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      Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism

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          ABSTRACT

          The formation of SCFA is the result of a complex interplay between diet and the gut microbiota within the gut lumen environment. The discovery of receptors, across a range of cell and tissue types for which short chain fatty acids SCFA appear to be the natural ligands, has led to increased interest in SCFA as signaling molecules between the gut microbiota and the host. SCFA represent the major carbon flux from the diet through the gut microbiota to the host and evidence is emerging for a regulatory role of SCFA in local, intermediary and peripheral metabolism. However, a lack of well-designed and controlled human studies has hampered our understanding of the significance of SCFA in human metabolic health. This review aims to pull together recent findings on the role of SCFA in human metabolism to highlight the multi-faceted role of SCFA on different metabolic systems.

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          Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides.

          David Topping, Peter M. Clifton (2001)
          Resistant starch (RS) is starch and products of its small intestinal digestion that enter the large bowel. It occurs for various reasons including chemical structure, cooking of food, chemical modification, and food mastication. Human colonic bacteria ferment RS and nonstarch polysaccharides (NSP; major components of dietary fiber) to short-chain fatty acids (SCFA), mainly acetate, propionate, and butyrate. SCFA stimulate colonic blood flow and fluid and electrolyte uptake. Butyrate is a preferred substrate for colonocytes and appears to promote a normal phenotype in these cells. Fermentation of some RS types favors butyrate production. Measurement of colonic fermentation in humans is difficult, and indirect measures (e.g., fecal samples) or animal models have been used. Of the latter, rodents appear to be of limited value, and pigs or dogs are preferable. RS is less effective than NSP in stool bulking, but epidemiological data suggest that it is more protective against colorectal cancer, possibly via butyrate. RS is a prebiotic, but knowledge of its other interactions with the microflora is limited. The contribution of RS to fermentation and colonic physiology seems to be greater than that of NSP. However, the lack of a generally accepted analytical procedure that accommodates the major influences on RS means this is yet to be established.
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            Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation.

            Emmanuel Le Poul, Cécile Loison, Sofie Struyf … (2003)
            Short chain fatty acids (SCFAs), including acetate, propionate, and butyrate, are produced at high concentration by bacteria in the gut and subsequently released in the bloodstream. Basal acetate concentrations in the blood (about 100 microm) can further increase to millimolar concentrations following alcohol intake. It was known previously that SCFAs can activate leukocytes, particularly neutrophils. In the present work, we have identified two previously orphan G protein-coupled receptors, GPR41 and GPR43, as receptors for SCFAs. Propionate was the most potent agonist for both GPR41 and GPR43. Acetate was more selective for GPR43, whereas butyrate and isobutyrate were more active on GPR41. The two receptors were coupled to inositol 1,4,5-trisphosphate formation, intracellular Ca2+ release, ERK1/2 activation, and inhibition of cAMP accumulation. They exhibited, however, a differential coupling to G proteins; GPR41 coupled exclusively though the Pertussis toxin-sensitive Gi/o family, whereas GPR43 displayed a dual coupling through Gi/o and Pertussis toxin-insensitive Gq protein families. The broad expression profile of GPR41 in a number of tissues does not allow us to infer clear hypotheses regarding its biological functions. In contrast, the highly selective expression of GPR43 in leukocytes, particularly polymorphonuclear cells, suggests a role in the recruitment of these cell populations toward sites of bacterial infection. The pharmacology of GPR43 matches indeed the effects of SCFAs on neutrophils, in terms of intracellular Ca2+ release and chemotaxis. Such a neutrophil-specific SCFA receptor is potentially involved in the development of a variety of diseases characterized by either excessive or inefficient neutrophil recruitment and activation, such as inflammatory bowel diseases or alcoholism-associated immune depression. GPR43 might therefore constitute a target allowing us to modulate immune responses in these pathological situations.
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              The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation.

              Dallas R. Donohoe, Leonard Collins, Aminah Wali … (2012)
              Widespread changes in gene expression drive tumorigenesis, yet our knowledge of how aberrant epigenomic and transcriptome profiles arise in cancer cells is poorly understood. Here, we demonstrate that metabolic transformation plays an important role. Butyrate is the primary energy source of normal colonocytes and is metabolized to acetyl-CoA, which was shown to be important not only for energetics but also for HAT activity. Due to the Warburg effect, cancerous colonocytes rely on glucose as their primary energy source, so butyrate accumulated and functioned as an HDAC inhibitor. Although both mechanisms increased histone acetylation, different target genes were upregulated. Consequently, butyrate stimulated the proliferation of normal colonocytes and cancerous colonocytes when the Warburg effect was prevented from occurring, whereas it inhibited the proliferation of cancerous colonocytes undergoing the Warburg effect. These findings link a common metabolite to epigenetic mechanisms that are differentially utilized by normal and cancerous cells because of their inherent metabolic differences. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Gut Microbes
                Journal ID (iso-abbrev): Gut Microbes
                Journal ID (pmc): KGMI
                Title: Gut Microbes
                Publisher: Taylor & Francis
                ISSN (Print): 1949-0976
                ISSN (Electronic): 1949-0984
                Publication date Collection: 2016
                Publication date (Electronic): 10 March 2016
                Publication date PMC-release: 10 March 2016
                Volume: 7
                Issue: 3 , Gut Microbiota Metabolites in Health and Disease
                Pages: 189-200
                Affiliations
                Scottish Universities Environmental Research Centre, University of Glasgow , East Kilbride, Scotland
                Author notes
                CONTACT Douglas J. Morrison, Douglas.Morrison@ 123456glasgow.ac.uk Stable Isotope Biochemistry Laboratory, Scottish Universities Environmental Research Centre , Rankine Avenue, East Kilbride, Glasgow G75 0QF, Scotland;
                Article
                Publisher ID: 1134082
                DOI: 10.1080/19490976.2015.1134082
                PMC ID: 4939913
                PubMed ID: 26963409
                SO-VID: 3e65dcd0-19d6-4dac-b874-5065e048f1b1
                Copyright © © 2016 The Author(s). Published with license by Taylor & Francis
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

                History
                Date received : 31 August 2015
                Date revision received : 4 December 2015
                Date accepted : 15 December 2015
                Page count
                Figures: 2, Tables: 0, References: 93, Pages: 12
                Categories
                Subject: Review

                ScienceOpen disciplines: Microbiology & Virology
                Keywords: gut microbiota,glucose homeostasis,host metabolic health,inflammation,short chain fatty acids
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology
                Keywords: gut microbiota, glucose homeostasis, host metabolic health, inflammation, short chain fatty acids

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