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1
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Yan R, Zhang L, Chen Y, Zheng Y, Xu P, Xu Z. Therapeutic potential of gut microbiota modulation in epilepsy: A focus on short-chain fatty acids. Neurobiol Dis 2025; 209:106880. [PMID: 40118219 DOI: 10.1016/j.nbd.2025.106880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 03/17/2025] [Accepted: 03/18/2025] [Indexed: 03/23/2025] Open
Abstract
According to the criteria established by the International League Against Epilepsy (ILAE), epilepsy is defined as a disorder characterized by at least two unprovoked seizures occurring more than 24 h apart. Its pathogenesis is closely related to various physiological and pathological factors. Advances in high-throughput metagenomic sequencing have increasingly highlighted the role of gut microbiota dysbiosis in epilepsy. Short-chain fatty acids (SCFAs), the major metabolites of the gut microbiota and key regulators of the gut-brain axis, support physiological homeostasis through multiple mechanisms. Recent studies have indicated that SCFAs not only regulate seizures by maintaining intestinal barrier integrity and modulating intestinal immune responses, but also affect the structure and function of the blood-brain barrier (BBB) and regulate neuroinflammation. This review, based on current literatures, explores the relationship between SCFAs and epilepsy, emphasizing how SCFAs affect epilepsy by modulating the intestinal barrier and BBB. In-depth studies on SCFAs may reveal their therapeutic potential and inform the development of gut microbiota-targeted epilepsy treatments.
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Affiliation(s)
- Rong Yan
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Linhai Zhang
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Ya Chen
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yongsu Zheng
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Ping Xu
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
| | - Zucai Xu
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China; Key Laboratory of Brain Function and Brain Disease Prevention and Treatment of Guizhou Province, Zunyi, China.
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2
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Fabiano GA, Oliveira RPS, Rodrigues S, Santos BN, Venema K, Antunes AEC. Evidence of synbiotic potential of oat beverage enriched with inulin and fermented by L. rhamnosus LR B in a dynamic in vitro model of human colon. Food Res Int 2025; 211:116489. [PMID: 40356187 DOI: 10.1016/j.foodres.2025.116489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 04/14/2025] [Accepted: 04/16/2025] [Indexed: 05/15/2025]
Abstract
Fermented dairy products are known for their efficiency in delivering and protecting probiotic microorganisms. However, there is a growing demand for diversification of the market with plant-based products. The aim of this study was to develop an oat beverage enriched with inulin and fermented with Lacticaseibacillus rhamnosus LR B and evaluate its synbiotic effects in vitro. For this purpose, the validated dynamic colon model (the TNO Intestinal Model TIM-2) was used with focus on the composition of the gut microbiota and its production of metabolites to evaluate the functionality. The fermentation kinetics, sugars, organic acids and inulin dosage in the fermented oat beverage were also evaluated. The acidification rate was 16.91 10-3 pH units.min-1, reaching the final pH of 4.5 in 2.38 ± 0.05 h. Dosages of sucrose, glucose and lactic acid were 23.35 ± 0.45 g.L-1, 21.37 ± 0.77 g.L-1, 0.94 ± 0.05 g.L-1, respectively. After simulated in vitro digestion, the inulin concentration was partially preserved with 20.11 ± 0.21 maltose equivalent (μg.mL-1). The fermented and pre-digested oat beverage (with 7.71 ± 0.44 log CFU.mL-1) was fed into TIM-2, which was previously inoculated with feces from healthy adults. The analysis identified nine bacterial taxa that were significantly modulated compared to the standard ileal effluent medium (SIEM) control. An increase in relative abundance of Lactobacillus and Catenibacterium, and reduction in Citrobacter, Escherichia-Shigella, and Klebsiella was observed. In addition, the cumulative means of short-chain fatty acids (SCFAs) increased, especially for acetate and butyrate. These findings suggest that the developed oat beverage can positively influence the gut microbiota and its activity, highlighting possible health benefits.
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Affiliation(s)
- G A Fabiano
- Faculdade de Ciências Aplicadas, Universidade Estadual de Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - R P S Oliveira
- Department of Biochemical-Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - S Rodrigues
- Department of Food Engineering, Federal University of Ceara, Fortaleza, Ceara, Brazil
| | - B N Santos
- Department of Chemical Engineering, Federal University of Ceara, Fortaleza, Ceara, Brazil
| | - K Venema
- Maastricht University, Centre for Healthy Eating & Food Innovation (HEFI), Venlo, the Netherlands
| | - A E C Antunes
- Faculdade de Ciências Aplicadas, Universidade Estadual de Campinas (UNICAMP), Limeira, São Paulo, Brazil.
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3
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Ichikawa A, Takayama T, Kojima C, Fujie S, Iemitsu M, Inoue K. Conversion Reaction of Stable-Isotope Oxygen Labeling of Carboxylic Acids for Accurate Screening LC-MS/MS Assay: Application of Behavioral Changes of Short-Chain Fatty Acids in Sports Athletes under Exercise Loading. Anal Chem 2025; 97:7765-7771. [PMID: 40183608 DOI: 10.1021/acs.analchem.4c05872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
Short-chain fatty acids (SCFAs) have attracted considerable interest as potential biomarkers, therapeutic targets, and nutritional factors in athletic training. SCFAs are typically produced by the intestinal microbiome and exhibit various structural forms, including linear- and branched-chain types. In particular, branched-chain SCFAs have been associated with muscle metabolism during exercise loading. Consequently, accurate and efficient analytical methods are essential for identifying these biomarkers. Liquid chromatography-tandem mass spectrometry is a suitable and accurate technique for SCFA analysis; however, stable isotope calibrations are required for all analytes. Because of technological limitations, the available species are restricted to certain types of SCFAs. To address this issue, this study performed a simple conversion reaction involving the incorporation of 18O into the carboxyl group. Specifically, oxygen atoms in the carboxyl groups were substituted with 18O sourced from commercially available H218O. An SCFA mixture standard solution was successfully labeled under optimized conditions, and the SIL purity and amount were sufficient for isotope dilution (95.2-96.9%, 250 assays using 10 μL of H218O). Moreover, no reversion to 16O was observed during storage or analysis. Analytical validation was performed in human serum using the substituted isotopic standard mixture, achieving good accuracy (90-110%) and precision (<10% relative standard deviation) across three concentration levels. Finally, changes in SCFA patterns were examined in athletes during exercise loading.
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Affiliation(s)
- Aoi Ichikawa
- Laboratory of Clinical and Analytical Chemistry, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan
| | - Takahiro Takayama
- Laboratory of Clinical and Analytical Chemistry, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan
| | - Chihiro Kojima
- Faculty of Sport and Health Science, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan
| | - Shumpei Fujie
- Faculty of Sport and Health Science, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan
| | - Motoyuki Iemitsu
- Faculty of Sport and Health Science, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan
- Institute of Advanced Research for Sport and Health Science, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan
| | - Koichi Inoue
- Laboratory of Clinical and Analytical Chemistry, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan
- Institute of Advanced Research for Sport and Health Science, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan
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4
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Urbani G, Rondini E, Distrutti E, Marchianò S, Biagioli M, Fiorucci S. Phenotyping the Chemical Communications of the Intestinal Microbiota and the Host: Secondary Bile Acids as Postbiotics. Cells 2025; 14:595. [PMID: 40277921 PMCID: PMC12025480 DOI: 10.3390/cells14080595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/10/2025] [Accepted: 04/12/2025] [Indexed: 04/26/2025] Open
Abstract
The current definition of a postbiotic is a "preparation of inanimate microorganisms and/or their components that confers a health benefit on the host". Postbiotics can be mainly classified as metabolites, derived from intestinal bacterial fermentation, or structural components, as intrinsic constituents of the microbial cell. Secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) are bacterial metabolites generated by the enzymatic modifications of primary bile acids by microbial enzymes. Secondary bile acids function as receptor ligands modulating the activity of a family of bile-acid-regulated receptors (BARRs), including GPBAR1, Vitamin D (VDR) receptor and RORγT expressed by various cell types within the entire human body. Secondary bile acids integrate the definition of postbiotics, exerting potential beneficial effects on human health given their ability to regulate multiple biological processes such as glucose metabolism, energy expenditure and inflammation/immunity. Although there is evidence that bile acids might be harmful to the intestine, most of this evidence does not account for intestinal dysbiosis. This review examines this novel conceptual framework of secondary bile acids as postbiotics and how these mediators participate in maintaining host health.
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Affiliation(s)
- Ginevra Urbani
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, 06123 Perugia, Italy; (G.U.); (S.M.); (M.B.)
| | - Elena Rondini
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, 06123 Perugia, Italy; (E.R.); (E.D.)
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, 06123 Perugia, Italy; (E.R.); (E.D.)
| | - Silvia Marchianò
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, 06123 Perugia, Italy; (G.U.); (S.M.); (M.B.)
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, 06123 Perugia, Italy; (G.U.); (S.M.); (M.B.)
| | - Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, 06123 Perugia, Italy; (G.U.); (S.M.); (M.B.)
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5
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Liu J, Li F, Yang L, Luo S, Deng Y. Gut microbiota and its metabolites regulate insulin resistance: traditional Chinese medicine insights for T2DM. Front Microbiol 2025; 16:1554189. [PMID: 40177494 PMCID: PMC11963813 DOI: 10.3389/fmicb.2025.1554189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 02/27/2025] [Indexed: 04/05/2025] Open
Abstract
The gut microbiota is closely associated with the onset and development of type 2 diabetes mellitus (T2DM), characterized by insulin resistance (IR) and chronic low-grade inflammation. However, despite the widespread use of first-line antidiabetic drugs, IR in diabetes and its complications continue to rise. The gut microbiota and its metabolic products may promote the development of T2DM by exacerbating IR. Therefore, regulating the gut microbiota has become a promising therapeutic strategy, with particular attention given to probiotics, prebiotics, synbiotics, and fecal microbiota transplantation. This review first examines the relationship between gut microbiota and IR in T2DM, summarizing the research progress of microbiota-based therapies in modulating IR. We then delve into how gut microbiota-related metabolic products contribute to IR. Finally, we summarize the research findings on the role of traditional Chinese medicine in regulating the gut microbiota and its metabolic products to improve IR. In conclusion, the gut microbiota and its metabolic products play a crucial role in the pathophysiological process of T2DM by modulating IR, offering new insights into potential therapeutic strategies for T2DM.
