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A human gut microbial gene catalogue established by metagenomic sequencing
Gut bacteria use mostly fermentation to generate energy, converting sugars, in part, to short-chain fatty acid, that are used by the host as energy source. Acetate is important for muscle, heart and brain cells, propionate is used in host hepatic neoglucogenic processes, whereas, in addition, butyrate is important for enterocytes. Beyond short-chain fatty acid, a number of amino acids are indispensable to humans and can be provided by bacteria. Similarly, bacteria can contribute certain vitamins (for example, biotin, phylloquinone) to the host. All of the steps of biosynthesis of these molecules are encoded by the minimal metagenome.
A human gut microbial gene catalogue established by metagenomic sequencing - Nature
Microbiome–host systems interactions: protective effects of propionate upon the blood–brain barrier
Of the SCFAs, acetate is produced in the greatest quantity as a result of fermentation in the large intestine, followed by propionate and butyrate [37]. Over 95% of SCFAs produced are absorbed within the colon with virtually none appearing in the urine or faeces [35, 38].
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propionate has been shown to stimulate intestinal gluconeogenesis through direct stimulation of enteric–CNS pathways [42] and increased intestinal propionate has been associated with reduced stress behaviours [43] and reward pathway activity [44] in mice and humans
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Given that the main source of circulating propionate in humans is the intestinal microbiota [57, 58], following fermentation of non-digestible carbohydrates by select bacterial species (Fig. 4), propionate thus represents a paradigm of commensal, mutually beneficial interactions between the host and microbiota. Moreover, consumption of food containing non-digestible carbohydrates increases circulating propionate concentrations approximately tenfold [59, 60], suggesting that the anti-inflammatory effects of the SCFA upon the cerebrovascular endothelium may be another facet of the known health benefits of high-fibre diets [61].
Production of propionate by the human gut microbiota. Propionate can be produced directly or indirectly by cross-feeding from succinate and lactate producers (e.g. Selenomonas, Megasphaera and Veillonella spp.). Image produced using information taken from [57]. *Akkermansia muciniphila is known to produce propionate; it is thought to do this via the succinate pathway [57]
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That BBB integrity is influenced by the gut microbiota and that SCFAs may play a role in this process was recently emphasised in studies of germ-free vs. specific pathogen-free mice, with germ-free animals exhibiting enhanced BBB permeability and disrupted cerebral endothelial tight junctions [32]. These permeability defects were reversed fully upon conventionalisation with a pathogen-free microbiota and partially with monocultures producing various SCFAs. Moreover, defective BBB integrity could be ameliorated at least partially by extended oral administration of sodium butyrate.
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While the major ligands for this receptor, propionate and butyrate, were both able to prevent a functional decline in BBB integrity induced by LPS exposure, this was not the case for acetate, an SCFA with greater potency at FFAR2 [39]. Future work investigating the relative contributions of the two receptor types to BBB integrity will be informative.
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Notably, and perhaps unsurprisingly, SCFAs cannot fully recapitulate the BBB-restoring effects of conventionalisation of germ-free animals, as revealed in the current work and previously [32, 33].
Microbiome–host systems interactions: protective effects of propionate upon the blood–brain barrier - Microbiome
Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss
Also, a 14-day nutritional supplementation of sodium propionate (Propicum) in healthy humans significantly decreased serum parameters for bone resorption (Fig. 1k) while leaving OCN levels unchanged (Supplementary Fig. 1f).
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In accordance with direct SCFA supplementation, an 8-week exposure to fiber-rich diet (Supplementary Table 1) led to an increased bone mass (Fig. 1m) and decreased trabecular separation (Fig. 1n) associated with decreased osteoclast numbers and CTX-I serum levels (Fig. 1o and Supplementary Fig. 1h).
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Enhanced abundance of Prevotella copri has been described in early RA(rheumatoid arthritis)7. We therefore transferred three representative species from the genus Prevotella separately into WT mice and analyzed systemic bone mass 8 weeks later. Transfer of all Prevotella spp. significantly increased osteoclast numbers (Supplementary Fig. 1n) and the relative abundance of Prevotella spp. durably for 8 weeks (Supplementary Fig. 1o, p) but decreased SCFA levels (Fig. 1p) and systemic bone mass in the recipient mice (Fig. 1q, r),
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Treatments with C3(Propionate) and C4(Butyrate) effectively prevented OVX(ovariectomy)-induced(postmenopausal) bone loss (Fig. 3a–c). At the cellular level, we observed a complete rescue of OVX-induced osteoclast formation after C3 and C4 treatment (Fig. 3d).
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C3/C4 treatment significantly attenuated the severity of inflammation in the collagen-induced arthritis (CIA) mouse model (Fig. 4a, b), and systemic bone mass was increased after C3/C4 treatment (Fig. 4c).
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Of note, the observed effects seem to be largely independent of GPR43 as treatment with C3/C4 also maintained bone mass and suppressed osteoclast-specific genes in GPR43 −/− mice (Supplementary Fig. 4d–h).
Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss - Nature Communications
Phylogenetic distribution of three pathways for propionate production within the human gut microbiota
Butyrate, in particular, is believed to counteract colorectal cancer and inflammation (Hamer et al., 2008; Berni Canani et al., 2012). Propionate also has potential health-promoting effects that include anti-lipogenic, cholesterol-lowering, anti-inflammatory and anti-carcinogenic action (Hosseini et al., 2011; Vinolo et al., 2011). Furthermore, the potential role of propionate in enhancing satiety (Arora et al., 2011) is of increasing interest given the rising incidence of obesity across the world. Recent proteomic work suggests that some of the effects of propionate at the cellular level differ from the action of butyrate (Kilner et al., 2012).
Phylogenetic distribution of three pathways for propionate production within the human gut microbiota - The ISME Journal
Beneficial effect of the short-chain fatty acid propionate on vascular calcification through intestinal microbiota remodelling
According to correlation analysis, intestinal barrier parameters (crypt depth, intestinal wall thickness, goblet cell count and MUC2 accumulation) were negatively correlated with LPS content but were positively correlated with SCFA levels. Moreover, D-lactate and diamine oxidase formed negative correlations with SCFAs (Fig. 7h). In summary, these results suggest that the propionate-modulated intestinal microbiota exerts a protective function in the intestinal mucosal barrier.
Beneficial effect of the short-chain fatty acid propionate on vascular calcification through intestinal microbiota remodelling - Microbiome
Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer
Subsequently, EHMT2 downregulation by propionate-induced tumor necrosis factor α-induced protein 1 (TNFAIP1) expression by reducing H3K9me2 levels to promote colon cancer apoptosis.
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found that propionate treatment was related to the cell growth GO terms “negative regulation of biological process” and “positive regulation of cell death” (Supplementary Fig. S2). In addition, using the DAVID, we found enrichment of the negative regulation of growth, positive regulation of apoptosis, cell adhesion, and inflammatory response (Fig. 1F). Moreover, KEGG pathway analysis revealed that propionate treatment affected apoptosis, the TNF signaling pathway, and transcriptional misregulation in cancer (Fig. 1G). GSEA found that apoptosis was regulated by SP(Sodium Propionate) treatment compared with the control group (Fig. 1H).
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Propionate treatment did not affect the viability of human intestinal organoids treated with several concentrations of propionate (Fig. 1I, J and Supplementary Fig. S3). Thus, through hIO experiments, we suggest that the reaction concentration of propionate in this study effectively suppressed the viability of colon cancer cell lines but not the normal human intestine.
Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer - The ISME Journal
Commensal gut microbiota-derived acetate and propionate enhance heart adaptation in response to cardiac pressure overload in mice
We previously showed that mice depleted of gut microbiota with antibiotics (ABX mice) were more prone to cardiac rupture after infarction, suggesting that the gut microbiota impacts cardiac structural remodeling following injury. Here, we aimed to determine whether the gut microbiota is required for adaptive cardiac remodeling in response to pressure overload stress.
Commensal gut microbiota-derived acetate and propionate enhance heart adaptation in response to cardiac pressure overload in mice
A Gut Commensal-Produced Metabolite Mediates Colonization Resistance to Salmonella Infection
It is increasingly clear that SCFAs have anti-pathogenic properties. However, the effects that have been described within a mammalian host are largely a result of indirect mechanisms of immune activation rather than direct limitation of growth (Jung et al., 2015, Peng et al., 2009). In addition, SCFAs are known to regulate Salmonella virulence programs (El-Gedaily et al., 1997, Huang et al., 2008, Van Immerseel, 2003). In this study, we demonstrated that Bacteroides spp. limitation of intestinal Salmonella expansion through production of propionate is mediated by direct limitation of pathogen growth (Figures 5, 6, and 7). We were surprised to find that the magnitude of in vitro propionate-mediated growth inhibition we observed is quite large. If we imagine directly competing S. Typhimurium grown with and without the presence of propionate, the growth inhibition provided by propionate could compound to a 10- to 50-fold reduction in bacterial fitness over time. This difference is recapitulated in our in vivo experiments, where we observed a 10- to 100-fold decrease in S. Typhimurium levels in animals colonized with Bacteroides spp. or treated with an inulin propionate ester.
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Our findings suggest that when intracellular concentrations of propionate are high, cells are unable to raise their internal pH to facilitate cellular functions required for growth, leading to an extended lag time (Figure 5).
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Bacteroides spp. metabolize succinate through enzymatic steps culminating in the production of propionate as well as ATP and CO2, which are crucial for Bacteroides to survive in carbon-limiting conditions such as the intestinal lumen (Dimroth and Schink, 1998, Reichardt et al., 2014). Bacteroides spp. release propionate into the environment rather than utilize the metabolite for growth; the genomes of sequenced Bacteroides spp. do not contain genes homologous to known propionate utilization loci (Hammelman et al., 1996). Furthermore, human studies show direct correlations between Bacteroides spp. abundance and propionate levels (Salonen et al., 2014). Taken together, these observations are consistent with propionate as a byproduct of Bacteroides metabolism. Viewed in this light, our work presents an example in which a byproduct of normal commensal metabolism provides colonization resistance against invading enteric pathogens.
Propionate and other SCFAs have been utilized to control enteric pathogen infection in agricultural animals since the 1960s, and have even been proposed as a dietary supplement alternative to antibiotic treatment (Ricke, 2003). We demonstrated that the addition of Bacteroides spp. to mice leads to propionate production that is sufficient to limit pathogen expansion (Figure 7). Moreover, we showed that the prebiotic inulin propionate ester is sufficient to limit Salmonella fecal shedding, establishing that propionate mediates colonization resistance (Figure 7). Overall, these findings suggest that the addition of live Bacteroides spp., other SCFA-producing commensals, or even SCFA-related prebiotics to agricultural animals or humans may alter the intestinal environment to help control spread of Salmonella and perhaps other related enteric Enterobacteriaceae pathogens.
Effects of carbon dioxide on cell growth and propionic acid production from glycerol and glucose by Propionibacterium acidipropionici
In glycerol fermentation, the volumetric productivity of propionic acid with CO2 supplementation reached 2.94g/L/day, compared to 1.56g/L/day without CO2. The cell growth using glycerol was also significantly enhanced with CO2. In addition, the yield and productivity of succinate, the main intermediate in Wood-Werkman cycle, increased 81% and 280%, respectively; consistent with the increased activities of pyruvate carboxylase and propionyl CoA transferase, two key enzymes in the Wood-Werkman cycle. However, in glucose fermentation CO2 had minimal effect on propionic acid production and cell growth.
Effects of carbon dioxide on cell growth and propionic acid production from glycerol and glucose by Propionibacterium acidipropionici - PubMed
Short-Chain Fatty-Acid-Producing Bacteria: Key Components of the Human Gut Microbiota
Interestingly, the produced acetate benefits the growth of propionate and butyrate-producing bacteria and, at the same time, butyrate favors the growth of Bifidobacterium, leading to a cross-feeding between SCFA-producing bacteria [72,81].
Acetate production requires substrates described as acetogenic fibers (inulin, galacto-ligosaccharides, etc.) [66]. Those fibers may then enter two possible pathways: acetogenesis or carbon fixation pathway. Acetogenesis is the production of acetate, mediated by homoacetogenic bacteria, which can use both H2 and CO2, while the carbon-fixation pathway produces acetate directly from CO2 [66,82,83].
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Oral butyrate supplementation was also valued for IBDs. In UC(Ulcerative Colitis) patients, sodium butyrate microcapsules were effective in reducing the Mayo score and faecal calprotectin levels compared to mesalamine alone [172].
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On the other hand, studies evaluating the use of ketogenic diet (a low-carbohydrate, high-fat diet able to induce physiological ketosis) showed a decrease in beneficial bacteria (i.e., Bifidobacteria, Eubacterium rectale, Roseburia) and total bacterial count and abundance [20]. As a consequence, a ketogenic diet may induce a reduction in both total SCFAs and their single components [196].
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Both in vitro and in vivo studies confirmed a positive role of probiotics in increasing SCFAs [205]. The most used probiotics are those of Lactobacillus genera, mainly Lactobacillus plantarum [206,207], Lactobacillus paracasei [207], and Lactobacillus rhamnosus [208]; all the above studies confirmed, in animal models or in healthy volunteer humans, an increase in Bifidobacteria and in other beneficial microbes, leading to an increase in total SCFAs [206,207,208].
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Several recent lines of evidence suggest that that the increase in SCFAs may be a key determinant of FMT(Fecal microbiota transplantation) success in different diseases. First, in a mouse model of ischemic stroke, mice transplanted with feces rich in SCFAs, mainly butyrate, experienced an amelioration in neurological symptoms [215].
Moreover, in a randomized controlled trial where FMT from donors with balanced microbiome was more effective than placebo in reducing IBS-related symptoms, FMT increased the fecal SCFA levels, and the post-FMT increase in butyrate levels correlated inversely with symptoms [216]. Finally, in a small pilot trial, FMT from mixed lean donors was able to increase the levels of SCFAs-producing bacteria [217].
https://www.mdpi.com/2072-6643/15/9/2211
Formation of propionate and butyrate by the human colonic microbiota
Some fermentation products, including lactate, succinate and 1,2-propanediol, do not usually accumulate to high levels in the human colon of healthy adults, as they can also serve as substrates for other bacteria, including propionate and butyrate producers.
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Certain Lachnospiraceae have the ability to grow in the presence of lactate and acetate to produce butyrate, showing an overall net stoichiometry of 4 mol of lactate and 2 mol of acetate producing 3 mol of butyrate (Duncan et al., 2004).
