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      • Record: found
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      Regulation of Inflammation by Short Chain Fatty Acids

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          Abstract

          The short chain fatty acids (SCFAs) acetate (C 2), propionate (C 3) and butyrate (C 4) are the main metabolic products of anaerobic bacteria fermentation in the intestine. In addition to their important role as fuel for intestinal epithelial cells, SCFAs modulate different processes in the gastrointestinal (GI) tract such as electrolyte and water absorption. These fatty acids have been recognized as potential mediators involved in the effects of gut microbiota on intestinal immune function. SCFAs act on leukocytes and endothelial cells through at least two mechanisms: activation of GPCRs (GPR41 and GPR43) and inhibiton of histone deacetylase (HDAC). SCFAs regulate several leukocyte functions including production of cytokines (TNF-α, IL-2, IL-6 and IL-10), eicosanoids and chemokines (e.g., MCP-1 and CINC-2). The ability of leukocytes to migrate to the foci of inflammation and to destroy microbial pathogens also seems to be affected by the SCFAs. In this review, the latest research that describes how SCFAs regulate the inflammatory process is presented. The effects of these fatty acids on isolated cells (leukocytes, endothelial and intestinal epithelial cells) and, particularly, on the recruitment and activation of leukocytes are discussed. Therapeutic application of these fatty acids for the treatment of inflammatory pathologies is also highlighted.

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          HMG-1 as a late mediator of endotoxin lethality in mice.

          H Wang, O Bloom, M Zhang … (1999)
          Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.
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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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              Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models.

              E. Murphy, P. Cotter, S. Healy … (2010)
              Increased efficiency of energy harvest, due to alterations in the gut microbiota (increased Firmicutes and decreased Bacteroidetes), has been implicated in obesity in mice and humans. However, a causal relationship is unproven and contributory variables include diet, genetics and age. Therefore, we explored the effect of a high-fat (HF) diet and genetically determined obesity (ob/ob) for changes in microbiota and energy harvesting capacity over time. Seven-week-old male ob/ob mice were fed a low-fat diet and wild-type mice were fed either a low-fat diet or a HF-diet for 8 weeks (n=8/group). They were assessed at 7, 11 and 15 weeks of age for: fat and lean body mass (by NMR); faecal and caecal short-chain fatty acids (SCFA, by gas chromatography); faecal energy content (by bomb calorimetry) and microbial composition (by metagenomic pyrosequencing). A progressive increase in Firmicutes was confirmed in both HF-fed and ob/ob mice reaching statistical significance in the former, but this phylum was unchanged over time in the lean controls. Reductions in Bacteroidetes were also found in ob/ob mice. However, changes in the microbiota were dissociated from markers of energy harvest. Thus, although the faecal energy in the ob/ob mice was significantly decreased at 7 weeks, and caecal SCFA increased, these did not persist and faecal acetate diminished over time in both ob/ob and HF-fed mice, but not in lean controls. Furthermore, the proportion of the major phyla did not correlate with energy harvest markers. The relationship between the microbial composition and energy harvesting capacity is more complex than previously considered. While compositional changes in the faecal microbiota were confirmed, this was primarily a feature of high-fat feeding rather than genetically induced obesity. In addition, changes in the proportions of the major phyla were unrelated to markers of energy harvest which changed over time. The possibility of microbial adaptation to diet and time should be considered in future studies.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nutrients
                Journal ID (publisher-id): nutrients
                Title: Nutrients
                Publisher: MDPI
                ISSN (Electronic): 2072-6643
                Publication date (Electronic): 14 October 2011
                Publication date Collection: October 2011
                Volume: 3
                Issue: 10
                Pages: 858-876
                Affiliations
                Department of Physiology and Biophysics, Institute of Biomedical Sciences-ICB-I, Sao Paulo University, Brazil; Email: hosanagr@ 123456icb.usp.br (H.G.R.); nachbar@ 123456icb.usp.br (R.T.N.); ruicuri@ 123456icb.usp.br (R.C.)
                Author notes
                [* ] Author to whom correspondence should be addressed; Email: mramirez@ 123456icb.usp.br ; Tel.: +55-11-3091-7245; Fax: +55-11-3091-7285.
                Article
                Publisher ID: nutrients-03-00858
                DOI: 10.3390/nu3100858
                PMC ID: 3257741
                PubMed ID: 22254083
                SO-VID: ca1d340f-9d62-43bb-b142-aa03b0924a53
                Copyright © © 2011 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 18 July 2011
                Date revision received : 21 September 2011
                Date accepted : 08 October 2011
                Categories
                Subject: Review

                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: short chain fatty acids,leukocytes,propionate,neutrophils,acetate,butyrate,inflammation
                Data availability:
                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: short chain fatty acids, leukocytes, propionate, neutrophils, acetate, butyrate, inflammation

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