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Affiliation(s)
- Jing Liu
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Fuxing Li
- Ningxiang Traditional Chinese Medicine Hospital, Changsha, China
| | - Le Yang
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Shengping Luo
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Yihui Deng
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
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Jameson KG, Kazmi SA, Ohara TE, Son C, Yu KB, Mazdeyasnan D, Leshan E, Vuong HE, Paramo J, Lopez-Romero A, Yang L, Schweizer FE, Hsiao EY. Select microbial metabolites in the small intestinal lumen regulate vagal activity via receptor-mediated signaling. iScience 2025; 28:111699. [PMID: 39877906 PMCID: PMC11772968 DOI: 10.1016/j.isci.2024.111699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 09/22/2024] [Accepted: 12/24/2024] [Indexed: 01/31/2025] Open
Abstract
The vagus nerve is proposed to enable communication between the gut microbiome and the brain, but activity-based evidence is lacking. We find that mice reared germ-free exhibit decreased vagal tone relative to colonized controls, which is reversed via microbiota restoration. Perfusing antibiotics into the small intestines of conventional mice, but not germ-free mice, acutely decreases vagal activity which is restored upon re-perfusion with intestinal filtrates from conventional, but not germ-free, mice. Microbiome-dependent short-chain fatty acids, bile acids, and 3-indoxyl sulfate indirectly stimulate vagal activity in a receptor-dependent manner. Serial perfusion of each metabolite class activates both shared and distinct neuronal subsets with varied response kinetics. Metabolite-induced and receptor-dependent increases in vagal activity correspond with the activation of brainstem neurons. Results from this study reveal that the gut microbiome regulates select metabolites in the intestinal lumen that differentially activate vagal afferent neurons, thereby enabling the microbial modulation of chemosensory signals for gut-brain communication.
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Affiliation(s)
- Kelly G. Jameson
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Sabeen A. Kazmi
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Takahiro E. Ohara
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Celine Son
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Kristie B. Yu
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Donya Mazdeyasnan
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Emma Leshan
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Helen E. Vuong
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jorge Paramo
- UCLA Goodman-Luskin Microbiome Center, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, Los Angeles, CA 90095, USA
| | - Arlene Lopez-Romero
- UCLA Goodman-Luskin Microbiome Center, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, Los Angeles, CA 90095, USA
| | - Long Yang
- Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Felix E. Schweizer
- Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Elaine Y. Hsiao
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- UCLA Goodman-Luskin Microbiome Center, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, Los Angeles, CA 90095, USA
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7
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Shallangwa SM, Ross AW, Morgan PJ. Single, but not mixed dietary fibers suppress body weight gain and adiposity in high fat-fed mice. Front Microbiol 2025; 16:1544433. [PMID: 40012787 PMCID: PMC11861375 DOI: 10.3389/fmicb.2025.1544433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 01/13/2025] [Indexed: 02/28/2025] Open
Abstract
Dietary fiber can suppress excess adipose tissue and weight gain in rodents and humans when fed high fat diets. The gut microbiome is thought to have a key role, although exactly how remains unclear. In a tightly controlled murine study, we explored how different types of dietary fiber and doses affect the gut microbiota and gut epithelial gene expression. We show that 10% pectin and 10% FOS suppress high fat diet (HFD)-induced weight gain, effects not seen at 2% doses. Furthermore, 2 and 10% mixtures of dietary fiber were also without effect. Each fiber treatment stimulated a distinct gut microbiota profile at the family and operational taxonomic unit (OTU) level. Mechanistically it is likely that the single 10% fiber dose shifted selected bacteria above some threshold abundance, required to suppress body weight, which was not achieved by the 10% Mix, composed of 4 fibers each at 2.5%. Plasma levels of the gut hormone PYY were elevated by 10% pectin and FOS, but not 10% mixed fibers, and similarly RNA seq revealed some distinct effects of the 10% single fibers on gut epithelial gene expression. These data show how the ability of dietary fiber to suppress HFD-induced weight gain is dependent upon both fiber type and dose. It also shows that the microbial response to dietary fiber is distinct and that there is not a single microbial response associated with the inhibition of adiposity and weight gain. PYY seems key to the latter response, although the role of other factors such as Reg3γ and CCK needs to be explored.
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Affiliation(s)
| | | | - Peter J. Morgan
- Rowett Institute, University of Aberdeen, Aberdeen, United Kingdom
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8
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Olotu T, Ferrell JM. Lactobacillus sp. for the Attenuation of Metabolic Dysfunction-Associated Steatotic Liver Disease in Mice. Microorganisms 2024; 12:2488. [PMID: 39770690 PMCID: PMC11728176 DOI: 10.3390/microorganisms12122488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 11/19/2024] [Accepted: 11/26/2024] [Indexed: 01/05/2025] Open
Abstract
Probiotics are studied for their therapeutic potential in the treatment of several diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Part of the significant progress made in understanding the pathogenesis of steatosis has come from identifying the complex interplay between the gut microbiome and liver function. Recently, probiotics have shown beneficial effects for the treatment and prevention of steatosis and MASLD in rodent models and in clinical trials. Numerous studies have demonstrated the promising potential of lactic acid bacteria, especially the genus Lactobacillus. Lactobacillus is a prominent bile acid hydrolase bacterium that is involved in the biotransformation of bile acids. This genus' modulation of the gut microbiota also contributes to overall gut health; it controls gut microbial overgrowth, shapes the intestinal bile acid pool, and alleviates inflammation. This narrative review offers a comprehensive summary of the potential of Lactobacillus in the gut-liver axis to attenuate steatosis and MASLD. It also highlights the roles of Lactobacillus in hepatic lipid metabolism, insulin resistance, inflammation and fibrosis, and bile acid synthesis in attenuating MASLD.
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Affiliation(s)
- Titilayo Olotu
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA;
- School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
| | - Jessica M. Ferrell
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA;
- School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
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9
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Dagbasi A, Fuller A, Hanyaloglu AC, Carroll B, McLaughlin J, Frost G, Holliday A. The role of nutrient sensing dysregulation in anorexia of ageing: The little we know and the much we don't. Appetite 2024; 203:107718. [PMID: 39423861 DOI: 10.1016/j.appet.2024.107718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 08/01/2024] [Accepted: 10/15/2024] [Indexed: 10/21/2024]
Abstract
The age-related decline in appetite and food intake - termed "anorexia of ageing" - is implicated in undernutrition in later life and hence provides a public health challenge for our ageing population. Eating behaviour is controlled, in part, by homeostatic mechanisms which sense nutrient status and provide feedback to appetite control regions of the brain. Such feedback signals, propagated by episodic gut hormones, are dysregulated in some older adults. The secretory responses of appetite-related gut hormones to feeding are amplified, inducing a more anorexigenic signal which is associated with reduced appetite and food intake. Such an augmented response would indicate an increase in gut sensitivity to nutrients. Consequently, this review explores the role of gastrointestinal tract nutrient sensing in age-related appetite dysregulation. We review and synthesise evidence for age-related alterations in nutrient sensing which may explain the observed hormonal dysregulation. Drawing on what is known regarding elements of nutrient sensing pathways in animal models, in other tissues of the body, and in certain models of disease, we identify potential causal mechanisms including alterations in enteroendocrine cell number and distribution, dysregulation of cell signalling pathways, and changes in the gut milieu. From identified gaps in evidence, we highlight interesting and important avenues for future research.
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Affiliation(s)
- Aygul Dagbasi
- Section of Nutrition, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, London, W12 0NN, UK
| | - Amy Fuller
- Research Centre for Health and Life Sciences, Institute of Health and Wellbeing, Faculty of Health and Life Science, Coventry University, Coventry, CV1 5FB, UK
| | - Aylin C Hanyaloglu
- Institute of Reproductive and Developmental Biology (IRDB), Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK
| | - Bernadette Carroll
- School of Biochemistry, University of Bristol, University Walk, Bristol, BS1 8TD, UK
| | - John McLaughlin
- Division of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester and Manchester Academic Health Sciences Centre, Manchester, M13 9PT, UK
| | - Gary Frost
- Section of Nutrition, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, London, W12 0NN, UK
| | - Adrian Holliday
- School of Biomedical, Nutritional, and Sport Science, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK; Human Nutrition and Exercise Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
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10
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Datta S, Pasham S, Inavolu S, Boini KM, Koka S. Role of Gut Microbial Metabolites in Cardiovascular Diseases-Current Insights and the Road Ahead. Int J Mol Sci 2024; 25:10208. [PMID: 39337693 PMCID: PMC11432476 DOI: 10.3390/ijms251810208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of premature morbidity and mortality globally. The identification of novel risk factors contributing to CVD onset and progression has enabled an improved understanding of CVD pathophysiology. In addition to the conventional risk factors like high blood pressure, diabetes, obesity and smoking, the role of gut microbiome and intestinal microbe-derived metabolites in maintaining cardiovascular health has gained recent attention in the field of CVD pathophysiology. The human gastrointestinal tract caters to a highly diverse spectrum of microbes recognized as the gut microbiota, which are central to several physiologically significant cascades such as metabolism, nutrient absorption, and energy balance. The manipulation of the gut microbial subtleties potentially contributes to CVD, inflammation, neurodegeneration, obesity, and diabetic onset. The existing paradigm of studies suggests that the disruption of the gut microbial dynamics contributes towards CVD incidence. However, the exact mechanistic understanding of such a correlation from a signaling perspective remains elusive. This review has focused upon an in-depth characterization of gut microbial metabolites and their role in varied pathophysiological conditions, and highlights the potential molecular and signaling mechanisms governing the gut microbial metabolites in CVDs. In addition, it summarizes the existing courses of therapy in modulating the gut microbiome and its metabolites, limitations and scientific gaps in our current understanding, as well as future directions of studies involving the modulation of the gut microbiome and its metabolites, which can be undertaken to develop CVD-associated treatment options. Clarity in the understanding of the molecular interaction(s) and associations governing the gut microbiome and CVD shall potentially enable the development of novel druggable targets to ameliorate CVD in the years to come.