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On the other hand, some human colonic bacteria belonging to the Negativicutes class of Firmicutes (e.g., Phascolarctobacterium succinatutens; Watanabe et al., 2012), have the ability to convert succinate to propionate (Flint et al., 2014; Reichardt et al., 2014). This activity may explain why succinate accumulation is infrequently reported for human faecal samples, although 3 of the 14 overweight human volunteers in one recent dietary study showed elevated faecal succinate concentrations (>30 mM) in samples from a non-starch polysaccharide-supplemented diet (reported in Salonen et al., 2014, Supporting Information). Other Negativicutes bacteria convert lactate to propionate either via the succinate pathway (e.g., Veillonella spp.) or via the acrylate pathway (Megasphaera elsdenii) (Reichardt et al., 2014) (Fig. 2). The acrylate pathway has also been shown to operate recently in a species of Lachnospiraceae, Coprococcus catus (Reichardt et al., 2014).
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It has been show in a rodent model that limitation of dietary iron intake can dramatically decrease the production of both butyrate and propionate as lactobacilli and Proteobacteria are favoured (Dostal et al., 2012). Populations of Roseburia-related butyrate producers appear particularly sensitive to iron availability, while in pure cultures of R. intestinalis butyrate production was favoured at high iron concentrations with a switch to lactate production under iron-deficient conditions (Dostal et al., 2015). It remains to be established whether other growth factors also have a major impact on SCFA formation.
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Incorporation of exogenous acetate via the CoA-transferase reaction results in some loss of ATP production via acetyl-phosphate, but this is more than compensated by the additional ATP formed from proton export, giving a potential maximum of 4 ATP formed per glucose metabolized when 2 mol of acetate are taken in for each mol of glucose fermented.
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Propionate and butyrate are also formed as products from peptide and amino acid fermentation (Figs. 1 and 2), although the numbers of amino acid-fermenting bacteria have been estimated to constitute less than 1% of the large intestinal microbiota (Smith and Macfarlane, 1998; Dai et al., 2011). It is estimated that the colon receives approximately 13 g of protein and peptides per day, and large amounts of soluble protein and peptides were found in intestinal contents of sudden death victims (Smith and Macfarlane, 1998). Peptides seem to be preferred over free amino acids by gut bacteria. Low gut pH and the presence of carbohydrates reduces peptide and amino acid fermentation in vitro, which helps to explain why microbial amino acid fermentation is higher in the distal than the proximal colon contents (Smith and Macfarlane, 1998). Amino acid fermentation leads to the production of potentially harmful metabolites (for example phenolic and indolic compounds, amines, ammonia) in addition to branched-chain fatty acids (BCFA) and SCFA (Smith and Macfarlane, 1997; Dai et al., 2011).
In vitro incubations of faecal slurries with individual amino acids showed that propionate was produced mainly from aspartate, alanine, threonine and methionine, whereas butyrate was a major fermentation product from glutamate, lysine, histidine, cysteine, serine and methionine (Smith and Macfarlane, 1997).
https://enviromicro-journals.onlinelibrary.wiley.com/doi/full/10.1111/1462-2920.13589
The role of diet in shaping human gut microbiota
In a mouse model, high-sugar diet (HSD) consumption significantly increased the abundance of Escherichia coli in fecal samples and promoted gut inflammation and a systemic immune response [26]. Moreover, in other mice studies, high-sugar diets induced colon inflammation compared with a standard diet by altering the composition of the gut microbiota, increasing the levels of Akkermansia muciniphila, known to produce enzymes degrading the mucus layer [27]. Short-term exposure to a high-sugar diet in mice increases susceptibility to colitis by reducing the production of short-chain fatty acids (SCFAs) and increasing gut permeability [28].
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Akkermansia muciniphila, which is a habitant of the mucus layer of the intestine has been identified as a novel beneficial organism which modulates basal metabolism in rodents and in humans [23]. The decrease in Akkermansia in case of obesity leads to a gut barrier failure and increases the gut inflammatory response via elevated expression of endotoxins and LPS [23]. Indeed, a 3-month supplementation of A.muciniphila in obese patients have shown to decrease body weight and improve liver dysfunction that appears in the context of obesity [24].
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However, in various studies, the levels of fecal SCFAs and methane would not significantly differ between omnivore and vegan/vegetarian diet [80]. In other studies, following a vegan diet could substantially reduce the abundances of potentially harmful metabolites such as lithocholic acid, BCAAs, aromatic compounds and increase the production of SCFAs and their derivatives compared with an omnivore diet [81]. A short-term 3-month dietary intervention with MD or a vegetarian diet does not induce significant gut microbial changes at the family level [82]. At the genus level, MD(Mediterranean diet) could significantly change the abundance of Enterorhabdus, Lachnoclostridium and Parabacteroides while vegetarian diet could increase the quantity of Anaerostipes, Streptococcus, and Odoribacter. Regarding SCFAs, a MD could increase the production of propionic acid while a vegetarian diet decreases it [82].
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In IBS patients, some microbial signatures of IBS subtypes could predict the response to the low FODMAP from the alterations in gut microbiota and metabolites produced [90].
https://www.sciencedirect.com/science/article/pii/S1521691823000069
The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health
It is estimated that the fermentation of 50–60 g carbohydrates per day yields to the approximated production of 500–600 mmol of SCFAs in the gut.[71]
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Acetate, propionate, and butyrate concentrations in portal blood (375 µmol/l) are almost 5 times greater than peripheral venous blood (79 µmol/l), suggesting that the gut is a principal SCFA source, whereas SCFA concentrations in the hepatic vein SCFA (148 µmol/l) are 39% of those found in portal blood.
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Omega-3 rich diets have been also associated with an increase of SCFA-producing bacteria. Indeed, in a randomized trial, 2-month of treatment with omega-3 polyunsaturated fatty acids (PUFA) capsules or drinks was given to healthy middle-aged subjects to analyze the effect of omega-3 PUFA on the human gut microbiota. An increased abundance of SCFA-producing bacteria belonging to the Lachnospira, Roseburia, Lactobacillus, and Bifidobacterium genus was reported in the subjects taken one or both formulations (capsules and drinks). Noriega et colleagues (2016) showed a significant increase of the butyrate-producing bacteria Eubacterium, Roseburia, Anaerostipes, Coprococcus, Subdoligranulum, and Pseudobutyrivibrio after 2 weeks of an omega-3 rich diet.
Other studies have also reported this association and suggested the potential beneficial role of this type of diet in CMD. For instance, a recent human study showed a significant increase in Coprococcus spp. and Bacteroides spp., and in isobutyrate and isovalerate levels after a daily supplementation of 500 mg of omega-3 fatty acid for 6 weeks.190 Likewise, Coprococcus was positively associated with the branched-chain fatty acid isobutyric acid and negatively associated with the triglyceride-rich lipoproteins VLDL and VLDL-TG, suggesting that dietary omega-3 influences the gut microbiota composition and its benefits in CVD might be mediated by gut fermentation products.190 In another study, three different diets were fed to female mice, namely control, n-3 PUFA supplemented and n-3 PUFA deficient, during gestation, and then, the male offspring continued with the same diet for 3 months.170 Deficiency of n3-PUFA in diet reduced the levels of acetate and butyrate in feces, and the Clostridiaceae family, which can produce SCFAs, was not detected in this group. Likewise, the metabolic results revealed an increase of cecal metabolites involved in energy metabolism in n-3 PUFA supplemented mice. Thus, it was suggested that the observed impairment of SCFA production might disrupt the metabolism homeostasis and thus, having an impact on metabolic diseases. In a study conducted by Balfegó and coworkers,181 gut bacterial species were determined in drug-naïve patients with T2D before and after following either a standard diet (control) or the same diet but enriched with sardines for 6 months. Individuals following the latter diet presented an increase of Bacteroides and Prevotella (acetate-producing bacteria) in comparison with the baseline. It was indicated that this diet might present benefits for cardiovascular risk.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007165/
Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease
We therefore provided a mixture of SCFAs(Short-Chain Fatty Acids), or acetate, propionate, or butyrate individually, to GF mice for 4 weeks via their drinking water. As expected based on prior work, a mixture of SCFAs was able to reduce heightened microglia densities found in GF to normal microglia numbers observed under SPF conditions (Figures 4A and 4B). This effect was recapitulated by acetate alone, but not by butyrate or propionate.
