Butyrate’s Myriad Effects on the Gut and Overall Health
In this article we take a look at butyrate, a four-carbon short-chain fatty acid (SCFA), which plays an important role in health and perhaps even the aging process.
It is a naturally occurring product of the microbial fermentation of dietary fiber in the colon. Once produced, butyrate can be subject to many fates: it may be used by cells that make up the intestinal wall (enterocytes) for energy; it may function as a histone deacetylase (HDAC) to alter the expression of genes; it may act as a local signaling molecule; and it may make its way to the bloodstream, where it can be metabolized by the liver or deliver signals in parts of the brain and other organ systems. In the colon alone, butyrate has profound effects on colonocytes, inflamed cells, and cancer cells.
A gut microbiome staple
Butyrate is naturally fermented by friendly bacteria through two metabolic pathways. In the first pathway, butyryl-CoA becomes butyryl-phosphate and then butyrate via butyrate kinase. In the second pathway, acetate CoA-transferase moves the CoA part of butyryl-CoA to acetate, thus forming butyrate and acetyl-CoA [1,2]. Butyrate exerts its influence over metabolism through the receptors GPR109A, GPR43, and GPR41.
70% of the energy obtained by enterocytes is derived from butyrate. The primary producers of butyrate are beneficial bacteria such as Ruminococcus and Faecalibacterium . These bacteria account for 5-10% of the total microbiome .
Gene expression and signaling
Butyrate inhibits histone deacetylases , which typically reduce gene expression by removing an acetyl group from lysine on the histone molecule. This process creates a positive charge that causes the spooling up of DNA, which makes gene expression impossible. Therefore, the inhibition of HDACs prevents the spooling up of DNA, making it accessible to the gene expression machinery of the cell . Butyrate’s anti-tumor and anti-inflammatory actions likely occur through the inhibition of histone deacetylases (HDACs). HDAC inhibition has been shown to inhibit cell proliferation and differentiation [7,8]. Although the mechanism is unclear, it is believed that butyrate interferes with the ability of HDACs to reach lysine on histone molecules .
Butyrate participates in local and whole-organism signaling networks by binding to G-protein coupled receptors (GPACs) to exert a broad spectrum of effects. These effects include enhancement of intestinal barrier function, mucosal immunity, and intestinal homeostasis. In turn, these effects can lead to improvements in energy metabolism, promotion of weight loss, reduction of inflammation, and proper functioning of the gut-brain axis, which serves as a communication hub between intestinal bacteria and the brain .
Butyrate affects normal intestinal cells, inflamed intestinal cells, colon cancer cells, and neutrophils, among other immune cells in the colon, in interesting and different ways to maintain gut health.
An energy source and a regulator
As the primary energy source for intestinal cells, butyrate is critical to intestinal cell and general health. Without their normal energy substrate, intestinal cells’ metabolism would be crippled and these cells would be unable to optimally perform their normal tasks. One of the most important tasks is the maintenance of barrier function. Healthy enterocytes around the colon (colonocytes) produce a layer of mucus that enables safe interaction with the microbes inhabiting the intestinal lumen.
Butyrate improves the function of intestinal epithelial cells by upregulating genes like MUC2, which reinforce the mucosal layer and thereby guard the intestines against pathogens . Many bacteria reside in this mucosal layer. Butyrate improves intestinal barrier function by modulating the expression of tight junctions between colonocytes . Tight junctions bind colonocytes to one another to form a continuous intercellular barrier, which is necessary to separate tissue spaces and regulate the selective movement of solutes across the intestinal wall .
The way butyrate enters normal intestinal cells also plays a significant role in the absorption of water. Butyrate can be transported into cells in one of three ways. If it is undissociated, it will not carry a charge and can diffuse directly through the cell membrane. If that is not the case, then there are two transporters. Transporters are basically proteins that are engineered in a way that enables them to cross shuttle-specific molecules, like butyrate, across the cellular membrane.
In this case, however, these two transporters- monocarboxylate transporter 1 (MCT1) and sodium monocarboxylate transporter 1 (SMCT 1) also transport hydrogen ions (H+) and sodium (Na+), respectively. When butyrate enters the intestinal cells, it carries along sodium, which attracts water, and this mechanism optimizes water absorption in the intestine. Given that the bulk of chemical reactions in the body require water, this is quite important. This also acts as an antidiarrheal mechanism .
