreted IgA by intestinal cells in response to stress can cause unfavorable changes to the microbial ecosystem and increased inflammation. This is because secretory immunoglobulins like IgA are confer protection in mucosal environments and provide a substrate within which commensal microbes can reside.
In the endocrine system, stress leads to the activation of the hypothalamic-pituitary-adrenal (HPA) axis which results in the secretion of corticotropin-releasing hormone—a primary regulator of the HPA axis. This hormone leads to the release of corticotropic-releasing factor (CRF) which ultimately leads to the production of glucocorticoids (also known as “stress hormones”) from the adrenal glands.
Glucocorticoids accelerate inflammatory responses throughout the body, while inhibiting immune function broadly and shutting off intestinal immunity almost entirely through down-regulation of IgA antibody production. Furthermore, glucocorticoids inhibit proteins within the tight junctions of the intestinal barrier leading to increased gut permeability.
However, this increase in permeability actually enhances the function of the gut barrier acutely. Chronic stress on the other hand leads to a breakdown of the mucus-producing cells of the gut and results in intestinal inflammation.
There are three peptides secreted by enteroendocrine cells within the small intestine that play key roles in the regulation of energy balance (i.e. energy intake and expenditure) via their interactions with the central nervous system
GLP-1 is released in response to feeding. It both stimulates the vagus nerve and promoes insulin secretion from the pancreas. Subsequently, insulin increases energy expenditure by triggering sympathetic activity and tissue glucose oxidation. GLP-1 also reduces rates of gastric emptying and nutrient absorption, which results in increased satiety. For these reasons, it is perhaps unsurprising that GLP-1 receptor agonists (i.e. activators) have been wildly popular over the past few years as treatments for obesity and type 2 diabetes.
Similar to GLP-1, PYY is also released in response to feeding, and has been shown to inhibit food intake and delay gastric emptying. Thus, both GLP-1 and PYY can support healthy energy balance by decreasing the “energy intake” side of the equation.
Ghrelin is produced in the stomach and duodenum, and its release corresponds to nutrient availability. Specifically, ghrelin levels are at their highest when an individual is fasted, and its levels plummet shortly following food ingestion. Ghrelin is a driver of appetite and food consumption, and high levels of ghrelin inhibit glucose-stimulated insulin secretion and decrease glucose tolerance. This is likely to help the body to spare glucose for the brain in a fasted state.
As we have discussed up until this point, the microbiota plays an important role in the function of the central nervous system while also regulating energy intake and expenditure at the whole-body level. Similarly, microbial metabolites including SCFAs and bile acids also play regulatory roles in skeletal muscle. In particular, SCFAs activate the AMPK pathway within muscle cells. AMPK is the pathway that signals energy scarcity, and leads to:
Additionally, SCFAs indirectly support muscle health by stimulating GLP-1 secretion from the intestine and insulin from the pancreas which also promote GLUT4 translocation in muscle. In muscle, insulin supports muscle glucose oxidation and storage. Meanwhile, GLP-1:
Acetic acid in particular has been shown to activate programs within muscle that help to maintain oxidative, slow twitch muscle fibers that are lost with long periods of inactivity or in certain disease states.
On the other hand, secondary bile acids bind to receptors on the surface of muscle cells where they boost muscle energy consumption. Additionally, these bile acids support the activation of thyroid hormone thereby promoting whole body energy expenditure, and also inhibit muscle fat accumulation.
During exercise, muscle releases myokines including
IL-6 has been shown to increase GLP-1 release from the intestines which modulates the central nervous system to affect appetite. In rodent studies, irisin has been shown to increase food intake and ghrelin levels. However, exercise-induced decreases in appetite are thought to outweigh the appetite-promoting effects of irisin via IL-6, GLP-1, and PYY which has also been shown to elevate in response to exercise.
SCFAs produced in the gut have been shown to bind to receptors on muscle cells and trigger the release of insulin-like growth factor-1 (IGF-1). In doing so, they promote glucose uptake and oxidation within muscle. Thus, SCFAs promote the maintenance of healthy muscle that is more capable of producing myokines that can go on to confer effects like appetite regulation at the level of the central nervous system.
Figure 1. The Gut-Muscle-Brain Axis 
Prebiotics—like dietary fibers, resistant starches, polyphenols, and human milk oligosaccharides (HMOs)—undergo fermentation by beneficial microbes to support the production of the SCFAs. In muscle, acetate can be directly used as a fuel source to produce energy.
Meanwhile, carbohydrate consumption triggers the release of GLP-1 from the intestines which supports insulin secretion and glycogen storage within muscle. In this way, foods rich in resistant starches can benefit muscle by both supporting SCFA production and GLP-1 release. These foods include:
Additionally, adequate protein consumption is essential for both building and maintaining healthy muscle. Consuming around 1.6 grams of protein per kilogram of body weight (roughly 110 g protein for a 150 lb individual) daily is sufficient for the maintenance and building of muscle for the general population.
This protein benchmark is especially important for individuals who are older, sedentary, or injured as these demographics are at the greatest risk for muscle loss. A higher protein consumption benchmark is appropriate for athletes, roughly of 1 g of protein per pound of body weight.
 Role of brain-gut-muscle axis in human health and energy homeostasis. Front. Nutr., 06 October 2022 Sec. Nutrition and Metabolism. https://doi.org/10.3389/fnut.2022.947033
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