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An evaluation of TR+ plaque-associated Iba1+ microglia (those cells less than 10 mm from the TR+ plaques) revealed significantly more cells in close proximity to Ab in GF 5xFAD mice than in SPF 5xFAD mice, and acetate treatment reversed this effect (Figure 6E)
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we found reduced glucose uptake in microglia from GF 5xFAD mice, further supporting
impaired glycolysis (Figure S7E).
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Notably, supplementation of acetate restored the percentage of MXO4+ microglia to SPF levels (Figures 7D–7F), indicating that microglial phagocytosis of Ab is modified by acetate.
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Notably, microglia acquired more acetate from the medium in the presence of Ab (Figure 7L) and incorporated slightly more acetate-derived 13C into various metabolites including TCA cycle intermediates (Figures 7M and S7M), suggesting that acetate fuels at least partially the TCA cycle.
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SCFAs are known to be able to translocate from the intestine to the systemic circulation and to cross the blood-brain barrier (Frost et al., 2014). They have been reported to have various effects on immune cells including Treg cells (Duscha et al., 2020; Smith et al., 2013) or T effector cells (Qiu et al., 2019) and macrophages (Schulthess et al., 2019; Zhang et al., 2019). In our study, acetate was the most abundant SCFA in the brains of SPF mice and was significantly reduced in brains from GF(Germ-Free) mice.
High-Fiber Diet and Acetate Supplementation Change the Gut Microbiota and Prevent the Development of Hypertension and Heart Failure in Hypertensive Mice
Whereas a high-fiber diet reduced the heart/body weight ratio (P<0.0001; Figure 2D), it did not affect renal mass (P=0.73; Figure 2E). In contrast, acetate supplementation attenuated both cardiac (P=0.0002; Figure 2D) and renal (P<0.0001; Figure 2E) hypertrophy.
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Renal fibrosis was attenuated in mice provided with acetate supplementation, with glomerular fibrosis reduced to 2.16±0.26% (P<0.0001; Figure 3A and 3B) and tubulointerstitial fibrosis to 0.31±0.11% (P=005; Figure 3A and 3C), whereas high-fiber diet did not have a significant effect (P=0.97 and P=0.94, respectively; Figure 3A–3C).
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The perivascular collagen volume fraction increased from 2.2±0.8% in controls to 30.9±2.0% in DOCA-treated mice (P<0.0001). This was significantly reduced by both the high-fiber diet (19.4±2.2%; P<0.0001) and acetate supplementation (9.26±2.8%; P<0.0001; Figure 4A and 4B).
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Mice fed a diet rich in fiber had body weight similar those fed the control diet, whereas supplementation with acetate led to reduced body weight
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.116.024545
Prebiotic Dietary Fiber and Gut Health: Comparing the in Vitro Fermentations of Beta-Glucan, Inulin and Xylooligosaccharide
Oatwell(Oatbran containing 28% beta-glucan) had the highest production of propionate at 12 h (4.76 μmol/mL) compared to inulin, WholeFiber(dried chicory root containing inulin, pectin, and hemi/celluloses) and XOS(xylooligosaccharides) samples (p < 0.03). Oatwell’s effect was similar to those of the pure beta-glucan samples, both samples promoted the highest mean propionate production at 24 h.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748811/
Beta Glucan: Health Benefits in Obesity and Metabolic Syndrome
Among cereals, the highest content (g per 100 g dry weight) of β-glucan has been reported for barley: 2–20 g (65% is water-soluble fraction) and for oats: 3–8 g (82% is water-soluble fraction). Other cereals also contain β-glucan but in much lower amounts: sorghum 1.1–6.2 g, rye 1.3–2.7 g, maize 0.8–1.7 g, triticale 0.3–1.2 g, wheat 0.5–1.0 g, durum wheat 0.5-0.6 g, and rice 0.13 g [16]. Other sources of β-glucan include some types of seaweed [17] and various species of mushrooms such as Reishi, Shiitake, and Maitake [18].
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Oat β-glucan is found in greater concentrations in the bran as compared to the whole-oat groat and commercial oat bran contains 7–10% β-glucan [23]. However, extraction of pure β-glucan isolates is not straightforward and relatively costly since the aleurone and subaleurone cell walls also enclose starch, protein, and lipids [24]. Thus, pure β-glucan isolates are often ignored in food product development and relatively inexpensive oat and barley bran or flour fractions are typically used.
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The molecular weight of β-glucan in processed oat foods can be smaller than unprocessed. Solubility, which is related to extractability, typically increases initially with processing as depolymerisation occurs and β-glucan is released from the cell wall; however, as this degradation continues, solubility decreases as insoluble β-glucan aggregates are formed [361]. In products such as oat porridge and oat granola, there is little effect of processing on β-glucan molecular weight [172, 362]. However, the molecular weight of β-glucan in products such as oat crisp bread decreases by 92% compared to its original oat source [362]. Other studies have also seen reductions in molecular weight in similar products made from different grains [168, 172, 363] and attributed these reductions in molecular weight to the effects of β-glucanase enzymes in wheat flour used to make these products [168, 172, 364–366]. These reductions in molecular weight increase with the mixing and fermentation time of the dough [172]. Freezing was also found to affect β-glucan solubility. Frozen storage of oat bran muffins significantly lowered β-glucan solubility over time, using in vitro extraction simulating human digestion [231]. In addition, freeze-thaw cycle reduced the solubility of β-glucan in oat bran muffins by 9% to 55% of the fresh values.
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In fact, 85% of the variation in blood glucose concentrations is explained by the amount of β-glucan solubilized and not the total amount originally added to food [367].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236515/
Immunomodulatory and Anticancer Activities of Barley Bran Grown in Jordan: An in vitro and in vivo Study
For the in vivo part, the average tumor size and weight of mice given the 30% barley bran group was significantly reduced (p < 0.05) compared with the control group. During our study, higher levels of TH1 cytokines (IFN- γ, IL-2) and lower levels of TH2 cytokine (IL-4) and T regulatory cytokine (IL-10) were obtained due to consumption of barley bran in food. Barley bran can be used as a prophylactic agent because it has anti-cancer and immunomodulatory activities.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9159360/
Efficiency of Barley Bran and Oat Bran in Ameliorating Blood Lipid Profile and the Adverse Histological Changes in Hypercholesterolemic Male Rats
In contrast, the rats fed oat bran and barley bran showed significant decrease in the level of uric acid, urea, and creatinine compared with the positive control. This result agrees with the assumption that dietary fiber improves the level of kidney function [43].
Efficiency of Barley Bran and Oat Bran in Ameliorating Blood Lipid Profile and the Adverse Histological Changes in Hypercholesterolemic Male Rats
Barley bran flour accelerates gastrointestinal transit time
The group that consumed barley bran flour significantly decreased transit time by 8.02 hours from baseline, whereas the group that consumed cellulose increased transit time by 2.95 hours from baseline. Similarly, cellulose supplementation did not result in increased fecal weight, whereas daily fecal weight increased significantly by 48.6 g with supplementation with barley bran flour. This study shows that barley bran flour accelerates gastrointestinal transit and increases fecal weight.
