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Abstract
Bacterial fermentation of dietary fiber produces short-chain fatty acids in the colon. Entry of Short Chain Fatty Acid (SCFA) in its anionic form into the colonic epithelium is mediated mostly through carrier-mediated processes; however, protonated diffusion is also a key pathway. SCFA are taken up by cells through several different transport mechanisms. H+-coupled Monocarboxylate Transporter (MCT1) and MCT4 facilitate the electroneutral transportation of SCFA. Unlike MCT4, which is found exclusively in the apical membrane of colonic epithelium, MCT1 is expressed in both the apical and basolateral membranes. Both Monocarboxylate Transport (SMCT1) and (SMCT2) are Na+-coupled, with the former mediating electro-genic transport and the latter electroneutral transport (Stanescu et al., 2022). The apical membrane is the only location where SMCT1 and SMCT2 expression can be found (Tang et al., 2019). While the molecular identification of the exchanger that couples SCFA entrance in anionic form with bicarbonate efflux remains unclear, it is known that an anion-exchange process is at work in the apical membrane (Nickerson et al., 2021). This control occurs through cell-surface receptors that receive SCFA as signaling molecules, and it is exerted mostly by the substrates of these transporters.
These transporters dramatically altered expression characterizes ulcerative colitis and colon cancer. P53 and Hypoxia Inducible Factor (HIF1) regulate transcription, and promoter methylation contributes to tumor-associated alterations (Conway & Patole, 2022). The transporters involved in the entrance and trans-cellular transport of these endotoxins in the colonic epithelium are essential factors of colonic function under healthy settings and in disease situations because SCFA are essential for proper colonic health.
Introduction
The term commensal is often used to refer to the bacteria found in a healthy colon, with the clear implication that the bacteria gain nothing by living alongside their host. Recently, however, it has become clear that the symbiotic character of the connection is borne out by the fact that the bacterium and the host both benefit from cohabitation. Simply put, the host gives the bacteria a site to colonize and all the resources they need to thrive and grow (Mirzaei et al., 2022). More and more research in recent years has shown that colonic bacteria play an essential role in promoting and sustaining digestive and intestinal health (Kong, 2019). Due to the proximity of trillions of bacteria in the intestine and colonic lumen, the intestinal tract constitutes the bodys greatest immune system. Unlike pathogenic bacteria, the bacteria in a healthy colon are useful to the host. Thus, the mucosal immune system proactively learns to accept them without an unduly aggressive inflammatory response.
The intestinal epithelial cells separate the bacterial invaders from the host and mediate communication between the bacteria and lamina propria immune cells. Most contact between these organisms seems to occur via chemical signals (Guo et al., 2020). Various metabolites produced by gut bacteria operate as chemical messengers between the microorganisms and the host. Bacteria produce these metabolites as intermediates in their intrinsic metabolic pathways due to the enzymatic chemical alteration of particular feed components. Each of these metabolites has some positive impact on the host organism (Quanz et al., 2018). These include short-chain fatty acids, lactate, results of tryptophan breakdown, and altered fatty acids. These bacterial metabolites have been shown to interact with various cell-surface G-protein-coupled sensors, intracellular neurotransmitters, and enzymes in the intestinal epithelium and mucosal lymphocytes.
SCFA are a key contributor, numerically and qualitatively, to the group of bacterial metabolites that positively affect the host. SCFAs host-cell molecular targets are found on and within the target cells. Butyrate is the agonist for GPR109A, and all three SCFA are agonists for GPR43; these two cell-surface G-protein-coupled receptors are targets for SCFA in the colonic epithelium and mucosal immune cells (Rao et al., 2020). These receptors are located on the luminal side of the apical surface of the colonic epithelium (Khan et al., 2020). Therefore, luminal SCFA may activate them without penetrating the cells. By decreasing cAMP levels and increasing intracellular Ca2+, these receptors act as two reactions to induce certain biological responses. SCFA also have intracellular activities, which need their entrance into colonic epithelial cells and extra-cellular actions.
Finally, to influence immune cells in the lamina propria, SCFA must get through the epithelial cells and into the serosa. SCFA cannot create intracellular consequences in colonic epithelial cells or influence mucosal immune cells without transport systems that allow their entrance from the lumen into cells and transcellular transit (Rao et al., 2020). The positive effects of SCFA on the host are mostly determined by SCFA transporters present in the intestinal epithelium. Ulcerative colitis and colon cancer are two clinical diseases linked to abnormalities in the function and expression of these transporters. Here, we compile what is currently known about the expression, activity, and regulation of SCFA carriers in colonic epithelial cells, including their molecular identification.
