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      Desired Turbulence? Gut-Lung Axis, Immunity, and Lung Cancer

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          Abstract

          The microbiota includes different microorganisms consisting of bacteria, fungi, viruses, and protozoa distributed over many human body surfaces including the skin, vagina, gut, and airways, with the highest density found in the intestine. The gut microbiota strongly influences our metabolic, endocrine, and immune systems, as well as both the peripheral and central nervous systems. Recently, a dialogue between the gut and lung microbiota has been discovered, suggesting that changes in one compartment could impact the other compartment, whether in relation to microbial composition or function. Further, this bidirectional axis is evidenced in an, either beneficial or malignant, altered immune response in one compartment following changes in the other compartment. Stimulation of the immune system arises from the microbial cells themselves, but also from their metabolites. It can be either direct or mediated by stimulated immune cells in one site impacting the other site. Additionally, this interaction may lead to immunological boost, assisting the innate immune system in its antitumour response. Thus, this review offers an insight into the composition of these sites, the gut and the lung, their role in shaping the immune system, and, finally, their role in the response to lung cancer.

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          Most cited references63

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

          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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            Microbiota regulates immune defense against respiratory tract influenza A virus infection.

            Although commensal bacteria are crucial in maintaining immune homeostasis of the intestine, the role of commensal bacteria in immune responses at other mucosal surfaces remains less clear. Here, we show that commensal microbiota composition critically regulates the generation of virus-specific CD4 and CD8 T cells and antibody responses following respiratory influenza virus infection. By using various antibiotic treatments, we found that neomycin-sensitive bacteria are associated with the induction of productive immune responses in the lung. Local or distal injection of Toll-like receptor (TLR) ligands could rescue the immune impairment in the antibiotic-treated mice. Intact microbiota provided signals leading to the expression of mRNA for pro-IL-1β and pro-IL-18 at steady state. Following influenza virus infection, inflammasome activation led to migration of dendritic cells (DCs) from the lung to the draining lymph node and T-cell priming. Our results reveal the importance of commensal microbiota in regulating immunity in the respiratory mucosa through the proper activation of inflammasomes.
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              Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation.

              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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                Author and article information

                Contributors
                Journal
                J Oncol
                J Oncol
                JO
                Journal of Oncology
                Hindawi
                1687-8450
                1687-8469
                2017
                17 September 2017
                : 2017
                : 5035371
                Affiliations
                1University of Clermont-Auvergne, UMR 1019 INRA-UCA, Human Nutrition Unit (UNH), ECREIN Team, 63000 Clermont-Ferrand, France
                2Jean Perrin Comprehensive Cancer Centre, Thoracic Surgery Unit, 63011 Clermont-Ferrand, France
                3University of Clermont-Auvergne, Jean Perrin Comprehensive Cancer Centre, Department of Pathology, INSERM U1240 Molecular Imaging and Theranostic Strategies, 63000 Clermont-Ferrand, France
                4Greentech SA, Biopôle Clermont-Limagne, 63360 Saint-Beauzire, France
                5INRA, UR454 Microbiology Unit, Clermont-Ferrand/Theix Research Centre, 63122 Saint-Genès-Champanelle, France
                6Jean Perrin Comprehensive Cancer Centre, CHU Gabriel-Montpied, Human Nutrition Unit (UNH), CRNH Auvergne, 63000 Clermont-Ferrand, France
                7CIAMS, University Paris-Sud, University Paris-Saclay, 91405 Orsay Cedex, France
                8CIAMS, University of Orléans, 45067 Orléans, France
                Author notes

                Academic Editor: James L. Mulshine

                Author information
                http://orcid.org/0000-0002-7782-7538
                http://orcid.org/0000-0002-0337-6471
                http://orcid.org/0000-0001-9533-5409
                http://orcid.org/0000-0001-7541-4417
                http://orcid.org/0000-0002-5127-7486
                Article
                10.1155/2017/5035371
                5623803
                29075294
                2e3b443f-21a8-4f46-b6e0-5d7967501abd
                Copyright © 2017 Rea Bingula et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 8 March 2017
                : 30 June 2017
                : 3 August 2017
                Categories
                Review Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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