Barley bran flour accelerates gastrointestinal transit time - PubMed
Gut bacteria use mostly fermentation to generate energy, converting sugars, in part, to short-chain fatty acid, that are used by the host as energy source. Acetate is important for muscle, heart and brain cells, propionate is used in host hepatic neoglucogenic processes, whereas, in addition, butyrate is important for enterocytes. Beyond short-chain fatty acid, a number of amino acids are indispensable to humans and can be provided by bacteria. Similarly, bacteria can contribute certain vitamins (for example, biotin, phylloquinone) to the host. All of the steps of biosynthesis of these molecules are encoded by the minimal metagenome.
A human gut microbial gene catalogue established by metagenomic sequencing - Nature
Microbiome–host systems interactions: protective effects of propionate upon the blood–brain barrier
Of the SCFAs, acetate is produced in the greatest quantity as a result of fermentation in the large intestine, followed by propionate and butyrate [37]. Over 95% of SCFAs produced are absorbed within the colon with virtually none appearing in the urine or faeces [35, 38].
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propionate has been shown to stimulate intestinal gluconeogenesis through direct stimulation of enteric–CNS pathways [42] and increased intestinal propionate has been associated with reduced stress behaviours [43] and reward pathway activity [44] in mice and humans
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Given that the main source of circulating propionate in humans is the intestinal microbiota [57, 58], following fermentation of non-digestible carbohydrates by select bacterial species (Fig. 4), propionate thus represents a paradigm of commensal, mutually beneficial interactions between the host and microbiota. Moreover, consumption of food containing non-digestible carbohydrates increases circulating propionate concentrations approximately tenfold [59, 60], suggesting that the anti-inflammatory effects of the SCFA upon the cerebrovascular endothelium may be another facet of the known health benefits of high-fibre diets [61].
Production of propionate by the human gut microbiota. Propionate can be produced directly or indirectly by cross-feeding from succinate and lactate producers (e.g. Selenomonas, Megasphaera and Veillonella spp.). Image produced using information taken from [57]. *Akkermansia muciniphila is known to produce propionate; it is thought to do this via the succinate pathway [57]
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That BBB integrity is influenced by the gut microbiota and that SCFAs may play a role in this process was recently emphasised in studies of germ-free vs. specific pathogen-free mice, with germ-free animals exhibiting enhanced BBB permeability and disrupted cerebral endothelial tight junctions [32]. These permeability defects were reversed fully upon conventionalisation with a pathogen-free microbiota and partially with monocultures producing various SCFAs. Moreover, defective BBB integrity could be ameliorated at least partially by extended oral administration of sodium butyrate.
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While the major ligands for this receptor, propionate and butyrate, were both able to prevent a functional decline in BBB integrity induced by LPS exposure, this was not the case for acetate, an SCFA with greater potency at FFAR2 [39]. Future work investigating the relative contributions of the two receptor types to BBB integrity will be informative.
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Notably, and perhaps unsurprisingly, SCFAs cannot fully recapitulate the BBB-restoring effects of conventionalisation of germ-free animals, as revealed in the current work and previously [32, 33].
Microbiome–host systems interactions: protective effects of propionate upon the blood–brain barrier - Microbiome
Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss
Also, a 14-day nutritional supplementation of sodium propionate (Propicum) in healthy humans significantly decreased serum parameters for bone resorption (Fig. 1k) while leaving OCN levels unchanged (Supplementary Fig. 1f).
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In accordance with direct SCFA supplementation, an 8-week exposure to fiber-rich diet (Supplementary Table 1) led to an increased bone mass (Fig. 1m) and decreased trabecular separation (Fig. 1n) associated with decreased osteoclast numbers and CTX-I serum levels (Fig. 1o and Supplementary Fig. 1h).
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Enhanced abundance of Prevotella copri has been described in early RA(rheumatoid arthritis)7. We therefore transferred three representative species from the genus Prevotella separately into WT mice and analyzed systemic bone mass 8 weeks later. Transfer of all Prevotella spp. significantly increased osteoclast numbers (Supplementary Fig. 1n) and the relative abundance of Prevotella spp. durably for 8 weeks (Supplementary Fig. 1o, p) but decreased SCFA levels (Fig. 1p) and systemic bone mass in the recipient mice (Fig. 1q, r),
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Treatments with C3(Propionate) and C4(Butyrate) effectively prevented OVX(ovariectomy)-induced(postmenopausal) bone loss (Fig. 3a–c). At the cellular level, we observed a complete rescue of OVX-induced osteoclast formation after C3 and C4 treatment (Fig. 3d).
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C3/C4 treatment significantly attenuated the severity of inflammation in the collagen-induced arthritis (CIA) mouse model (Fig. 4a, b), and systemic bone mass was increased after C3/C4 treatment (Fig. 4c).
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Of note, the observed effects seem to be largely independent of GPR43 as treatment with C3/C4 also maintained bone mass and suppressed osteoclast-specific genes in GPR43 −/− mice (Supplementary Fig. 4d–h).
Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss - Nature Communications
Phylogenetic distribution of three pathways for propionate production within the human gut microbiota
Butyrate, in particular, is believed to counteract colorectal cancer and inflammation (Hamer et al., 2008; Berni Canani et al., 2012). Propionate also has potential health-promoting effects that include anti-lipogenic, cholesterol-lowering, anti-inflammatory and anti-carcinogenic action (Hosseini et al., 2011; Vinolo et al., 2011). Furthermore, the potential role of propionate in enhancing satiety (Arora et al., 2011) is of increasing interest given the rising incidence of obesity across the world. Recent proteomic work suggests that some of the effects of propionate at the cellular level differ from the action of butyrate (Kilner et al., 2012).
Phylogenetic distribution of three pathways for propionate production within the human gut microbiota - The ISME Journal
Beneficial effect of the short-chain fatty acid propionate on vascular calcification through intestinal microbiota remodelling
According to correlation analysis, intestinal barrier parameters (crypt depth, intestinal wall thickness, goblet cell count and MUC2 accumulation) were negatively correlated with LPS content but were positively correlated with SCFA levels. Moreover, D-lactate and diamine oxidase formed negative correlations with SCFAs (Fig. 7h). In summary, these results suggest that the propionate-modulated intestinal microbiota exerts a protective function in the intestinal mucosal barrier.
Beneficial effect of the short-chain fatty acid propionate on vascular calcification through intestinal microbiota remodelling - Microbiome
Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer
Subsequently, EHMT2 downregulation by propionate-induced tumor necrosis factor α-induced protein 1 (TNFAIP1) expression by reducing H3K9me2 levels to promote colon cancer apoptosis.
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found that propionate treatment was related to the cell growth GO terms “negative regulation of biological process” and “positive regulation of cell death” (Supplementary Fig. S2). In addition, using the DAVID, we found enrichment of the negative regulation of growth, positive regulation of apoptosis, cell adhesion, and inflammatory response (Fig. 1F). Moreover, KEGG pathway analysis revealed that propionate treatment affected apoptosis, the TNF signaling pathway, and transcriptional misregulation in cancer (Fig. 1G). GSEA found that apoptosis was regulated by SP(Sodium Propionate) treatment compared with the control group (Fig. 1H).
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Propionate treatment did not affect the viability of human intestinal organoids treated with several concentrations of propionate (Fig. 1I, J and Supplementary Fig. S3). Thus, through hIO experiments, we suggest that the reaction concentration of propionate in this study effectively suppressed the viability of colon cancer cell lines but not the normal human intestine.
Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer - The ISME Journal
Commensal gut microbiota-derived acetate and propionate enhance heart adaptation in response to cardiac pressure overload in mice
We previously showed that mice depleted of gut microbiota with antibiotics (ABX mice) were more prone to cardiac rupture after infarction, suggesting that the gut microbiota impacts cardiac structural remodeling following injury. Here, we aimed to determine whether the gut microbiota is required for adaptive cardiac remodeling in response to pressure overload stress.
Commensal gut microbiota-derived acetate and propionate enhance heart adaptation in response to cardiac pressure overload in mice
A Gut Commensal-Produced Metabolite Mediates Colonization Resistance to Salmonella Infection
It is increasingly clear that SCFAs have anti-pathogenic properties. However, the effects that have been described within a mammalian host are largely a result of indirect mechanisms of immune activation rather than direct limitation of growth (Jung et al., 2015, Peng et al., 2009). In addition, SCFAs are known to regulate Salmonella virulence programs (El-Gedaily et al., 1997, Huang et al., 2008, Van Immerseel, 2003). In this study, we demonstrated that Bacteroides spp. limitation of intestinal Salmonella expansion through production of propionate is mediated by direct limitation of pathogen growth (Figures 5, 6, and 7). We were surprised to find that the magnitude of in vitro propionate-mediated growth inhibition we observed is quite large. If we imagine directly competing S. Typhimurium grown with and without the presence of propionate, the growth inhibition provided by propionate could compound to a 10- to 50-fold reduction in bacterial fitness over time. This difference is recapitulated in our in vivo experiments, where we observed a 10- to 100-fold decrease in S. Typhimurium levels in animals colonized with Bacteroides spp. or treated with an inulin propionate ester.
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Our findings suggest that when intracellular concentrations of propionate are high, cells are unable to raise their internal pH to facilitate cellular functions required for growth, leading to an extended lag time (Figure 5).
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Bacteroides spp. metabolize succinate through enzymatic steps culminating in the production of propionate as well as ATP and CO2, which are crucial for Bacteroides to survive in carbon-limiting conditions such as the intestinal lumen (Dimroth and Schink, 1998, Reichardt et al., 2014). Bacteroides spp. release propionate into the environment rather than utilize the metabolite for growth; the genomes of sequenced Bacteroides spp. do not contain genes homologous to known propionate utilization loci (Hammelman et al., 1996). Furthermore, human studies show direct correlations between Bacteroides spp. abundance and propionate levels (Salonen et al., 2014). Taken together, these observations are consistent with propionate as a byproduct of Bacteroides metabolism. Viewed in this light, our work presents an example in which a byproduct of normal commensal metabolism provides colonization resistance against invading enteric pathogens.
Propionate and other SCFAs have been utilized to control enteric pathogen infection in agricultural animals since the 1960s, and have even been proposed as a dietary supplement alternative to antibiotic treatment (Ricke, 2003). We demonstrated that the addition of Bacteroides spp. to mice leads to propionate production that is sufficient to limit pathogen expansion (Figure 7). Moreover, we showed that the prebiotic inulin propionate ester is sufficient to limit Salmonella fecal shedding, establishing that propionate mediates colonization resistance (Figure 7). Overall, these findings suggest that the addition of live Bacteroides spp., other SCFA-producing commensals, or even SCFA-related prebiotics to agricultural animals or humans may alter the intestinal environment to help control spread of Salmonella and perhaps other related enteric Enterobacteriaceae pathogens.
Effects of carbon dioxide on cell growth and propionic acid production from glycerol and glucose by Propionibacterium acidipropionici
In glycerol fermentation, the volumetric productivity of propionic acid with CO2 supplementation reached 2.94g/L/day, compared to 1.56g/L/day without CO2. The cell growth using glycerol was also significantly enhanced with CO2. In addition, the yield and productivity of succinate, the main intermediate in Wood-Werkman cycle, increased 81% and 280%, respectively; consistent with the increased activities of pyruvate carboxylase and propionyl CoA transferase, two key enzymes in the Wood-Werkman cycle. However, in glucose fermentation CO2 had minimal effect on propionic acid production and cell growth.
Effects of carbon dioxide on cell growth and propionic acid production from glycerol and glucose by Propionibacterium acidipropionici - PubMed
Short-Chain Fatty-Acid-Producing Bacteria: Key Components of the Human Gut Microbiota
Interestingly, the produced acetate benefits the growth of propionate and butyrate-producing bacteria and, at the same time, butyrate favors the growth of Bifidobacterium, leading to a cross-feeding between SCFA-producing bacteria [72,81].
Acetate production requires substrates described as acetogenic fibers (inulin, galacto-ligosaccharides, etc.) [66]. Those fibers may then enter two possible pathways: acetogenesis or carbon fixation pathway. Acetogenesis is the production of acetate, mediated by homoacetogenic bacteria, which can use both H2 and CO2, while the carbon-fixation pathway produces acetate directly from CO2 [66,82,83].
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Oral butyrate supplementation was also valued for IBDs. In UC(Ulcerative Colitis) patients, sodium butyrate microcapsules were effective in reducing the Mayo score and faecal calprotectin levels compared to mesalamine alone [172].
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On the other hand, studies evaluating the use of ketogenic diet (a low-carbohydrate, high-fat diet able to induce physiological ketosis) showed a decrease in beneficial bacteria (i.e., Bifidobacteria, Eubacterium rectale, Roseburia) and total bacterial count and abundance [20]. As a consequence, a ketogenic diet may induce a reduction in both total SCFAs and their single components [196].
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Both in vitro and in vivo studies confirmed a positive role of probiotics in increasing SCFAs [205]. The most used probiotics are those of Lactobacillus genera, mainly Lactobacillus plantarum [206,207], Lactobacillus paracasei [207], and Lactobacillus rhamnosus [208]; all the above studies confirmed, in animal models or in healthy volunteer humans, an increase in Bifidobacteria and in other beneficial microbes, leading to an increase in total SCFAs [206,207,208].
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Several recent lines of evidence suggest that that the increase in SCFAs may be a key determinant of FMT(Fecal microbiota transplantation) success in different diseases. First, in a mouse model of ischemic stroke, mice transplanted with feces rich in SCFAs, mainly butyrate, experienced an amelioration in neurological symptoms [215].
Moreover, in a randomized controlled trial where FMT from donors with balanced microbiome was more effective than placebo in reducing IBS-related symptoms, FMT increased the fecal SCFA levels, and the post-FMT increase in butyrate levels correlated inversely with symptoms [216]. Finally, in a small pilot trial, FMT from mixed lean donors was able to increase the levels of SCFAs-producing bacteria [217].
https://www.mdpi.com/2072-6643/15/9/2211
Formation of propionate and butyrate by the human colonic microbiota
Some fermentation products, including lactate, succinate and 1,2-propanediol, do not usually accumulate to high levels in the human colon of healthy adults, as they can also serve as substrates for other bacteria, including propionate and butyrate producers.
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Certain Lachnospiraceae have the ability to grow in the presence of lactate and acetate to produce butyrate, showing an overall net stoichiometry of 4 mol of lactate and 2 mol of acetate producing 3 mol of butyrate (Duncan et al., 2004).
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On the other hand, some human colonic bacteria belonging to the Negativicutes class of Firmicutes (e.g., Phascolarctobacterium succinatutens; Watanabe et al., 2012), have the ability to convert succinate to propionate (Flint et al., 2014; Reichardt et al., 2014). This activity may explain why succinate accumulation is infrequently reported for human faecal samples, although 3 of the 14 overweight human volunteers in one recent dietary study showed elevated faecal succinate concentrations (>30 mM) in samples from a non-starch polysaccharide-supplemented diet (reported in Salonen et al., 2014, Supporting Information). Other Negativicutes bacteria convert lactate to propionate either via the succinate pathway (e.g., Veillonella spp.) or via the acrylate pathway (Megasphaera elsdenii) (Reichardt et al., 2014) (Fig. 2). The acrylate pathway has also been shown to operate recently in a species of Lachnospiraceae, Coprococcus catus (Reichardt et al., 2014).