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Affiliation(s)
- Sayantap Datta
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Sindhura Pasham
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA
| | - Sriram Inavolu
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA
| | - Krishna M Boini
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Saisudha Koka
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA
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11
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Kirtipal N, Seo Y, Son J, Lee S. Systems Biology of Human Microbiome for the Prediction of Personal Glycaemic Response. Diabetes Metab J 2024; 48:821-836. [PMID: 39313228 PMCID: PMC11449821 DOI: 10.4093/dmj.2024.0382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 08/29/2024] [Indexed: 09/25/2024] Open
Abstract
The human gut microbiota is increasingly recognized as a pivotal factor in diabetes management, playing a significant role in the body's response to treatment. However, it is important to understand that long-term usage of medicines like metformin and other diabetic treatments can result in problems, gastrointestinal discomfort, and dysbiosis of the gut flora. Advanced sequencing technologies have improved our understanding of the gut microbiome's role in diabetes, uncovering complex interactions between microbial composition and metabolic health. We explore how the gut microbiota affects glucose metabolism and insulin sensitivity by examining a variety of -omics data, including genomics, transcriptomics, epigenomics, proteomics, metabolomics, and metagenomics. Machine learning algorithms and genome-scale modeling are now being applied to find microbiological biomarkers associated with diabetes risk, predicted disease progression, and guide customized therapy. This study holds promise for specialized diabetic therapy. Despite significant advances, some concerns remain unanswered, including understanding the complex relationship between diabetes etiology and gut microbiota, as well as developing user-friendly technological innovations. This mini-review explores the relationship between multiomics, precision medicine, and machine learning to improve our understanding of the gut microbiome's function in diabetes. In the era of precision medicine, the ultimate goal is to improve patient outcomes through personalized treatments.
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Affiliation(s)
- Nikhil Kirtipal
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Youngchang Seo
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Jangwon Son
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Korea
| | - Sunjae Lee
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
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Yang G, Khan A, Liang W, Xiong Z, Stegbauer J. Aortic aneurysm: pathophysiology and therapeutic options. MedComm (Beijing) 2024; 5:e703. [PMID: 39247619 PMCID: PMC11380051 DOI: 10.1002/mco2.703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 08/06/2024] [Accepted: 08/06/2024] [Indexed: 09/10/2024] Open
Abstract
Aortic aneurysm (AA) is an aortic disease with a high mortality rate, and other than surgery no effective preventive or therapeutic treatment have been developed. The renin-angiotensin system (RAS) is an important endocrine system that regulates vascular health. The ACE2/Ang-(1-7)/MasR axis can antagonize the adverse effects of the activation of the ACE/Ang II/AT1R axis on vascular dysfunction, atherosclerosis, and the development of aneurysms, thus providing an important therapeutic target for the prevention and treatment of AA. However, products targeting the Ang-(1-7)/MasR pathway still lack clinical validation. This review will outline the epidemiology of AA, including thoracic, abdominal, and thoracoabdominal AA, as well as current diagnostic and treatment strategies. Due to the highest incidence and most extensive research on abdominal AA (AAA), we will focus on AAA to explain the role of the RAS in its development, the protective function of Ang-(1-7)/MasR, and the mechanisms involved. We will also describe the roles of agonists and antagonists, suggest improvements in engineering and drug delivery, and provide evidence for Ang-(1-7)/MasR's clinical potential, discussing risks and solutions for clinical use. This study will enhance our understanding of AA and offer new possibilities and promising targets for therapeutic intervention.
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Affiliation(s)
- Guang Yang
- Division of Renal Medicine Peking University Shenzhen Hospital Shenzhen China
- Shenzhen Institute of Translational Medicine Shenzhen Second People's Hospital The First Affiliated Hospital of Shenzhen University Shenzhen China
- Department of Life Sciences Yuncheng University Yuncheng China
- Shenzhen Clinical Research Center for Urology and Nephrology Shenzhen China
| | - Abbas Khan
- Department of Nutrition and Health Promotion University of Home Economics Lahore Pakistan Lahore Pakistan
| | - Wei Liang
- Division of Renal Medicine Peking University Shenzhen Hospital Shenzhen China
- Shenzhen Clinical Research Center for Urology and Nephrology Shenzhen China
| | - Zibo Xiong
- Division of Renal Medicine Peking University Shenzhen Hospital Shenzhen China
- Shenzhen Clinical Research Center for Urology and Nephrology Shenzhen China
| | - Johannes Stegbauer
- Department of Nephrology Medical Faculty University Hospital Düsseldorf Heinrich Heine University Düsseldorf Düsseldorf Germany
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Shokr SM, Kahlert S, Kluess J, Hradsky J, Dänicke S, Rothkötter HJ, Nossol C. Modeling of culture conditions by culture system, glucose and propionic acid and their impact on metabolic profile in IPEC-J2. PLoS One 2024; 19:e0307411. [PMID: 39024309 PMCID: PMC11257281 DOI: 10.1371/journal.pone.0307411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 07/04/2024] [Indexed: 07/20/2024] Open
Abstract
The microbiological environment and their corresponding secreted metabolite spectrum are an essential modulator of the enterocyte function, effecting the whole organism. Intestinal porcine jejunal epithelial cell line (IPEC-J2) is an established in vitro model for differentiation of enterocytes in different cell culture models. An improved oxygen supply seems to be the main reason for differentiation in an air-liquid-interface culture, but this has not yet been conclusively clarified. In this context, the nutrition of the cell and its influence on the metabolism is also of crucial importance. The interest in short-chain fatty acids (SCFAs) has grown steadily in recent years due to their clinical relevance in certain diseases such as multiple sclerosis and other inflammatory diseases, but not much is known of FFAR2 and FFAR3 (free fatty acid receptor 2 and 3) in pigs. We want to address the questions: 1. about the distribution of FFAR2 and FFAR3 in vivo and in vitro in sus scrofa 2. whether there is an influence of propionic acid, glucose content and cultivation on metabolism of enterocytes? The morphological analysis of FFAR2 and FFAR3 in vivo was investigated through immunostaining of frozen sections of the porcine gut segments jejunum, ileum and colon. Both receptors are expressed along the gut and were found in the smooth muscle cells of the tunica muscularis and lamina muscularis mucosae. Furthermore, a high expression of FFAR2 and a low expression of FFAR3 in the enteric nerve system was also observed in jejunum, ileum and colon of sus scrofa. In addition, FFAR2 and FFAR3 within the vessels was investigated. FFAR3 showed a strong expression on endothelial cells of veins and lymphatic vessels but was not detectable on arteries. Furthermore, we demonstrate for the first time, FFAR2 and FFAR3 in IPEC-J2 cells on RNA- and protein level, as well as with confocal microscopy. In addition, ENO1 and NDUFA4 were investigated on RNA-level in IPEC-J2 cells as 2 important genes, which play an essential role in metabolism. Here, NDUFA4 is detected in the model animal sus scrofa as well as in the porcine cell line IPEC-J2. A potential impact of propionic acid and/or glucose and/or cultivation method on the metabolism of the cells was tested with the Seahorse analyzer. Here, a significant higher ECAR was observed in the SMC than in the OCR. In summary, we were able to show that the cultivation system appears to have a greater influence than the medium composition or nutrition of the cells. However, this can be modulated by incubation time or combination of different SCFAs.
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Affiliation(s)
- Shirko Marcel Shokr
- Institute of Anatomy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
| | - Stefan Kahlert
- Institute of Anatomy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
| | | | - Johannes Hradsky
- Institute for Biochemistry and Cell Biology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
| | - Sven Dänicke
- Friedrich-Loeffler Institute, Braunschweig, Germany
| | | | - Constanze Nossol
- Institute of Anatomy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
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14
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Dehkordi SR, Pahlavani N, Nikbaf-Shandiz M, Bagheri R, Rasaei N, Darzi M, Rastgoo S, Bahari H, Shiraseb F, Asbaghi O. A systematic review, meta-analysis, dose-response, and meta-regression of the effects of acarbose intake on glycemic markers in adults. J Diabetes Metab Disord 2024; 23:135-172. [PMID: 38932875 PMCID: PMC11196564 DOI: 10.1007/s40200-023-01336-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 10/19/2023] [Indexed: 06/28/2024]
Abstract
Purpose Prior research has yielded mixed results regarding the impact of acarbose intake on glycemic markers. To provide a more comprehensive analysis, a systematic review and meta-analysis was performed to compile data from various randomized controlled trials (RCTs) examining the effects of acarbose intake on fasting blood sugar (FBS), insulin, hemoglobin A1C (HbA1c), and homeostasis model assessment of insulin resistance (HOMA-IR) in adults. Methods To identify relevant literature up to April 2023, a comprehensive search was conducted on various scholarly databases, including PubMed, Web of Science, and Scopus databases. The effect size of the studies was evaluated using a random-effects model to calculate the weighted mean differences (WMD) and 95% confidence intervals (CI). Heterogeneity between studies was assessed using Cochran's Q test and I2. Results This systematic review and meta-analysis included a total of 101 RCTs with a total of 107 effect sizes. The effect sizes for FBS in milligrams per deciliter (mg/dl), insulin in picomoles per liter (pmol/l), hemoglobin A1C (HbA1c) in percentage (%), and homeostasis model assessment of insulin resistance (HOMA-IR) were 92, 46, 80, and 22, respectively. The pooled analysis indicated that acarbose intake resulted in significant decreases in FBS (p = 0.018), insulin (p < 0.001), HbA1c (p < 0.001), and HOMA-IR (p < 0.001). Conclusion The findings of this systematic review and meta-analysis suggest that acarbose intake can potentially lead to significant improvements in glycemic parameters by decreasing the levels of FBS, HbA1c, and insulin. However, larger and more rigorously designed studies are still needed to further evaluate and strengthen this association.
