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Production of Short-Chain Fatty Acids and Hydrogen Metabolism
The stomach and proximal small intestine are responsible for most nutrient digestion and absorption in humans. In an otherwise healthy individual without prior surgical resection of the small bowel, about 85% of carbohydrates, 66%–95% of proteins, and all fats are absorbed before entering the large intestine. The indigestible carbohydrates and proteins that the colon receives represent from 10%–30% of the total ingested energyand, without the activity of the colonic microbiota, would generally be eliminated via the stool without further absorption because the human large intestine has limited digestive capability.
In the colon, microorganisms ferment starch (including resistant starch), unabsorbed sugars, cellulosic and noncellulosic polysaccharides, and mucins into short-chain fatty acids (SCFAs) and gases such as CO2, CH4, and H2. The type and quantity of SCFA and gases produced in the gut depend on multiple factors, including age, diet, especially the availability of nondigested carbohydrates, the gut microbial community composition, gut transit time, pH of the colon, and the segment of the colon. The major SCFAs produced as a result of carbohydrate and protein fermentation are acetate, propionate, and butyrate. In addition to the major SCFAs, formate, valerate, caproate, isobutyrate, 2-methyl-butyrate, and isovalerate can be produced during the breakdown of branched-chain amino acids.
Microorganisms in the gut work in symbiosis; the manner in which they interact with each other and with their environment will determine the final metabolic and environmental outcome. Because much of the gut is anaerobic, disposal of H2 strongly influences microbial interactions. As illustrated in Figure 1, fermentation breaks down complex organic compounds producing SCFA and H2. H2 is then excreted in the breath and/or consumed (oxidized) by 3 groups of microorganisms: methanogens, acetogens (homo-acetogens), and/or sulfate reducers, all of which coexist in the colon in differing proportions. These H2-based interactions are critical for fermentation to proceed because accumulation of H2 in the colon inhibits further fermentation. Our group and others have verified the enrichment of H2-oxidizing methanogens in obese compared with normal-weight individuals. Of the homo-acetogens detected in the human gut, many belong to the Firmicutes phylum, and this may partly explain why an increase inFirmicutes has been demonstrated in obesity. Sulfate-reducing bacteria (SRB) may be present within the gut even when sulfate is absent as an electron acceptor. In this case, they act as fermenters and, in some instances, may function as H2-producing acetogens, which convert acetate to CO2 and H2.
Microbial H2-producing and consuming reactions in the human intestine. SCFA, short-chain fatty acid.
With reference to the 3 enterotypes described previously, each enterotype was defined by the variation of 3 genera: Bacteroides (enterotype 1), Prevotella (enterotype 2), andRuminococcus (enterotype 3). The key microorganisms within each enterotype are involved in degradation of polymers such as plant carbohydrates. The principal microorganisms in enterotypes 1 and 2 interact with other community members to achieve sugar or mucin degradation and are intimately involved in H2 transfer and disposal. Interestingly, the enriched genera within each enterotype were shown to use different routes to generate energy from fermentable colonic substrates, suggesting that they could be triggered by the 3 distinct pathways for hydrogen disposal described above. Indeed, despite their low abundance, the sulfate reducer, Desulfovibrio, and methanogen,Methanobrevibacter, were found to be enriched in enterotypes 1 and 3, respectively.
Absorption of Monosaccharides and SCFA by the Host Epithelium
Monosaccharides are directly absorbed by the intestinal epithelium via monosaccharide transporters. In a healthy individual consuming a typical Western diet, about 100–200 mM SCFAs are produced per day in the large intestine, of which about 90%–95% are absorbed in the colon. The molar ratio of acetate to propionate and to butyrate varies around 40:40:20 to 75:15:10 depending on the diet consumed. The absorption of SCFA is an efficient process involving passive diffusion or ion exchange.
Absorbed SCFAs are used as energy for the colonocytes or transported to various peripheral tissues for further metabolism. Butyrate is the colonic epithelial cells’ preferred nutrient for their metabolism and development. Substantial amounts of propionate traverse the colonocyte and are transported to the liver, where it serves as a substrate for gluconeogenesis or regulates cholesterol synthesis. Acetate is the principal SCFA in the blood and is an important energy source to peripheral tissues, including the liver, where acetate is used for lipogenesis and cholesterol synthesis. SCFAs absorbed in the colon contribute 6%–10% of the entire energy requirements in humans, and their contribution likely increases in humans who ingest more dietary fiber. Although SCFAs account for a relatively small portion of energy acquisition, their impact on energy balance in humans is significant because of other roles they play in energy regulation as discussed in the following sections.
SCFAs and Obesity
The abundance of SCFAs and their concentration in the colon has recently been associated with the health of humans and, pertinent to this review, linked to obesity.Transplantation of the gut microbiome from obese and lean mice to germ-free mice resulted in higher acetate and butyrate production in obese microbiome recipients. In humans, Schwiertz et al reported a greater concentration of total SCFAs, particularly propionate, in fecal samples of obese adults compared with their lean counterparts. These observations are supported by a study conducted in obese and normal-weight children. Although fecal acetate, glucose, and lactate concentrations were relatively similar in both groups, butyrate, propionate, and intermediate fermentation compounds such as formate and isobutyrate were significantly higher in the obese children.