Monocarboxylate Transporter 1
Characterization at the molecular level and Broad Functional Characteristics Monocarboxylate transporter 1 (MCT1) has a fascinating backstory that began with its molecular discovery. Mevalonate is a precursor for the endogenous production of cholesterol. This mutant protein was first cloned from a particular clone of Chinese hamster ovary (CHO) cells capable of transporting mevalonate. In contrast to its parent CHO cell line, this clonal cell line could survive in the presence of small amounts of mevalonate in culture media when endogenous production of mevalonate was suppressed using a pharmacological agent. The original cell line did not behave this way (Karunaratne et al., 2020). Finally, the transporters responsible for succinate uptake in the clonal CHO cell line were cloned and demonstrated to have mevalonate transport activity. Interestingly, the same amounts of mRNA and protein for the cloned transporter were present in the parent cell line that lacked mevalonate transport function as in the mutant cell line (Leu et al., 2021). As it turned out, the parent cell line produced a wild-type version of the transporter.
However, the mutant cell lines point mutation resulted in the replacement of a single amino acid, resulting in a gain of function to transport mevalonate. The wild-type transporters precise transport role was not understood (Wang et al., 2021). Two years later, the same research group that cloned the mutant transporter determined that the wild-type transporter also served as an H+-coupled carrier for monocarboxylates like lactate and pyruvate. The transporter was given the name monocarboxylate transporter one because of its role in transporting monocarboxylate (MCT1). MCT1 is classified as SLC16A1 by the Human Genome Organization (Braga et al., 2020). MCT1 recognizes aliphatic short-chain monocarboxylates as substrates and is stereo-selective for L-lactate over D-lactate, and the transport mechanism is electroneutral due to the 1:1 H+: monocarboxylate stoichiometry (Massidda et al., 2018). L-lactate has a relatively small Michaelis constant (in the millimolar range). -Cyano-4-hydroxycinnamate, bioactive flavonoids, and thiol-modifying compounds are all known to inhibit MCT1 (Granlund et al 2020). However, several recently discovered inhibitors that are selective for MCT1 and have inhibitor efficacy in the nanomolar range; AstraZenecas AR-C155858 and AZD3965 are two such examples.
Human SLC16A1 is a 500-amino-acid protein with 12 putative polypeptide chains; its amino and carboxy termini are anticipated to be on the intracellular side of the plasma membranes. Human ancestors inherited the gene from chromosome 1 (Chen et al., 2019). Five exons make up the 44 kb MCT1 gene, although only exons 24 are responsible for the proteins production (Rao et al., 2020). The nuclear factor for the immunoglobulin light chain in B cells, accelerator proteins 1 and 2, T-cell factor/lymphoid promoter element, and the oncogene c-MYC have binding sites in the promoter region. CD147, also known as basigin or EMMPRIN, is a widely expressed glycoprotein that aids MCT1 in its transport to and location in the plasma membrane. MCT1 and CD147 continue to be closely linked in the plasma membrane.
Though thiol-modifying compounds may decrease MCT1s transport activity, removing all cysteine residues in MCT1 does not render the transporter insensitive to inhibition, suggesting that the suppression is not due to immediate alteration of any of the transporters thiol groups. Specifically, CD147, an accessory protein, is to blame for this blockage (Blaak et al., 2020). This demonstrates that CD147 plays an important role in MCT1s transport function beyond its chaperone role (Sandforth et al., 2020). It has been shown that MCT1 interacts with embigin. This protein has structural similarities with basigin and is part of the same immunoglobulin superfamily subfamily in certain cell types.
The natural chaperone for MCT1 in most cell types is basigin, while in vitro ectopic expression experiments have shown that embigin and basigin may interact with MCT1 and serve as chaperones (Guan et al., 2019). Homology modeling using the known structure of Escherichia coli glycerol-3-phosphate carrier allowed us to identify the locations on MCT1 that interact with its chaperones basigin and embigin, as well as the selective inhibitor AR-C155858 (Abbaspour, 2018).Basins trans-membrane domain is near MCT1s kinase domains 3 and 6.
Intestinal MCT1 Expression and the Role of SCFA Transport MCT1 mRNA and protein have been found in almost every human tissue (Rao et al., 2020). It should be no surprise that MCT1 is widely expressed, given that lactate is a substrate for the transporter and almost all tissues produce or use this molecule in metabolic processes. Many other endogenous metabolites, including acetate, propionate, and pyruvate, fall within the substrate selectivity of MCT1. -hydroxybutyrate, the major ketone body, is a substrate for MCT1 (Shah 2018). Its circulation levels rise dramatically during hunger to millimolar concentrations from hepatic production to serve as the metabolic fuel to neurons in place of glucose (Mashaqi & Gozal, 2020). This transporters link to the intestines is predicated on its ability to recognize short-chain aliphatic monocarboxylates as substrates. Short-chain monocarboxylates (SCFA) are produced when bacteria in the intestines ferment fibre in the food. Also, lactate may be found in fermented milk products like yoghurt and cheese. Some of these food components and microbial metabolites are absorbed efficiently by enterocytes in the small intestine and colonocytes in the colon.