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It has been show in a rodent model that limitation of dietary iron intake can dramatically decrease the production of both butyrate and propionate as lactobacilli and Proteobacteria are favoured (Dostal et al., 2012). Populations of Roseburia-related butyrate producers appear particularly sensitive to iron availability, while in pure cultures of R. intestinalis butyrate production was favoured at high iron concentrations with a switch to lactate production under iron-deficient conditions (Dostal et al., 2015). It remains to be established whether other growth factors also have a major impact on SCFA formation.
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Incorporation of exogenous acetate via the CoA-transferase reaction results in some loss of ATP production via acetyl-phosphate, but this is more than compensated by the additional ATP formed from proton export, giving a potential maximum of 4 ATP formed per glucose metabolized when 2 mol of acetate are taken in for each mol of glucose fermented.
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Propionate and butyrate are also formed as products from peptide and amino acid fermentation (Figs. 1 and 2), although the numbers of amino acid-fermenting bacteria have been estimated to constitute less than 1% of the large intestinal microbiota (Smith and Macfarlane, 1998; Dai et al., 2011). It is estimated that the colon receives approximately 13 g of protein and peptides per day, and large amounts of soluble protein and peptides were found in intestinal contents of sudden death victims (Smith and Macfarlane, 1998). Peptides seem to be preferred over free amino acids by gut bacteria. Low gut pH and the presence of carbohydrates reduces peptide and amino acid fermentation in vitro, which helps to explain why microbial amino acid fermentation is higher in the distal than the proximal colon contents (Smith and Macfarlane, 1998). Amino acid fermentation leads to the production of potentially harmful metabolites (for example phenolic and indolic compounds, amines, ammonia) in addition to branched-chain fatty acids (BCFA) and SCFA (Smith and Macfarlane, 1997; Dai et al., 2011).
In vitro incubations of faecal slurries with individual amino acids showed that propionate was produced mainly from aspartate, alanine, threonine and methionine, whereas butyrate was a major fermentation product from glutamate, lysine, histidine, cysteine, serine and methionine (Smith and Macfarlane, 1997).
https://enviromicro-journals.onlinelibrary.wiley.com/doi/full/10.1111/1462-2920.13589
The role of diet in shaping human gut microbiota
In a mouse model, high-sugar diet (HSD) consumption significantly increased the abundance of Escherichia coli in fecal samples and promoted gut inflammation and a systemic immune response [26]. Moreover, in other mice studies, high-sugar diets induced colon inflammation compared with a standard diet by altering the composition of the gut microbiota, increasing the levels of Akkermansia muciniphila, known to produce enzymes degrading the mucus layer [27]. Short-term exposure to a high-sugar diet in mice increases susceptibility to colitis by reducing the production of short-chain fatty acids (SCFAs) and increasing gut permeability [28].
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Akkermansia muciniphila, which is a habitant of the mucus layer of the intestine has been identified as a novel beneficial organism which modulates basal metabolism in rodents and in humans [23]. The decrease in Akkermansia in case of obesity leads to a gut barrier failure and increases the gut inflammatory response via elevated expression of endotoxins and LPS [23]. Indeed, a 3-month supplementation of A.muciniphila in obese patients have shown to decrease body weight and improve liver dysfunction that appears in the context of obesity [24].
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However, in various studies, the levels of fecal SCFAs and methane would not significantly differ between omnivore and vegan/vegetarian diet [80]. In other studies, following a vegan diet could substantially reduce the abundances of potentially harmful metabolites such as lithocholic acid, BCAAs, aromatic compounds and increase the production of SCFAs and their derivatives compared with an omnivore diet [81]. A short-term 3-month dietary intervention with MD or a vegetarian diet does not induce significant gut microbial changes at the family level [82]. At the genus level, MD(Mediterranean diet) could significantly change the abundance of Enterorhabdus, Lachnoclostridium and Parabacteroides while vegetarian diet could increase the quantity of Anaerostipes, Streptococcus, and Odoribacter. Regarding SCFAs, a MD could increase the production of propionic acid while a vegetarian diet decreases it [82].
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In IBS patients, some microbial signatures of IBS subtypes could predict the response to the low FODMAP from the alterations in gut microbiota and metabolites produced [90].
https://www.sciencedirect.com/science/article/pii/S1521691823000069
The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health
It is estimated that the fermentation of 50–60 g carbohydrates per day yields to the approximated production of 500–600 mmol of SCFAs in the gut.[71]
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Acetate, propionate, and butyrate concentrations in portal blood (375 µmol/l) are almost 5 times greater than peripheral venous blood (79 µmol/l), suggesting that the gut is a principal SCFA source, whereas SCFA concentrations in the hepatic vein SCFA (148 µmol/l) are 39% of those found in portal blood.
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Omega-3 rich diets have been also associated with an increase of SCFA-producing bacteria. Indeed, in a randomized trial, 2-month of treatment with omega-3 polyunsaturated fatty acids (PUFA) capsules or drinks was given to healthy middle-aged subjects to analyze the effect of omega-3 PUFA on the human gut microbiota. An increased abundance of SCFA-producing bacteria belonging to the Lachnospira, Roseburia, Lactobacillus, and Bifidobacterium genus was reported in the subjects taken one or both formulations (capsules and drinks). Noriega et colleagues (2016) showed a significant increase of the butyrate-producing bacteria Eubacterium, Roseburia, Anaerostipes, Coprococcus, Subdoligranulum, and Pseudobutyrivibrio after 2 weeks of an omega-3 rich diet.
Other studies have also reported this association and suggested the potential beneficial role of this type of diet in CMD. For instance, a recent human study showed a significant increase in Coprococcus spp. and Bacteroides spp., and in isobutyrate and isovalerate levels after a daily supplementation of 500 mg of omega-3 fatty acid for 6 weeks.190 Likewise, Coprococcus was positively associated with the branched-chain fatty acid isobutyric acid and negatively associated with the triglyceride-rich lipoproteins VLDL and VLDL-TG, suggesting that dietary omega-3 influences the gut microbiota composition and its benefits in CVD might be mediated by gut fermentation products.190 In another study, three different diets were fed to female mice, namely control, n-3 PUFA supplemented and n-3 PUFA deficient, during gestation, and then, the male offspring continued with the same diet for 3 months.170 Deficiency of n3-PUFA in diet reduced the levels of acetate and butyrate in feces, and the Clostridiaceae family, which can produce SCFAs, was not detected in this group. Likewise, the metabolic results revealed an increase of cecal metabolites involved in energy metabolism in n-3 PUFA supplemented mice. Thus, it was suggested that the observed impairment of SCFA production might disrupt the metabolism homeostasis and thus, having an impact on metabolic diseases. In a study conducted by Balfegó and coworkers,181 gut bacterial species were determined in drug-naïve patients with T2D before and after following either a standard diet (control) or the same diet but enriched with sardines for 6 months. Individuals following the latter diet presented an increase of Bacteroides and Prevotella (acetate-producing bacteria) in comparison with the baseline. It was indicated that this diet might present benefits for cardiovascular risk.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007165/
Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease
We therefore provided a mixture of SCFAs(Short-Chain Fatty Acids), or acetate, propionate, or butyrate individually, to GF mice for 4 weeks via their drinking water. As expected based on prior work, a mixture of SCFAs was able to reduce heightened microglia densities found in GF to normal microglia numbers observed under SPF conditions (Figures 4A and 4B). This effect was recapitulated by acetate alone, but not by butyrate or propionate.
