Gut Microbiota-Derived Short-Chain Fatty Acids, T Cells, and Inflammation

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Abstract

T cells are central players in the regulation of adaptive immunity and immune tolerance. In the periphery, T cell differentiation for maturation and effector function is regulated by a number of factors. Various factors such as antigens, co-stimulation signals, and cytokines regulate T cell differentiation into functionally specialized effector and regulatory T cells. Other factors such as nutrients, micronutrients, nuclear hormones and microbial products provide important environmental cues for T cell differentiation. A mounting body of evidence indicates that the microbial metabolites short-chain fatty acids (SCFAs) have profound effects on T cells and directly and indirectly regulate their differentiation. We review the current status of our understanding of SCFA functions in regulation of peripheral T cell activity and discuss their impact on tissue inflammation.

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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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Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).

Ikuo Kimura, Daisuke Inoue, Takeshi Maeda … (2011)

The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gβγ-PLCβ-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis.

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Author and article information

Journal

Journal ID (nlm-ta): Immune Netw

Journal ID (iso-abbrev): Immune Netw

Journal ID (publisher-id): IN

Title: Immune Network

Publisher: The Korean Association of Immunologists

ISSN (Print): 1598-2629

ISSN (Electronic): 2092-6685

Publication date (Print): December 2014

Publication date (Electronic): 22 December 2014

Volume: 14

Issue: 6

Pages: 277-288

Affiliations

Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, Purdue Veterinary Medicine; Weldon School of Biomedical Engineering; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.

Author notes

Corresponding Author. Chang H. Kim, Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, Purdue Veterinary Medicine; Weldon School of Biomedical Engineering; Center for Cancer Research, Purdue University, VPTH 126, 725 Harrison Street, Purdue University, West Lafayette, IN 47907, USA. Tel: 1-765-494-0976; Fax: 1-765-494-9830; chkim@ 123456purdue.edu

Article

DOI: 10.4110/in.2014.14.6.277

PMC ID: 4275385

PubMed ID: 25550694

SO-VID: 4dfb83e8-d3a3-4532-a71c-e87d5578610f

License:

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 16 October 2014

Date revision received : 19 November 2014

Date accepted : 28 November 2014

Funding

Funded by: NIH

Award ID: R01AI074745

Award ID: R01DK076616

Award ID: 1R01AI080769

Award ID: R21AI105620

Award ID: 1S10RR028293

Funded by: USDA-NIFA

Funded by: National Multiple Sclerosis Society

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Gut Microbiota-Derived Short-Chain Fatty Acids, T Cells, and Inflammation

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Gamma Delta T cells

Most cited references 95

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

Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation.

Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).

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