Host-Microbial Mutualism in Energy Harvest
Microbes in the large intestine allow the host to salvage energy from otherwise indigestible carbohydrates and proteins by providing a variety of enzymes required for their metabolism. For example, Bacteroides thetaiotaomicron (B theta), a prominent commensal gut microbe, produces 226 predicted glycoside hydrolases and 15 polysaccharide lyases, whereas the human genome only contains 98 potential glycoside hydrolases.Therefore, the gut microbiota provides the human host an ability to degrade plant polysaccharides, enhancing the host’s energy balance. The genes involved in the metabolism of starch, sucrose, glucose, galactose, fructose, arabinose, mannose, and xylose, as well as fucose from host mucus, are enriched in the distal colon microbiome.Cluster of Orthologous Groups (COG) analysis has shown that the gut microbiome is dominated by genes that drive production of acetate, butyrate, lactate, and succinate. The gut microbiome is also enriched in genes that code for amino acid and vitamin synthesis and enzymes that detoxify xenobiotics such as β-glucosidase.
Enrichment of some bacterial genes in the gut microbiome has recently been linked to obesity. In an obese microbiome, Eubacterium rectale (a Firmicutes) genes that encode for primary fermentation enzymes that digest dietary polysaccharides, α- and β-galactosidases that generate acetate and butyrate, and ABC transporters were all found to be enriched. Another study involving monozygotic and dizygotic twins showed a higher abundance of Bacteroidetes and an enrichment of genes related to carbohydrate metabolism in lean individual microbiomes, whereas Firmicutes dominated the obese microbiome, which was enriched with genes related to nutrient transporters. In addition to a transporter-related mechanism, members of Firmicutes such as the Ruminococcusgenus can also degrade cellulose and produce acetate, succinate, and ethanol.
Fat Storage: Lipoprotein Lipase Activity and Gut Microorganisms
Intestinal microbes affect energy balance through metabolites they produce by regulating gene expression via complex mechanisms initiated by monosaccharides and SCFAs (Figure 2). The gut microbiota induces monosaccharide cellular uptake and stimulates hepatic triglyceride production (lipogenesis) by activating the transcription factors, carbohydrate response element binding protein (ChREBP), and sterol response element binding protein (SREBP). The product of hepatic lipogenesis, triacylglycerols, are secreted from the liver to the bloodstream in the form of very low-density lipoprotein (VLDL) and chylomicrons and influence host nutrient balance and insulin resistance.
The gut microbiome has a regulatory function on host energy metabolism. By breaking down nondigestible polysaccharides, gut microorganisms produce monosaccharides and short-chain fatty acids (SCFAs). SCFAs bind to GPR 41/43 receptors and stimulate peptide ...
SCFAs also act as signaling molecules that interact with the G-protein-coupled receptors, Gpr41 and Gpr43, expressed on adipocytes and intestinal epithelium. Propionate and butyrate have higher activity than acetate toward the Gpr41 receptor; however, all 3 SCFAs share equal potency toward GPR43. Following Gpr41 activation, SCFAs stimulate leptin expression, which suppresses appetite. Samuel et al emphasized the role of Gpr41 as a key regulator between microbial-host communications. In their investigation, mice deficient in Gpr41 (Gpr41−/−) weighed significantly less than germ-free and wild-type mice when both types of mice were colonized by gut microbes. It was speculated that the weight gain in the wild-type mice was due to an increased expression of the gut-derived hormone, peptide YY (PYY), which inhibits gut motility, thereby allowing more intestinal epithelial contact time in which to extract and absorb energy. Although Gpr43 binding by SCFAs is known to inhibit inflammatory responses, it also participates in energy regulation. Xiong et al observed an increase in both leptin expression and adipogenesis via interactions with Gpr43 in the adipose tissue of mice.
Energy balance is also associated with another key modulator, fasting-induced adipocyte factor (Fiaf). Reduced expression of Fiaf induces the activity of circulating lipoprotein lipase (LPL),50 which hydrolyzes circulating triacylglycerols to free fatty acid (FFA) at various peripheral tissues.76 The distribution of FFA deposit is not well known, but a high ratio of adipose tissue to muscle-LPL activity directs more FFA to adipose tissues, while a low ratio induces more FFA deposit to muscles.77,78 The expansion of adipose tissue, in turn, results in an inability to store surplus FFA, which raises blood FFA levels and contributes to insulin resistance.79 Backhed et al80 showed that B theta monocolonized mice increased their body fat because of bacterial suppression of Fiaf.22 Germ-free (GF) knockout mice lacking Fiaf (Fiaf−/−) have also been shown to be susceptible to diet-induced obesity because of a lower expression of the peroxisomal proliferator-activated receptor coactivator (Pgc-1α) that increases expression of genes regulating fatty acid oxidation.
Adipocytes have an important role in obesity as a source of hormones, such as leptin and adiponectin.81 Adipocytes sense the increase of SCFA levels produced by intestinal microbe fermentation and respond by inducing leptin production. Leptin signals the brain to regulate the appetite and energy expenditure, thereby tightly connecting host energy balance.82 Adiponectin is associated with adenosine monophosphate-activated protein kinase (AMPK), an enzyme that monitors cellular energy status and stimulates fatty acid oxidation in peripheral tissues. Increased AMPK activity was shown to prevent GF mice from diet-induced obesity.80 In obesity, the level of adiponectin decreases,83 causing a deactivation of AMPK and leading to a reduction in fatty acid oxidation and an increased influx of free fatty acids into the liver.84
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