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Affiliation(s)
| | - Naseh Pahlavani
- Health Sciences Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | | | - Reza Bagheri
- Department of Exercise Physiology, University of Isfahan, Isfahan, Iran
| | - Niloufar Rasaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Melika Darzi
- Department of Nutrition Sciences and Research Branch, Islamic Azad University, Tehran, Iran
| | - Samira Rastgoo
- Department of Cellular and Molecular Nutrition, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Bahari
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farideh Shiraseb
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Omid Asbaghi
- Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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15
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Yao MX, Yu HX, Mo HL, Zhang ZH, Song QC, Liu Q, Yang QY, Wang LX, Li Y. Structural and pharmacological characterization of a medium-chain fatty acid receptor GPR84 in common carp (Cyprinus carpio). DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2024; 153:105126. [PMID: 38160872 DOI: 10.1016/j.dci.2023.105126] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 12/23/2023] [Accepted: 12/24/2023] [Indexed: 01/03/2024]
Abstract
The medium-chain fatty acid receptor GPR84, a member of the G protein-coupled receptor family, is mainly expressed in macrophages and microglia, and is involved in the regulation of inflammatory responses and retinal development in mammals and amphibians. However, structure, tissue distribution, and pharmacology of this receptor have rarely been reported in fish. In this study, we cloned the coding sequence (CDS) of common carp GPR84 (ccGPR84), examined its tissue distribution, and explored its cellular signaling function. The results showed that the CDS of ccGPR84 is 1191 bp and encodes a putative protein with 396 amino acids. Phylogenetic and chromosomal synteny analyses revealed that ccGPR84 was evolutionarily conserved with Cyprinids. Real-time quantitative PCR (qPCR) indicated that ccGPR84 was predominantly expressed in the intestine and spleen. Luciferase reporter assay demonstrated that nonanoic acid, capric acid (decanoic acid), undecanoic acid and lauric acid could inhibit cAMP signaling pathway and activate MAPK/ERK signaling pathway, while the potencies of these four fatty acids on the two signaling pathways were different. Lauric acid has the highest inhibitory potency on cAMP signaling pathway, followed by undecanoic acid, nonanoic acid, and capric acid. While for MAPK/ERK signaling pathway, nonanoic acid has the highest activation potency, followed by undecanoic acid, capric acid, and lauric acid. These findings lay the foundation for revealing the roles of different medium-chain fatty acids in the inflammatory response of common carp.
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Affiliation(s)
- Ming-Xing Yao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Hui-Xia Yu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Hao-Lin Mo
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Zhi-Hao Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Qing-Chuan Song
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Qiao Liu
- Department of Pathology, The Second Affiliated Hospital of Air Force Medical University, Xi'an, Shaanxi, 710038, China
| | - Qi-Yuan Yang
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts, Medical School, Worcester, MA, 01605, USA
| | - Li-Xin Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Yang Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.
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16
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Gunn D, Yeldho C, Hoad C, Menys A, Gowland P, Marciani L, Spiller R. Mechanisms underlying the laxative effect of lactulose: A randomized placebo-controlled trial showing increased small bowel water and motility unaltered by the 5-HT 3 receptor antagonist, ondansetron. Neurogastroenterol Motil 2024; 36:e14754. [PMID: 38316636 DOI: 10.1111/nmo.14754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 01/16/2024] [Accepted: 01/18/2024] [Indexed: 02/07/2024]
Abstract
BACKGROUND Lactulose is a laxative which accelerates transit and softens stool. Our aim was to investigate its mechanism of action and use this model of diarrhea to investigate the anti-diarrheal actions of ondansetron. METHODS A double-blind, randomized, placebo-controlled crossover study of the effect of ondansetron 8 mg in 16 healthy volunteers. Serial MRI scans were performed fasted and 6 h after a meal. Participants then received lactulose 13.6 g twice daily and study drug for a further 36 h. On Day 3, they had further serial MRI scans for 4 h. Measurements included small bowel water content (SBWC), colonic volume, colonic gas, small bowel motility, whole gut transit, and ascending colon relaxation time (T1AC), a measure of colonic water content. KEY RESULTS Lactulose increased area under the curve (AUC) of SBWC from 0 to 240 min, mean difference 14.2 L · min (95% CI 4.1, 24.3), p = 0.009, and substantially increased small bowel motility after 4 h (mean (95% CI) 523 (457-646) a.u. to 852 (771-1178) a.u., p = 0.007). There were no changes in T1AC after 36 h treatment. Ondansetron did not significantly alter SBWC, small bowel motility, transit, colonic volumes, colonic gas nor T1AC, with or without lactulose. CONCLUSION & INFERENCES Lactulose increases SBWC and stimulates small bowel motility; however, unexpectedly it did not significantly alter colonic water content, suggesting its laxative effect is not osmotic but due to stimulation of motility. Ondansetron's lack of effect on intestinal water suggests its anti-diarrheal effect is not due to inhibition of secretion but more likely altered colonic motility.
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Affiliation(s)
- D Gunn
- NIHR Nottingham Biomedical Research Centre, Nottingham, UK
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
| | - C Yeldho
- NIHR Nottingham Biomedical Research Centre, Nottingham, UK
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
| | - C Hoad
- NIHR Nottingham Biomedical Research Centre, Nottingham, UK
- Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK
| | - A Menys
- Division of Medicine, Centre for Medical Imaging, University College London, London, UK
| | - P Gowland
- NIHR Nottingham Biomedical Research Centre, Nottingham, UK
- Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK
| | - L Marciani
- NIHR Nottingham Biomedical Research Centre, Nottingham, UK
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
| | - R Spiller
- NIHR Nottingham Biomedical Research Centre, Nottingham, UK
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
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17
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Abou-Khalil R, Andary J, El-Hayek E. Apple cider vinegar for weight management in Lebanese adolescents and young adults with overweight and obesity: a randomised, double-blind, placebo-controlled study. BMJ Nutr Prev Health 2024; 7:61-67. [PMID: 38966098 PMCID: PMC11221284 DOI: 10.1136/bmjnph-2023-000823] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/10/2024] [Indexed: 07/06/2024] Open
Abstract
Background and aims Obesity and overweight have become significant health concerns worldwide, leading to an increased interest in finding natural remedies for weight reduction. One such remedy that has gained popularity is apple cider vinegar (ACV). Objective To investigate the effects of ACV consumption on weight, blood glucose, triglyceride and cholesterol levels in a sample of the Lebanese population. Materials and methods 120 overweight and obese individuals were recruited. Participants were randomly assigned to either an intervention group receiving 5, 10 or 15 mL of ACV or a control group receiving a placebo (group 4) over a 12-week period. Measurements of anthropometric parameters, fasting blood glucose, triglyceride and cholesterol levels were taken at weeks 0, 4, 8 and 12. Results Our findings showed that daily consumption of the three doses of ACV for a duration of between 4 and 12 weeks is associated with significant reductions in anthropometric variables (weight, body mass index, waist/hip circumferences and body fat ratio), blood glucose, triglyceride and cholesterol levels. No significant risk factors were observed during the 12 weeks of ACV intake. Conclusion Consumption of ACV in people with overweight and obesity led to an improvement in the anthropometric and metabolic parameters. ACV could be a promising antiobesity supplement that does not produce any side effects.
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Affiliation(s)
- Rony Abou-Khalil
- Department of Biology, Holy Spirit University of Kaslik, Jounieh, Lebanon
| | - Jeanne Andary
- Nutrition and Food Science Department, American University of Science and Technology, Beirut, Lebanon
| | - Elissar El-Hayek
- Department of Biology, Holy Spirit University of Kaslik, Jounieh, Lebanon
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18
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Furune S, Suzuki T, Honda T, Yamamoto K, Furukawa K, Nakamura M, Ishigami M, Kinoshita F, Kadota Y, Tochio T, Shimomura Y, Hirooka Y, Fujishiro M, Kawashima H. Effects of 1-kestose on microbiome changes caused by vonoprazan: a randomized, double-blind, placebo-controlled pilot study. J Gastroenterol Hepatol 2024; 39:480-488. [PMID: 38149305 DOI: 10.1111/jgh.16445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 11/20/2023] [Accepted: 11/23/2023] [Indexed: 12/28/2023]
Abstract
BACKGROUND AND AIM Potassium-competitive acid blockers more strongly suppress the gastric acid barrier than proton pump inhibitors and cause dysbiosis. However, preventive measures in this regard have not been established. We aimed to evaluate whether 1-kestose, a known prebiotic, was effective at alleviating dysbiosis caused by potassium-competitive acid blockers. METHODS Patients scheduled to undergo endoscopic resection for superficial gastroduodenal tumors were enrolled and randomized 1:1 to receive either 1-kestose or placebo. All patients were started on potassium-competitive acid blocker (vonoprazan 20 mg/day) and took 1-kestose 10 g/day or placebo (maltose) 5 g/day for 8 weeks. The primary outcome was the effect of 1-kestose on potassium-competitive acid blocker-induced alterations in the microbiome. The fecal microbiome was analyzed before and after potassium-competitive acid blocker treatment via MiSeq (16S rRNA gene V3-V4 region). RESULTS Forty patients were enrolled, and 16 in each group were analyzed. In the placebo group, the Simpson index, an alpha diversity, was significantly decreased and relative abundance of Streptococcus was significantly increased by 1.9-fold. In the kestose group, the Simpson index did not change significantly and relative abundance of Streptococcus increased 1.3-fold, but this was not a significant change. In both groups, no adverse events occurred, ulcers were well healed, and pretreatment and posttreatment short-chain fatty acid levels did not differ. CONCLUSIONS The potassium-competitive acid blocker caused dysbiosis in the placebo group; this effect was prevented by 1-kestose. Thus, 1-kestose may be useful in dysbiosis treatment.