Therefore, monocarboxylates must be transported into the cells by the apical membrane (which faces the lumen) and out of the cells (via the basolateral membrane, which faces the serosa) into the portal blood. The colon, which produces a lot of SCFA, is an important setting to observe this process. In light of this, several researchers have looked at the transport of SCFA, especially butyrate, in apical membrane vesicles and basolateral membrane vesicles isolated from the colonic epithelium (Zhong et al., 2020). Butyrate uptake was increased by an internally directed H+ gradient and an outward directed HCO3 gradient, indicating two possible pathways for butyrate uptake: SCFA/H+ co-transport and SCFA/HCO3 exchange, respectively, in both membrane preparations. However, the uptake was saturable and inhibitable by structurally identical SCFA, indicating that the co-transport mechanism was not due to nonionic diffusion.
Regulation of MCT1 Expression in Normal Colon
There is physiological and therapeutic importance to the regulation of MCT1 in the intestine because of the impact of SCFA on colonic health. The therapeutic benefits of these bacterial metabolites are mediated by their intracellular activities; therefore, decreased expression of the transporter would result in the poor entry of SCFA into the intestine and colonic epithelial cells. IEC6 from the rat small intestine and Caco-2 from the human colon are two examples of intestinal cell lines that express MCT1 and have been shown to take part in H+-coupled absorption of butyrate and other SCFA (Sadforth et al., 2020). The expression and function of MCT1 and the mechanisms that regulate them have been studied largely in Caco-2 cells.
The transcription factor AP2 mediates this impact. Somatostatin, an intestinal neuropeptide, similarly activates the p38 mitogen-activated protein kinase signaling pathway to increase MCT1 and CD147 expression. Regarding repressing MCT1 expression, however, transcription factors Upstream stimulatory factor (USF1) and USF2 do not need to use the Sp1 site in the MCT1 promoter (Mashaqi & Gozal, 2020). Butyrates capacity to regulate MCT1 via affecting plasma membrane transporter protein density provides further evidence that luminal butyrate is a crucial regulator of MCT1 activity in the colon.
Epigenetic regulation through butyrate-dependent suppression of histone deacetylase (HDAC) and the cell-surface receptor GPR109A for butyrate have both been implicated in these observations. The GPR109A-mediated increase in MCT1 protein density in the plasma membrane is pertussis toxin-sensitive and is linked with lower cellular levels of cAMP. However, unlike protein kinase A and protein kinase C, the transcription factor NF-B is not required for butyrate-induced overexpression of MCT1 (Mashaqi & Gozal, 2020). The substrate-dependent modulation of MCT1 expression in Caco-2 cells could also occur in vivo. Oral ingestion of dietary fibre enhances the overall cellular MCT1 protein levels and the apical membrane expression and function of MCT1 in the cecum and colon in animal models. It is believed that these dietary modifications enhance the formation of butyrate by bacteria in the cecum and colon, which subsequently activate the expression of MCT1 (Huang et al., 2021). The presence of cis regions in the MCT1 promoter predicted to respond to Wnt-signalling is noteworthy. This route is critical in controlling the proliferation and differentiation of intestinal and colonic epithelial stem cells. Physiologically, the expression of MCT1 in the intestine may be regulated by Wnt-signalling.
Alteration in MCT1 Expression in Colon Disease states
At least in part, SCFA prevents colonic inflammation and colon carcinogenesis by acting on the epithelial cells lining the colon. It has been shown that the expression and function of SCFA transporters are key modifiers of risk for colitis and colon cancer since this is the principal mechanism through which these bacterial metabolites enter the colonic epithelium (Ndou, 2018). Reduced expression of SCFA transporters has been linked to a higher risk for and severity of colitis and colon cancer, which makes sense given the recognized benefits of SCFA (Jha et al., 2020). However, at butyrate concentrations typically encountered in the lumen (10-15 mmol/L), MCT1 is expected to be the primary contributor to butyrate absorption into colonic epithelial cells since the Michaelis constant for MCT1-mediated butyrate absorption is in the 4 to 10 mmol/L range (Puri et at., 2020). The decreased butyrate accessibility to colonic epithelial cells and the information it provides as to the processes underlying the pathophysiology of both illnesses suggest that alterations in MCT1 transcription in the colon may have clinical and therapeutic importance in colitis and colon cancer.