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An evaluation of TR+ plaque-associated Iba1+ microglia (those cells less than 10 mm from the TR+ plaques) revealed significantly more cells in close proximity to Ab in GF 5xFAD mice than in SPF 5xFAD mice, and acetate treatment reversed this effect (Figure 6E)
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we found reduced glucose uptake in microglia from GF 5xFAD mice, further supporting
impaired glycolysis (Figure S7E).
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Notably, supplementation of acetate restored the percentage of MXO4+ microglia to SPF levels (Figures 7D–7F), indicating that microglial phagocytosis of Ab is modified by acetate.
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Notably, microglia acquired more acetate from the medium in the presence of Ab (Figure 7L) and incorporated slightly more acetate-derived 13C into various metabolites including TCA cycle intermediates (Figures 7M and S7M), suggesting that acetate fuels at least partially the TCA cycle.
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SCFAs are known to be able to translocate from the intestine to the systemic circulation and to cross the blood-brain barrier (Frost et al., 2014). They have been reported to have various effects on immune cells including Treg cells (Duscha et al., 2020; Smith et al., 2013) or T effector cells (Qiu et al., 2019) and macrophages (Schulthess et al., 2019; Zhang et al., 2019). In our study, acetate was the most abundant SCFA in the brains of SPF mice and was significantly reduced in brains from GF(Germ-Free) mice.
High-Fiber Diet and Acetate Supplementation Change the Gut Microbiota and Prevent the Development of Hypertension and Heart Failure in Hypertensive Mice
Whereas a high-fiber diet reduced the heart/body weight ratio (P<0.0001; Figure 2D), it did not affect renal mass (P=0.73; Figure 2E). In contrast, acetate supplementation attenuated both cardiac (P=0.0002; Figure 2D) and renal (P<0.0001; Figure 2E) hypertrophy.
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Renal fibrosis was attenuated in mice provided with acetate supplementation, with glomerular fibrosis reduced to 2.16±0.26% (P<0.0001; Figure 3A and 3B) and tubulointerstitial fibrosis to 0.31±0.11% (P=005; Figure 3A and 3C), whereas high-fiber diet did not have a significant effect (P=0.97 and P=0.94, respectively; Figure 3A–3C).
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The perivascular collagen volume fraction increased from 2.2±0.8% in controls to 30.9±2.0% in DOCA-treated mice (P<0.0001). This was significantly reduced by both the high-fiber diet (19.4±2.2%; P<0.0001) and acetate supplementation (9.26±2.8%; P<0.0001; Figure 4A and 4B).
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Mice fed a diet rich in fiber had body weight similar those fed the control diet, whereas supplementation with acetate led to reduced body weight
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.116.024545
Prebiotic Dietary Fiber and Gut Health: Comparing the in Vitro Fermentations of Beta-Glucan, Inulin and Xylooligosaccharide
Oatwell(Oatbran containing 28% beta-glucan) had the highest production of propionate at 12 h (4.76 μmol/mL) compared to inulin, WholeFiber(dried chicory root containing inulin, pectin, and hemi/celluloses) and XOS(xylooligosaccharides) samples (p < 0.03). Oatwell’s effect was similar to those of the pure beta-glucan samples, both samples promoted the highest mean propionate production at 24 h.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748811/
Beta Glucan: Health Benefits in Obesity and Metabolic Syndrome
Among cereals, the highest content (g per 100 g dry weight) of β-glucan has been reported for barley: 2–20 g (65% is water-soluble fraction) and for oats: 3–8 g (82% is water-soluble fraction). Other cereals also contain β-glucan but in much lower amounts: sorghum 1.1–6.2 g, rye 1.3–2.7 g, maize 0.8–1.7 g, triticale 0.3–1.2 g, wheat 0.5–1.0 g, durum wheat 0.5-0.6 g, and rice 0.13 g [16]. Other sources of β-glucan include some types of seaweed [17] and various species of mushrooms such as Reishi, Shiitake, and Maitake [18].
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Oat β-glucan is found in greater concentrations in the bran as compared to the whole-oat groat and commercial oat bran contains 7–10% β-glucan [23]. However, extraction of pure β-glucan isolates is not straightforward and relatively costly since the aleurone and subaleurone cell walls also enclose starch, protein, and lipids [24]. Thus, pure β-glucan isolates are often ignored in food product development and relatively inexpensive oat and barley bran or flour fractions are typically used.
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The molecular weight of β-glucan in processed oat foods can be smaller than unprocessed. Solubility, which is related to extractability, typically increases initially with processing as depolymerisation occurs and β-glucan is released from the cell wall; however, as this degradation continues, solubility decreases as insoluble β-glucan aggregates are formed [361]. In products such as oat porridge and oat granola, there is little effect of processing on β-glucan molecular weight [172, 362]. However, the molecular weight of β-glucan in products such as oat crisp bread decreases by 92% compared to its original oat source [362]. Other studies have also seen reductions in molecular weight in similar products made from different grains [168, 172, 363] and attributed these reductions in molecular weight to the effects of β-glucanase enzymes in wheat flour used to make these products [168, 172, 364–366]. These reductions in molecular weight increase with the mixing and fermentation time of the dough [172]. Freezing was also found to affect β-glucan solubility. Frozen storage of oat bran muffins significantly lowered β-glucan solubility over time, using in vitro extraction simulating human digestion [231]. In addition, freeze-thaw cycle reduced the solubility of β-glucan in oat bran muffins by 9% to 55% of the fresh values.
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In fact, 85% of the variation in blood glucose concentrations is explained by the amount of β-glucan solubilized and not the total amount originally added to food [367].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236515/
Immunomodulatory and Anticancer Activities of Barley Bran Grown in Jordan: An in vitro and in vivo Study
For the in vivo part, the average tumor size and weight of mice given the 30% barley bran group was significantly reduced (p < 0.05) compared with the control group. During our study, higher levels of TH1 cytokines (IFN- γ, IL-2) and lower levels of TH2 cytokine (IL-4) and T regulatory cytokine (IL-10) were obtained due to consumption of barley bran in food. Barley bran can be used as a prophylactic agent because it has anti-cancer and immunomodulatory activities.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9159360/
Efficiency of Barley Bran and Oat Bran in Ameliorating Blood Lipid Profile and the Adverse Histological Changes in Hypercholesterolemic Male Rats
In contrast, the rats fed oat bran and barley bran showed significant decrease in the level of uric acid, urea, and creatinine compared with the positive control. This result agrees with the assumption that dietary fiber improves the level of kidney function [43].
Efficiency of Barley Bran and Oat Bran in Ameliorating Blood Lipid Profile and the Adverse Histological Changes in Hypercholesterolemic Male Rats
Barley bran flour accelerates gastrointestinal transit time
The group that consumed barley bran flour significantly decreased transit time by 8.02 hours from baseline, whereas the group that consumed cellulose increased transit time by 2.95 hours from baseline. Similarly, cellulose supplementation did not result in increased fecal weight, whereas daily fecal weight increased significantly by 48.6 g with supplementation with barley bran flour. This study shows that barley bran flour accelerates gastrointestinal transit and increases fecal weight.
Barley bran flour accelerates gastrointestinal transit time - PubMed