Another effect of butyrate is the lowering of intestinal pH. The mechanism by which this occurs is not clear; however, it does directly affect the local microbiome, as different microbes flourish optimally at different pH levels .
Another means by which butyrate impacts barrier function is through the activation of AMPK in different layers of the intestine . AMPK activation promotes the differentiation of enterocytes and aids in the establishment of cellular polarity, as both strengthen the epithelial barrier. Additionally, AMPK also promotes the assembly of tight junctions and related adherens junctions by phosphorylating the proteins that make up apical junctions, junctional anchors, and cytoskeletons .
Finally, in normal intestinal cells, butyrate regulates DNA expression to maintain normal intestinal homeostasis. This mechanism occurs through butyrate’s ability to inhibit histone deacetylases (HDACs). HDACs tend to dampen gene expression, but butyrate can balance out this effect. Butyrate also binds to the common receptor GPR109A, which can lead to both activation and inhibition of certain gene sets. Of course, butyrate metabolism and its influence over gene expression is complex [5,9]. Collectively, these effects help optimize barrier function and protect the body from invasion by unwanted antigenic molecules.
Cells of the colon exist near microbes and their products. Consequently, this can trigger inflammation in otherwise normal colonocytes. Butyrate participates in the control of inflammation in such instances. In inflamed cells, activated transcription factors lead to the production of inflammatory cytokines and related proteins, including NF-κB . NF-κB triggers the transcription of inflammatory mediators and proteins, which are themselves released by inflamed cells . Without control mechanisms in place, such as those governed by butyrate, this process could quickly spiral out of control.
In inflamed colon cells, HDACs can suppress important genes that normally maintain colon function and health. Butyrate can enter inflamed cells through the transporters to inhibit HDACs and thereby enable the activation of genes such as glutathiol-s-transferases (GSTs). GSTs reduce oxidative stress associated with inflammation . Its activation of the GPR109A receptor has been shown to inhibit NF-κB activation . Butyrate may also reduce inflammation by upregulating PPAR-γ and inhibiting IFN-γ [21,22].
Butyrate also exerts antiproliferative effects over cancer cells in the colon. The effect of butyrate on inflamed cells also applies to cancer cells, which frequently release inflammatory cytokines . Butyrate dampens the expression of NF-κB in cancer cells . Hypermethylation is a common feature in cancer cells, and typically, areas of hypermethylation are located on promoter regions that initiate transcription.
Often, these patterns of methylation imbue cancer cells with the ability to proliferate indefinitely and evade apoptosis . HDACs are often more active in colon cancer cells, which are driven to proliferate and require a great deal of energy to do so. They are known to this by switching to glucose as their primary source of energy, and butyrate interferes with this process .
Additionally, there is an increase in HIF-1α and VEGF, which are factors that promote blood vessel formation (angiogenesis) . Butyrate can enter a cancer cell or activate GPR109A, which activates p53 independently of HDAC. p53 is a transcription factor that regulates the expression of the stress response genes and many anti-proliferative processes, and p53 inhibits cancer cell growth and proliferation by activating p21, a stop signal for cellular division. Furthermore, activated p53 can initiate apoptosis .
Butyrate within the cell can inhibit HDAC directly, and cancer cells, for reasons that are unclear, are more sensitive to HDAC inhibitors [27,28]. Butyrate also binds to GPR41 in cancer cells, which has also been shown to inhibit cell growth through HDAC inhibition . Inhibition of HDACs in cancer cells enables the expression of genes that code for proteins, such as glutathione, that reduce oxidative damage .
Interestingly, at lower concentrations, butyrate can stimulate cellular growth and DNA synthesis ; at higher concentrations, it can induce growth arrest in the G1 phase or trigger apoptosis. Concentrations of butyrate greater than 5-8 millimoles are known to induce apoptosis .