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Affiliation(s)
- Satoshi Furune
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takahiro Suzuki
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenta Yamamoto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazuhiro Furukawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masanao Nakamura
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fumie Kinoshita
- Statistical Analysis Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
| | | | | | - Yoshiharu Shimomura
- Department of Food and Nutritional Sciences, College of Bioscience and Biotechnology, Chubu University, Kasugai, Japan
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Elangovan A, Dahiya B, Kirola L, Iyer M, Jeeth P, Maharaj S, Kumari N, Lakhanpal V, Michel TM, Rao KRSS, Cho SG, Yadav MK, Gopalakrishnan AV, Kadhirvel S, Kumar NS, Vellingiri B. Does gut brain axis has an impact on Parkinson's disease (PD)? Ageing Res Rev 2024; 94:102171. [PMID: 38141735 DOI: 10.1016/j.arr.2023.102171] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/04/2023] [Accepted: 12/13/2023] [Indexed: 12/25/2023]
Abstract
Parkinson's Disease (PD) is becoming a growing global concern by being the second most prevalent disease next to Alzheimer's Disease (AD). Henceforth new exploration is needed in search of new aspects towards the disease mechanism and origin. Evidence from recent studies has clearly stated the role of Gut Microbiota (GM) in the maintenance of the brain and as a root cause of various diseases and disorders including other neurological conditions. In the case of PD, with an unknown etiology, the GM is said to have a larger impact on the disease pathophysiology. Although GM and its metabolites are crucial for maintaining the normal physiology of the host, it is an undeniable fact that there is an influence of GM in the pathophysiology of PD. As such the Enteroendocrine Cells (EECs) in the epithelium of the intestine are one of the significant regulators of the gut-brain axis and act as a communication mediator between the gut and the brain. The communication is established via the molecules of neuroendocrine which are said to have a crucial part in neurological diseases such as AD, PD, and other psychiatry-related disorders. This review is focused on understanding the proper role of GM and EECs in PD. Here, we also focus on some of the metabolites and compounds that can interact with the PD genes causing various dysfunctions in the cell and facilitating the disease conditions using bioinformatical tools. Various mechanisms concerning EECs and PD, their identification, the latest studies, and available current therapies have also been discussed.
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Affiliation(s)
- Ajay Elangovan
- Human Cytogenetics and Stem Cell Laboratory, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Bhawna Dahiya
- Human Cytogenetics and Stem Cell Laboratory, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Laxmi Kirola
- Department of Biotechnology, School of Health Sciences and Technology (SoHST), UPES University, Dehradun, Uttarakhand 248007, India
| | - Mahalaxmi Iyer
- Department of Microbiology, Central University of Punjab, Bathinda 151401, Punjab, India; Department of Biotechnology, Karpagam Academy of Higher Education (Deemed to be University), Coimbatore 641021, Tamil Nadu, India
| | - Priyanka Jeeth
- Department of Computational Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Sakshi Maharaj
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Nikki Kumari
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Vikas Lakhanpal
- Department of Neurology, All India Institute of Medical Sciences, Bathinda 151005, Punjab, India
| | - Tanja Maria Michel
- Research Unit of Psychiatry, Dept. of Psychiatry Odense, Clinical Institute, University of Southern Denmark, J.B. Winslowsvej 20, Indg. 220B, Odense, Denmark
| | - K R S Sambasiva Rao
- Mangalayatan University - Jabalpur, Jabalpur - 481662, Madhya Pradesh, India
| | - Ssang-Goo Cho
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, 120 Neungdong-ro Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Mukesh Kumar Yadav
- Department of Microbiology, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore 632 014, India
| | - Saraboji Kadhirvel
- Department of Computational Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Nachimuthu Senthil Kumar
- Department of Biotechnology, Mizoram University (A Central University), Aizawl, 796 004 Mizoram, India
| | - Balachandar Vellingiri
- Human Cytogenetics and Stem Cell Laboratory, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda 151401, Punjab, India.
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20
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Lee YJ, Son SE, Im DS. Free fatty acid 3 receptor agonist AR420626 reduces allergic responses in asthma and eczema in mice. Int Immunopharmacol 2024; 127:111428. [PMID: 38159551 DOI: 10.1016/j.intimp.2023.111428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 12/15/2023] [Accepted: 12/19/2023] [Indexed: 01/03/2024]
Abstract
Free fatty acid 3 receptor (FFA3; previously GPR41) is a G protein-coupled receptor that senses short-chain fatty acids and dietary metabolites produced by the gut microbiota. FFA3 deficiency reportedly exacerbates inflammatory events in asthma. Herein, we aimed to determine the therapeutic potential of FFA3 agonists in treating inflammatory diseases. We investigated the effects of N-(2,5-dichlorophenyl)-4-(furan-2-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide (AR420626), an FFA3 agonist, in in vivo models of chemically induced allergic asthma and eczema in BALB/c mice. Administration of AR420626 decreased the number of immune cells in the bronchoalveolar lavage fluid and skin. AR420626 suppressed inflammatory cytokine expression in the lung and skin tissues. Histological examination revealed that AR420626 suppressed inflammation in the lungs and skin. Treatment with AR420626 significantly suppressed the enhanced lymph node size and inflammatory cytokine levels. Overall, FFA3 agonist AR420626 could suppress allergic asthma and eczema, implying that activation of FFA3 might be a therapeutic target for allergic diseases.
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Affiliation(s)
- Ye-Ji Lee
- Department of Biomedical and Pharmaceutical Sciences, Seoul 02446, Republic of Korea
| | - So-Eun Son
- Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea
| | - Dong-Soon Im
- Department of Biomedical and Pharmaceutical Sciences, Seoul 02446, Republic of Korea; Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea.
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Jameson KG, Kazmi SA, Son C, Mazdeyasnan D, Leshan E, Vuong HE, Paramo J, Lopez-Romero A, Yang L, Schweizer FE, Hsiao EY. Vagal interoception of microbial metabolites from the small intestinal lumen. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.18.572257. [PMID: 38187610 PMCID: PMC10769238 DOI: 10.1101/2023.12.18.572257] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
The vagus nerve is proposed to enable communication between the gut microbiome and brain, but activity-based evidence is lacking. Herein, we assess the extent of gut microbial influences on afferent vagal activity and metabolite signaling mechanisms involved. We find that mice reared without microbiota (germ-free, GF) exhibit decreased vagal afferent tone relative to conventionally colonized mice (specific pathogen-free, SPF), which is reversed by colonization with SPF microbiota. Perfusing non-absorbable antibiotics (ABX) into the small intestine of SPF mice, but not GF mice, acutely decreases vagal activity, which is restored upon re-perfusion with bulk lumenal contents or sterile filtrates from the small intestine and cecum of SPF, but not GF, mice. Of several candidates identified by metabolomic profiling, microbiome-dependent short-chain fatty acids, bile acids, and 3-indoxyl sulfate stimulate vagal activity with varied response kinetics, which is blocked by co-perfusion of pharmacological antagonists of FFAR2, TGR5, and TRPA1, respectively, into the small intestine. At the single-unit level, serial perfusion of each metabolite class elicits more singly responsive neurons than dually responsive neurons, suggesting distinct neuronal detection of different microbiome- and macronutrient-dependent metabolites. Finally, microbial metabolite-induced increases in vagal activity correspond with activation of neurons in the nucleus of the solitary tract, which is also blocked by co-administration of their respective receptor antagonists. Results from this study reveal that the gut microbiome regulates select metabolites in the intestinal lumen that differentially activate chemosensory vagal afferent neurons, thereby enabling microbial modulation of interoceptive signals for gut-brain communication. HIGHLIGHTS Microbiota colonization status modulates afferent vagal nerve activityGut microbes differentially regulate metabolites in the small intestine and cecumSelect microbial metabolites stimulate vagal afferents with varied response kineticsSelect microbial metabolites activate vagal afferent neurons and brainstem neurons via receptor-dependent signaling.
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22
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Fabiano GA, Shinn LM, Antunes AEC. Relationship between Oat Consumption, Gut Microbiota Modulation, and Short-Chain Fatty Acid Synthesis: An Integrative Review. Nutrients 2023; 15:3534. [PMID: 37630725 PMCID: PMC10459712 DOI: 10.3390/nu15163534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/27/2023] Open
Abstract
The gut microbiota consists of a set of microorganisms that colonizes the intestine and ferment fibers, among other nutrients, from the host's diet. A healthy gut microbiota, colonized mainly by beneficial microorganisms, has a positive effect on digestion and plays a role in disease prevention. However, dysregulation of the gut microbiota can contribute to various diseases. The nutrition of the host plays an important role in determining the composition of the gut microbiota. A healthy diet, rich in fiber, can beneficially modulate the gut microbiota. In this sense, oats are a source of both soluble and insoluble fiber. Oats are considered a functional ingredient with prebiotic potential and contain plant proteins, unsaturated fats, and antioxidant compounds. The impact of oat consumption on the gut microbiota is still emerging. Associations between oat consumption and the abundance of Akkermansia muciniphila, Roseburia, Lactobacillus, Bifidobacterium, and Faecalibacterium prausnitzii have already been observed. Therefore, this integrative review summarizes the findings from studies on the relationship between oat consumption, the gut microbiota, and the metabolites, mainly short-chain fatty acids, it produces.