Since lactate is a substrate for MCT1, it stands to reason that MCT1 is closely linked to cancer. Although oxygen is present, most cancer cells still produce lactate as a glycolytic end product, a phenomenon known as the Warburg effect (Drozdzik et al., 2020). Without lactate removal, intracellular acidification would occur, with deleterious consequences on cancer cells (Li et al., 2021). Most cancer cells upregulate MCT1, a lactate/H+ symporter, to rid themselves of lactic acid. Positive regulation of MCT1 expression by c-MYC is relevant to the functional role of this transporter in cancer cells (Rao et al., 2020). Colon cancer and MCT1 are not as easily linked as malignancies of other organs. Under physiological circumstances, this transporter allows SCFA to enter colonic epithelial cells from the lumen.
Genetic mutations in MCT1 resulting in the loss of functionality have been found in humans, and their effects have been documented (Ndou, 2018). The inability to properly use ketone bodies in extrahepatic organs as a consequence of homozygosity for mutations that cause the deactivation of the transporter results in severe ketoacidosis, which may be exacerbated by fasting or infections even in young children (Rao, 2022). The afflicted youngsters also suffer from major delays in their development. Lactate transport in erythrocytes is poor. Ketone body excretion in the urine is also increased, at least during ketoacidosis episodes. Patients may also develop an intolerance for physical activity. These signs and symptoms are reduced when glucose is given intravenously. The most common ketone body in circulation, beta-hydroxybutyrate, is used largely in the brain, skeletal muscle, and cardiac muscle and is carried into cells and across the blood-brain barrier via the mitochondrial coenzyme transporter 1 (MCT1). As a result, loss-of-function mutations in MCT1 would have the reported clinical implications.
However, whether or not these individuals have a distinct colon clinical or pathological profile is unknown. Interestingly, mutations in MCT1 leading to enhanced expression of the transporter have also been described (Beloueche-Babari et al., 2020). Their workout routines cause hyperinsulinism in these people. Enhanced MCT1-mediated entrance and subsequent consumption of lactate for ATP synthesis in pancreatic cells is the probable mechanism driving this occurrence, leading to increased insulin output (Holy et al., 2019). Homozygous deletion of MCT1 in mice is related to axon damage and neuronal loss in the brain and is embryonically fatal.
In contrast, a high-fat diet does not promote obesity in individuals with a heterozygous deletion, who show enhanced insulin sensitivity and no signs of hepatic steatosis. Even if the effects and severity vary between people and mice with loss of function of MCT1, our results show a critical role for this transporter in energy balance (Kong et al., 2019). While the synthesis of SCFA is most apparent in the large bowel in nonruminants, bacterial fermenting occurs predominantly in the foregut in ruminants (Kobayashi et al., 2021). Therefore, it is important to learn how monocarboxylate transporters affect SCFA absorption in the ruminant digestive tract. The overall cellular levels of MCT1 protein in the rumen are in the following order: rumen > cecum > colon > small intestine (Kong et al., 2019). Protein expression is mostly localized in the basolateral membrane, indicating that the transporter is involved in the outflow of SCFA from the cells into the subepithelial side rather than in the inflow of SCFA into cells through the lumen.
Conclusion
Once thought to be absorbed mostly by nonionic diffusion, it is understood that the bacterially produced SCFA are principally carrier-mediated during colon absorption. Colonic epithelial cells have been shown to exhibit SCFA transporters in both the lumen-facing apical membrane and the serosa-facing basolateral membrane. The transporters involved in the entrance of SCFA, especially butyrate, are essential for colon health because SCFA serve as the primary metabolic fuel for the colonic epithelium (Rahman et al., 2021). There are three major transporters involved in SCFA processing in the colon.
The butyrate in the luminal compartment of the colon and the bacteria that live there stimulate the expression of MCT1 and SMCT1 in the colon. SCFA prevents colitis and colon cancer by reducing inflammation and inhibiting carcinogenesis in the colon. Hence MCT1 and SMCT1 are considered suppressor genes. It follows that colitis and colon cancer are associated with a large reduction in the levels of these two transporters in the colon. To sum up, the SCFA transporters MCT1 and SMCT1 are crucial for the favourable effects of colonic bacteria and their fermentation products on colon health and offer a connection between them. However, more information is needed about the relative contribution of the ATP-dependent efflux transporter ABCG2, which takes butyrate as a substrate. It is expressed in the apical membrane to the total processing of butyrate by the colonic epithelium.
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Li, B., Yang, Q., L
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