Gut immune function effects
Butyrate, through a variety of mechanisms, has a wide array of effects on immune function in the gut. The immense surface area of the intestine requires continual surveillance to deal with potentially infectious microbes. Enterocytes continually generate low-grade inflammation as part of this process . If this process is destabilized and inflammation begins to spiral out of control, oxidative damage and eventually cancer may occur [12,34].
The inflammatory cytokines IFN-γ, TNF-α, IL-1β, and IL-6 are inhibited in the presence of butyrate. Butyrate can affect neutrophils and other immune cells in a variety of ways, as it binds to GPR43 and GPR41 receptors [35,36]. Through the signaling cascades initiated by the activation of these receptors, butyrate enables neutrophils to better attract other neutrophils to remove unwanted substances, potentially pathogenic substances in the colon .
GPR43 is most highly expressed on certain immune cells, polymorphonuclear neutrophils, which suggests that butyrate and similar SCFAs may play a role in the activation of leukocytes. Butyrate has a stronger affinity for GPR41, however, which is primarily present on immune and fat cells. The function of these receptors varies according to the tissue or cell type in which they are expressed.
Butyrate also acts on GPR109A to activate the inflammasome pathway in immune cells, including macrophages and dendrites that reside in the colon. This results in the differentiation of regulatory T cells and IL-10-producing T cells . Butyrate’s activation of GPR109A is also responsible for the secretion of IL-18, a pro-inflammatory cytokine, from enterocytes , showing how this biology is complex and, occasionally, seemingly paradoxical. The anti-inflammatory properties of butyrate are achieved through the inhibition of pro-inflammatory enzymes and cytokine production .
Does butyrate induce obesity or facilitate weight loss?
The effect of butyrate on body composition is controversial. Evidence indicates that butyrate improves glucose homeostasis in rodents . Further evidence points to butyrate-mediated downregulation of PPAR-γ, which shifts metabolism away from the creation of fat (lipogenesis) and toward its oxidation . Downregulation of PPAR-γ would also be expected to increase the ratio of AMP to ATP, further stimulating oxidative metabolism in the liver and fat tissue .
Butyrate enhances the secretion of GLP-1 and peptide YY [44,45]. GLP-1 is a gastrointestinal hormone secreted by enteroendocrine L cells in the distal gut. It exerts multiple biological effects, including a glucose-dependent insulin-stimulating effect on pancreatic B cells, reduction in appetite, and inhibition of gastric emptying . Butyrate has also been shown to increase the secretion of growth hormone, which increases the use of fat for energy and spares the use of muscle tissue for energy .
Butyrate regulates appetite and eating behavior through the gut-brain axis. There is an elaborate communications network between the gut microbiome and the brain . Known as the gut-brain axis, this communications hub is comprised of the central nervous system, enteric nervous system, and different types of sensory and motor neurons that are involved in signal transmission between the gut and brain . Two-way communications between the brain and gut also involve the vagus nerve, neuroimmune pathways, and neuroendocrine pathways [50,51].
Butyrate is a microbiome metabolite that has been shown to exert its influence through the gut-brain axis in numerous ways including enhancement of the proportion of cholinergic enteric neurons via epigenetic mechanisms . Butyrate is also able to cross the blood-brain barrier and activate the vagus nerve and hypothalamus, thereby regulating both appetite and eating behavior . Butyrate also directly regulates GPR41-mediated sympathetic nervous system activity to control energy expenditure and maintain metabolic homeostasis.
A 2021 study on rabbits indicated that butyrate, injected into the abdomen, affects lipid metabolism by reducing lipid synthesis and enhancing decomposition of adipose tissue. The study found the mechanism was governed through the GPR41-mediated ERK-AMPK pathway .
Not all studies support the notion that butyrate contributes to weight loss. Obese people have more SCFAs than lean people, and some evidence indicates that these SCFAs can end up being converted to carbohydrates via gluconeogenesis, lipids via lipogenesis, and cholesterol [31,47,55]. Therefore, butyrate can play a role in promoting obesity if it is used as an energy substrate or if the signaling action of butyrate ifs exerted on glycolipid metabolism. This seems especially true in women.
More studies are needed to clarify the specific factors that lead to weight loss in most situations but weight gain in a minority of others [56,57].
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