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Affiliation(s)
- Giovanna Alexandre Fabiano
- School of Applied Sciences (FCA), State University of Campinas, 1300 Pedro Zaccaria St., Limeira 13484-350, SP, Brazil;
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23
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Masse KE, Lu VB. Short-chain fatty acids, secondary bile acids and indoles: gut microbial metabolites with effects on enteroendocrine cell function and their potential as therapies for metabolic disease. Front Endocrinol (Lausanne) 2023; 14:1169624. [PMID: 37560311 PMCID: PMC10407565 DOI: 10.3389/fendo.2023.1169624] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 07/05/2023] [Indexed: 08/11/2023] Open
Abstract
The gastrointestinal tract hosts the largest ecosystem of microorganisms in the body. The metabolism of ingested nutrients by gut bacteria produces novel chemical mediators that can influence chemosensory cells lining the gastrointestinal tract. Specifically, hormone-releasing enteroendocrine cells which express a host of receptors activated by these bacterial metabolites. This review will focus on the activation mechanisms of glucagon-like peptide-1 releasing enteroendocrine cells by the three main bacterial metabolites produced in the gut: short-chain fatty acids, secondary bile acids and indoles. Given the importance of enteroendocrine cells in regulating glucose homeostasis and food intake, we will also discuss therapies based on these bacterial metabolites used in the treatment of metabolic diseases such as diabetes and obesity. Elucidating the mechanisms gut bacteria can influence cellular function in the host will advance our understanding of this fundamental symbiotic relationship and unlock the potential of harnessing these pathways to improve human health.
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Affiliation(s)
| | - Van B. Lu
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
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24
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Dallatana A, Cremonesi L, Trombetta M, Fracasso G, Nocini R, Giacomello L, Innamorati G. G Protein-Coupled Receptors and the Rise of Type 2 Diabetes in Children. Biomedicines 2023; 11:1576. [PMID: 37371671 DOI: 10.3390/biomedicines11061576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 05/26/2023] [Accepted: 05/27/2023] [Indexed: 06/29/2023] Open
Abstract
The human genome counts hundreds of GPCRs specialized to sense thousands of different extracellular cues, including light, odorants and nutrients in addition to hormones. Primordial GPCRs were likely glucose transporters that became sensors to monitor the abundance of nutrients and direct the cell to switch from aerobic metabolism to fermentation. Human β cells express multiple GPCRs that contribute to regulate glucose homeostasis, cooperating with many others expressed by a variety of cell types and tissues. These GPCRs are intensely studied as pharmacological targets to treat type 2 diabetes in adults. The dramatic rise of type 2 diabetes incidence in pediatric age is likely correlated to the rapidly evolving lifestyle of children and adolescents of the new century. Current pharmacological treatments are based on therapies designed for adults, while youth and puberty are characterized by a different hormonal balance related to glucose metabolism. This review focuses on GPCRs functional traits that are relevant for β cells function, with an emphasis on aspects that could help to differentiate new treatments specifically addressed to young type 2 diabetes patients.
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Affiliation(s)
- Alessia Dallatana
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, 37134 Verona, Italy
| | - Linda Cremonesi
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, 37134 Verona, Italy
| | - Maddalena Trombetta
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, 37124 Verona, Italy
| | - Giulio Fracasso
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
| | - Riccardo Nocini
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, 37134 Verona, Italy
| | - Luca Giacomello
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, 37134 Verona, Italy
| | - Giulio Innamorati
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, 37134 Verona, Italy
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25
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Pinho SCM, Faria MA, Alves R, Cabrita ARJ, Fonseca AJM, M P L V O Ferreira I. Gastric epithelial response to milk fat using the semi-dynamic INFOGEST digestion model coupled with NCI-N87 cells. Food Res Int 2023; 166:112576. [PMID: 36914314 DOI: 10.1016/j.foodres.2023.112576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/21/2023] [Accepted: 02/02/2023] [Indexed: 02/08/2023]
Abstract
The stomach is a relevant spot of lipolysis for milk fat, but research on the effect of digested milk fat in the gastric epithelium is scarce and difficult to evaluate. In the present study, we implemented the semi-dynamic in vitro digestion model of INFOGEST, combined with gastric NCI-N87 cells, to study the effect of fat-free, whole conventional, and whole pasture-based milk on gastric epithelium. Cellular messenger ribonucleic acid (mRNA) expression of membrane fatty acids receptors (GPR41, GPR84), antioxidant enzymes (CAT, SOD, GPX), and inflammatory molecules (NF-κB p65, IL-1β, IL-6, IL-8 and TNF-α) was assessed. No significant differences were observed in mRNA expression of GPR41, GPR84, SOD, GPX, IL-6, IL-8, and TNF-α, after exposure of the NCI-N87 cells to milk digesta samples (p > 0.05). An increase of CAT mRNA expression was observed (p < 0.05), at a similar level, for all milk types. Whole milk digested samples induced higher mRNA expression of NF-κB p65 and IL-1β than fat-free milk (p < 0.05); while no differences were observed between whole conventional and whole pasture-based milk (p > 0.05). Moreover, the effect of milk digesta on gastric mRNA expression was studied in a scenario of subsequent stimulation of NCI-N87 monolayer with the pro-inflammatory cytokine IFN-γ. In these conditions, milk digesta samples increased CAT mRNA expression (p < 0.05), but had no effect in the expression of NF-κB p65 and IL-1β (p > 0.05). The increase of CAT mRNA expression suggests that milk fatty acids are used for energy production by gastric epithelial cells. Cellular antioxidant response to higher milk fatty acids availability could be associated to gastric epithelial inflammation, but did not contribute to increased inflammation in case of an external contact with IFN-γ. Besides, a conventional or a pasture-based origin did not affect the impact of whole milk in the NCI-N87 monolayer. The combined model responded to differences in milk fat content, which indicates its usefulness to study effects of foods at the gastric level.
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Affiliation(s)
- Susana C M Pinho
- LAQV/REQUIMTE, Department of Chemical Sciences, Laboratory of Food Science and Hydrology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; LAQV/REQUIMTE, ICBAS, School of Medicine and Biomedical Sciences, University of Porto, Rua de Jorge Viterbo, Ferreira 228, 4050-313 Porto, Portugal
| | - Miguel A Faria
- LAQV/REQUIMTE, Department of Chemical Sciences, Laboratory of Food Science and Hydrology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
| | - Rui Alves
- SORGAL, Sociedade de Óleos e Rações S.A., Estrada Nacional 109, Lugar da Pardala, 3880-728 S. João Ovar, Portugal
| | - Ana R J Cabrita
- LAQV/REQUIMTE, ICBAS, School of Medicine and Biomedical Sciences, University of Porto, Rua de Jorge Viterbo, Ferreira 228, 4050-313 Porto, Portugal
| | - António J M Fonseca
- LAQV/REQUIMTE, ICBAS, School of Medicine and Biomedical Sciences, University of Porto, Rua de Jorge Viterbo, Ferreira 228, 4050-313 Porto, Portugal
| | - Isabel M P L V O Ferreira
- LAQV/REQUIMTE, Department of Chemical Sciences, Laboratory of Food Science and Hydrology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
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26
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Abstract
A large body of evidence has emerged in the past decade supporting a role for the gut microbiome in the regulation of blood pressure. The field has moved from association to causation in the last 5 years, with studies that have used germ-free animals, antibiotic treatments and direct supplementation with microbial metabolites. The gut microbiome can regulate blood pressure through several mechanisms, including through gut dysbiosis-induced changes in microbiome-associated gene pathways in the host. Microbiota-derived metabolites are either beneficial (for example, short-chain fatty acids and indole-3-lactic acid) or detrimental (for example, trimethylamine N-oxide), and can activate several downstream signalling pathways via G protein-coupled receptors or through direct immune cell activation. Moreover, dysbiosis-associated breakdown of the gut epithelial barrier can elicit systemic inflammation and disrupt intestinal mechanotransduction. These alterations activate mechanisms that are traditionally associated with blood pressure regulation, such as the renin-angiotensin-aldosterone system, the autonomic nervous system, and the immune system. Several methodological and technological challenges remain in gut microbiome research, and the solutions involve minimizing confounding factors, establishing causality and acting globally to improve sample diversity. New clinical trials, precision microbiome medicine and computational methods such as Mendelian randomization have the potential to enable leveraging of the microbiome for translational applications to lower blood pressure.
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27
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Guo Q, Hou X, Cui Q, Li S, Shen G, Luo Q, Wu H, Chen H, Liu Y, Chen A, Zhang Z. Pectin mediates the mechanism of host blood glucose regulation through intestinal flora. Crit Rev Food Sci Nutr 2023; 64:6714-6736. [PMID: 36756885 DOI: 10.1080/10408398.2023.2173719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
Pectin is a complex polysaccharide found in plant cell walls and interlayers. As a food component, pectin is benefit for regulating intestinal flora. Metabolites of intestinal flora, including short-chain fatty acids (SCFAs), bile acids (BAs) and lipopolysaccharides (LPS), are involved in blood glucose regulation. SCFAs promote insulin synthesis through the intestine-GPCRs-derived pathway and hepatic adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway to promote hepatic glycogen synthesis. On the one hand, BAs stimulate intestinal L cells and pancreatic α cells to secrete Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) through receptors G protein-coupled receptor (TGR5) and farnesoid X receptor (FXR). On the other hand, BAs promote hepatic glycogen synthesis through AMPK pathway. LPS inhibits the release of inflammatory cytokines through Toll-like receptors (TLRs)-myeloid differentiation factor 88 (MYD88) pathway and mitogen-activated protein kinase (MAPK) pathway, thereby alleviating insulin resistance (IR). In brief, both SCFAs and BAs promote GLP-1 secretion through different pathways, employing strategies of increasing glucose consumption and decreasing glucose production to maintain normal glucose levels. Notably, pectin can also directly inhibit the release of inflammatory cytokines through the -TLRs-MYD88 pathway. These data provide valuable information for further elucidating the relationship between pectin-intestinal flora-glucose metabolism.
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Affiliation(s)
- Qing Guo
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Xiaoyan Hou
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Qiang Cui
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Shanshan Li
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Guanghui Shen
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Qingying Luo
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Hejun Wu
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Hong Chen
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Yuntao Liu
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Anjun Chen
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Zhiqing Zhang
- College of Food Science, Sichuan Agricultural University, Ya'an, China
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28
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Dietary fiber and SCFAs in the regulation of mucosal immunity. J Allergy Clin Immunol 2023; 151:361-370. [PMID: 36543697 DOI: 10.1016/j.jaci.2022.11.007] [Citation(s) in RCA: 130] [Impact Index Per Article: 65.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 11/01/2022] [Accepted: 11/04/2022] [Indexed: 12/24/2022]
Abstract
Gut bacterial metabolites such as short-chain fatty acids (SCFAs) have important effects on immune cells and the gut. SCFAs derive from the fermentation of dietary fiber by gut commensal bacteria. Insufficient fiber intake thus compromises SCFA production and, as a consequence, the host's physiology (particularly immune functions). We propose that many Western diseases, including those associated with impaired mucosal responses such as food allergy and asthma, may be affected by insufficient fiber intake and reduced SCFA levels in the gut and blood. Insufficient fiber intake is 1 alternative, or contributor, on top of the "hygiene hypothesis" to the rise of Western lifestyle diseases, and the 2 ideas need to be reconciled. The mechanisms by which SCFAs influence immunity and gut homeostasis are varied; they include stimulation of G protein-coupled receptors (GPCRs), such as GPR43 or GPR41; inhibition of histone deacetylases (and hence, gene transcription changes); and induction of intracellular metabolic changes. SCFAs modulate at many different levels to alter mucosal homeostasis, including changes to gut epithelial integrity, increases in regulatory T-cell numbers and function, and decreased expression of numerous inflammatory cytokines. There is scope for preventing and/or treating diseases by using diets that alter SCFA levels.
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29
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Chen S, Wang J, Dong N, Fang Q, Zhang Y, Chen C, Cui SW, Nie S. Polysaccharides from natural Cordyceps sinensis attenuated dextran sodium sulfate-induced colitis in C57BL/6J mice. Food Funct 2023; 14:720-733. [PMID: 36598450 DOI: 10.1039/d2fo02555h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
As potential candidates for treating ulcerative colitis (UC), polysaccharides have been attracting extensive interest in recent years. Cordyceps sinensis (C. sinensis) is a kind of traditional Chinese edible food, and its polysaccharide fractions have been found to be effective in regulating immunity and protecting the kidneys. To determine the potential function of polysaccharides from natural C. sinensis on UC, their effects in terms of histological, serological, biochemical, and immunological aspects on dextran sulphate sodium (DSS)-induced colitis mice model were investigated. Results showed that the polysaccharides significantly alleviated colitis by increasing the colon length, alleviating colon tissue damage, and inhibiting the activation of the NF-κB pathway. In addition, polysaccharides reduced the contents of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the serum, increased the number of goblet cells, and improved the expression of intestinal tight junction proteins (Occludin and Claudin-1). They also evidently enhanced the formation of IgA-secretory cells and sIgA contents. Furthermore, the polysaccharides modulated the gut microbiota by decreasing the relative abundance of Bilophila and increasing the relative abundance of Dehalobacterium, Coprococcus, Oscillospira, and Desulfovibrio, which is accompanied by an increase in the short chain fatty acids' (SCFAs) concentrations in cecal contents. These results suggested that C. sinensis polysaccharides possessed promising intervening effects on experimental acute UC in mice.
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Affiliation(s)
- Shuping Chen
- Jiangxi Key Laboratory of Natural Products and Functional Foods, Jiangxi Agricultural University, Nanchang 330045, China.,State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang 330047, China
| | - Junqiao Wang
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang 330047, China
| | - Nan Dong
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang 330047, China
| | - Qiuyue Fang
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang 330047, China
| | - Yanli Zhang
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang 330047, China
| | - Chunhua Chen
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang 330047, China
| | - Steve W Cui
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang 330047, China.,Guelph Research and Development Centre, Agriculture and Agri-Food Canada, 93 Stone Road West, Guelph, Ontario, N1G 5C9, Canada
| | - Shaoping Nie
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang 330047, China
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30
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Tu Y, Kuang X, Zhang L, Xu X. The associations of gut microbiota, endocrine system and bone metabolism. Front Microbiol 2023; 14:1124945. [PMID: 37089533 PMCID: PMC10116073 DOI: 10.3389/fmicb.2023.1124945] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 03/16/2023] [Indexed: 04/25/2023] Open
Abstract
Gut microbiota is of great importance in human health, and its roles in the maintenance of skeletal homeostasis have long been recognized as the "gut-bone axis." Recent evidence has indicated intercorrelations between gut microbiota, endocrine system and bone metabolism. This review article discussed the complex interactions between gut microbiota and bone metabolism-related hormones, including sex steroids, insulin-like growth factors, 5-hydroxytryptamine, parathyroid hormone, glucagon-like peptides, peptide YY, etc. Although the underlying mechanisms still need further investigation, the regulatory effect of gut microbiota on bone health via interplaying with endocrine system may provide a new paradigm for the better management of musculoskeletal disorders.
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Affiliation(s)
- Ye Tu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xinyi Kuang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ling Zhang
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- *Correspondence: Ling Zhang,
| | - Xin Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Xin Xu,
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31
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Milano W, Carizzone F, Foia M, Marchese M, Milano M, Saetta B, Capasso A. Obesity and Its Multiple Clinical Implications between Inflammatory States and Gut Microbiotic Alterations. Diseases 2022; 11:7. [PMID: 36648872 PMCID: PMC9844347 DOI: 10.3390/diseases11010007] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 12/16/2022] [Accepted: 12/21/2022] [Indexed: 12/31/2022] Open
Abstract
Obesity is a chronic multifactorial disease that has become a serious health problem and is currently widespread over the world. It is, in fact, strongly associated with many other conditions, including insulin resistance, type 2 diabetes, cardiovascular and neurodegenerative diseases, the onset of different types of malignant tumors and alterations in reproductive function. According to the literature, obesity is characterized by a state of low-grade chronic inflammation, with a substantial increase in immune cells, specifically macrophage infiltrates in the adipose tissue which, in turn, secrete a succession of pro-inflammatory mediators. Furthermore, recent studies on microbiota have postulated new possible mechanisms of interaction between obesity and unbalanced nutrition with inflammation. This intestinal "superorganism" complex seems to influence not only the metabolic balance of the host but also the immune response, favoring a state of systemic inflammation and insulin resistance. This review summarizes the major evidence on the interactions between the gut microbiota, energetic metabolism and host immune system, all leading to a convergence of the fields of immunology, nutrients physiology and microbiota in the context of obesity and its possible clinical complications. Finally, possible therapeutic approaches aiming to rebalance the intestinal microbial ecosystem are evaluated to improve the alteration of inflammatory and metabolic states in obesity and related diseases.
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Affiliation(s)
- Walter Milano
- UOSD Eating Disorder Unit, Mental Health Department, ASL Napoli 2 Nord, 80027 Napoli, Italy
| | - Francesca Carizzone
- UOSD Eating Disorder Unit, Mental Health Department, ASL Napoli 2 Nord, 80027 Napoli, Italy
| | | | - Magda Marchese
- Clinical Pathology Services, Santa Maria Delle Grazie Hospital Pozzuoli, Asl Napoli 2 Nord, 80027 Napoli, Italy
| | - Mariafrancesca Milano
- UOSD Eating Disorder Unit, Mental Health Department, ASL Napoli 2 Nord, 80027 Napoli, Italy
| | - Biancamaria Saetta
- UOSD Eating Disorder Unit, Mental Health Department, ASL Napoli 2 Nord, 80027 Napoli, Italy
| | - Anna Capasso
- Department of Pharmacy, University of Salerno, Fisciano, 84084 Salerno, Italy
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32
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Camilleri M, Zhernakova A, Bozzarelli I, D'Amato M. Genetics of irritable bowel syndrome: shifting gear via biobank-scale studies. Nat Rev Gastroenterol Hepatol 2022; 19:689-702. [PMID: 35948782 DOI: 10.1038/s41575-022-00662-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/29/2022] [Indexed: 12/19/2022]
Abstract
The pathophysiology of irritable bowel syndrome (IBS) is multifactorial and probably involves genetic predisposition and the effect of environmental factors. Unlike other gastrointestinal diseases with a heritable component, genetic research in IBS has been scarce and mostly characterized by small underpowered studies, leading to inconclusive results. The availability of genomic and health-related data from large international cohorts and population-based biobanks offers unprecedented opportunities for long-awaited, well-powered genetic studies in IBS. This Review focuses on the latest advances that provide compelling evidence for the importance of genes involved in the digestion of carbohydrates, ion channel function, neurotransmitters and their receptors, neuronal pathways and the control of gut motility. These discoveries have generated novel information that might be further refined for the identification of predisposed individuals and selection of management strategies for patients. This Review presents a conceptual framework, the advantages and potential limitations of modern genetic research in IBS, and a summary of available evidence.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Alexandra Zhernakova
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
| | | | - Mauro D'Amato
- Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain. .,Ikerbasque, Basque Foundation for Science, Bilbao, Spain. .,Department of Medicine and Surgery, LUM University, Casamassima, Italy.
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33
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Short-Chain Fatty Acids in Gut-Heart Axis: Their Role in the Pathology of Heart Failure. J Pers Med 2022; 12:jpm12111805. [PMID: 36579524 PMCID: PMC9695649 DOI: 10.3390/jpm12111805] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022] Open
Abstract
Heart failure (HF) is a syndrome with global clinical and socioeconomic burden worldwide owing to its poor prognosis. Accumulating evidence has implicated the possible contribution of gut microbiota-derived metabolites, short-chain fatty acids (SCFAs), on the pathology of a variety of diseases. The changes of SCFA concentration were reported to be observed in various cardiovascular diseases including HF in experimental animals and humans. HF causes hypoperfusion and/or congestion in the gut, which may lead to lowered production of SCFAs, possibly through the pathological changes of the gut microenvironment including microbiota composition. Recent studies suggest that SCFAs may play a significant role in the pathology of HF, possibly through an agonistic effect on G-protein-coupled receptors, histone deacetylases (HDACs) inhibition, restoration of mitochondrial function, amelioration of cardiac inflammatory response, its utilization as an energy source, and remote effect attributable to a protective effect on the other organs. Collectively, in the pathology of HF, SCFAs might play a significant role as a key mediator in the gut-heart axis. However, these possible mechanisms have not been entirely clarified and need further investigation.
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Jiang W, Wu J, Zhu S, Xin L, Yu C, Shen Z. The Role of Short Chain Fatty Acids in Irritable Bowel Syndrome. J Neurogastroenterol Motil 2022; 28:540-548. [PMID: 36250361 PMCID: PMC9577580 DOI: 10.5056/jnm22093] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 10/07/2022] [Indexed: 11/20/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that is characterized by abdominal pain and disordered bowel habits. The etiology of IBS is multifactorial, including abnormal gut-brain interactions, visceral hypersensitivity, altered colon motility, and psychological factors. Recent studies have shown that the intestinal microbiota and its metabolites short chain fatty acids (SCFAs) may be involved in the pathogenesis of IBS. SCFAs play an important role in the pathophysiology of IBS. We discuss the underlying mechanisms of action of SCFAs in intestinal inflammation and immunity, intestinal barrier integrity, motility, and the microbiota-gut-brain axis. Limited to previous studies, further studies are required to investigate the mechanisms of action of SCFAs in IBS and provide more precise therapeutic strategies for IBS.
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Affiliation(s)
- Wenxi Jiang
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jiali Wu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Shefeng Zhu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Linying Xin
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Chaohui Yu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhe Shen
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Ilyés T, Silaghi CN, Crăciun AM. Diet-Related Changes of Short-Chain Fatty Acids in Blood and Feces in Obesity and Metabolic Syndrome. BIOLOGY 2022; 11:1556. [PMID: 36358258 PMCID: PMC9687917 DOI: 10.3390/biology11111556] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/17/2022] [Accepted: 10/20/2022] [Indexed: 09/13/2023]
Abstract
Obesity-related illnesses are one of the leading causes of death worldwide. Metabolic syndrome has been associated with numerous health issues. Short-chain fatty acids (SCFAs) have been shown to have multiple effects throughout the body, both directly as well as through specific G protein-coupled receptors. The main SCFAs produced by the gut microbiota are acetate, propionate, and butyrate, which are absorbed in varying degrees from the large intestine, with some acting mainly locally and others systemically. Diet has the potential to influence the gut microbial composition, as well as the type and amount of SCFAs produced. High fiber-containing foods and supplements increase the production of SCFAs and SCFA-producing bacteria in the gut and have been shown to have bodyweight-lowering effects. Dietary supplements, which increase SCFA production, could open the way for novel approaches to weight loss interventions. The aim of this review is to analyze the variations of fecal and blood SCFAs in obesity and metabolic syndrome through a systematic search and analysis of existing literature.
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Affiliation(s)
| | - Ciprian N. Silaghi
- Department of Molecular Sciences, University of Medicine and Pharmacy “Iuliu Hațieganu”, 400012 Cluj-Napoca, Romania
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Yu L, Li Y. Involvement of Intestinal Enteroendocrine Cells in Neurological and Psychiatric Disorders. Biomedicines 2022; 10:biomedicines10102577. [PMID: 36289839 PMCID: PMC9599815 DOI: 10.3390/biomedicines10102577] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/21/2022] [Accepted: 09/21/2022] [Indexed: 11/24/2022] Open
Abstract
Neurological and psychiatric patients have increased dramatically in number in the past few decades. However, effective treatments for these diseases and disorders are limited due to heterogeneous and unclear pathogenic mechanisms. Therefore, further exploration of the biological aspects of the disease, and the identification of novel targets to develop alternative treatment strategies, is urgently required. Systems-level investigations have indicated the potential involvement of the brain–gut axis and intestinal microbiota in the pathogenesis and regulation of neurological and psychiatric disorders. While intestinal microbiota is crucial for maintaining host physiology, some important sensory and regulatory cells in the host should not be overlooked. Intestinal epithelial enteroendocrine cells (EECs) residing in the epithelium throughout intestine are the key regulators orchestrating the communication along the brain-gut-microbiota axis. On one hand, EECs sense changes in luminal microorganisms via microbial metabolites; on the other hand, they communicate with host body systems via neuroendocrine molecules. Therefore, EECs are believed to play important roles in neurological and psychiatric disorders. This review highlights the involvement of EECs and subtype cells, via secretion of endocrine molecules, in the development and regulation of neurological and psychiatric disorders, including Parkinson’s disease (PD), schizophrenia, visceral pain, neuropathic pain, and depression. Moreover, the current paper summarizes the potential mechanism of EECs in contributing to disease pathogenesis. Examination of these mechanisms may inspire and lead to the development of new aspects of treatment strategies for neurological and psychiatric disorders in the future.
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Affiliation(s)
- Liangen Yu
- Department of Animal and Food Sciences, University of Delaware, Newark, DE 19716, USA
| | - Yihang Li
- Department of Animal and Food Sciences, University of Delaware, Newark, DE 19716, USA
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
- Correspondence:
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Caetano MAF, Castelucci P. Role of short chain fatty acids in gut health and possible therapeutic approaches in inflammatory bowel diseases. World J Clin Cases 2022; 10:9985-10003. [PMID: 36246826 PMCID: PMC9561599 DOI: 10.12998/wjcc.v10.i28.9985] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 08/02/2022] [Accepted: 08/25/2022] [Indexed: 02/05/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are characterized by inflammation in the gastrointestinal tract and include Ulcerative Colitis and Crohn's Disease. These diseases are costly to health services, substantially reduce patients' quality of life, and can lead to complications such as cancer and even death. Symptoms include abdominal pain, stool bleeding, diarrhea, and weight loss. The treatment of these diseases is symptomatic, seeking disease remission. The intestine is colonized by several microorganisms, such as fungi, viruses, and bacteria, which constitute the intestinal microbiota (IM). IM bacteria promotes dietary fibers fermentation and produces short-chain fatty acids (SCFAs) that exert several beneficial effects on intestinal health. SCFAs can bind to G protein-coupled receptors, such as GPR41 and GPR43, promoting improvements in the intestinal barrier, anti-inflammatory, and antioxidant effects. Thus, SCFAs could be a therapeutic tool for IBDs. However, the mechanisms involved in these beneficial effects of SCFAs remain poorly understood. Therefore, this paper aims to provide a review addressing the main aspects of IBDs, and a more detailed sight of SCFAs, focusing on the main effects on different aspects of the intestine with an emphasis on IBDs.
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Affiliation(s)
| | - Patricia Castelucci
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508900, SP, Brazil
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Xu J, Moore BN, Pluznick JL. Short-Chain Fatty Acid Receptors and Blood Pressure Regulation: Council on Hypertension Mid-Career Award for Research Excellence 2021. Hypertension 2022; 79:2127-2137. [PMID: 35912645 PMCID: PMC9458621 DOI: 10.1161/hypertensionaha.122.18558] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The gut microbiome influences host physiology and pathophysiology through several pathways, one of which is microbial production of chemical metabolites which interact with host signaling pathways. Short-chain fatty acids (SCFAs) are a class of gut microbial metabolites known to activate multiple signaling pathways in the host. Growing evidence indicates that the gut microbiome is linked to blood pressure, that SCFAs modulate blood pressure regulation, and that delivery of exogenous SCFAs lowers blood pressure. Given that hypertension is a key risk factor for cardiovascular disease, the examination of novel contributors to blood pressure regulation has the potential to lead to novel approaches or treatments. Thus, this review will discuss SCFAs with a focus on their host G protein-coupled receptors including GPR41 (G protein-coupled receptor 41), GPR43, and GPR109A, as well as OLFR78 (olfactory receptor 78) and OLFR558. This includes a discussion of the ligand profiles, G protein coupling, and tissue distribution of each receptor. We will also review phenotypes relevant to blood pressure regulation which have been reported to date for Gpr41, Gpr43, Gpr109a, and Olfr78 knockout mice. In addition, we will consider how SCFA signaling influences physiology at baseline, and, how SCFA signaling may contribute to blood pressure regulation in settings of hypertension. In sum, this review will integrate current knowledge regarding how SCFAs and their receptors regulate blood pressure.
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Affiliation(s)
- Jiaojiao Xu
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Brittni N. Moore
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Jennifer L. Pluznick
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205
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van Deuren T, Blaak EE, Canfora EE. Butyrate to combat obesity and obesity-associated metabolic disorders: Current status and future implications for therapeutic use. Obes Rev 2022; 23:e13498. [PMID: 35856338 PMCID: PMC9541926 DOI: 10.1111/obr.13498] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 06/04/2022] [Accepted: 06/28/2022] [Indexed: 12/17/2022]
Abstract
Evidence is increasing that disturbances in the gut microbiome may play a significant role in the etiology of obesity and type 2 diabetes. The short chain fatty acid butyrate, a major end product of the bacterial fermentation of indigestible carbohydrates, is reputed to have anti-inflammatory properties and positive effects on body weight control and insulin sensitivity. However, whether butyrate has therapeutic potential for the treatment and prevention of obesity and obesity-related complications remains to be elucidated. Overall, animal studies strongly indicate that butyrate administered via various routes (e.g., orally) positively affects adipose tissue metabolism and functioning, energy and substrate metabolism, systemic and tissue-specific inflammation, and insulin sensitivity and body weight control. A limited number of human studies demonstrated interindividual differences in clinical effectiveness suggesting that outcomes may depend on the metabolic, microbial, and lifestyle-related characteristics of the target population. Hence, despite abundant evidence from animal data, support of human data is urgently required for the implementation of evidence-based oral and gut-derived butyrate interventions. To increase the efficacy of butyrate-focused interventions, future research should investigate which factors impact treatment outcomes including baseline gut microbial activity and functionality, thereby optimizing targeted-interventions and identifying individuals that merit most from such interventions.
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Affiliation(s)
- Thirza van Deuren
- Department of Human Biology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Ellen E Blaak
- Department of Human Biology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Emanuel E Canfora
- Department of Human Biology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center+, Maastricht, The Netherlands
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Lednovich KR, Nnyamah C, Gough S, Priyadarshini M, Xu K, Wicksteed B, Mishra S, Jain S, Zapater JL, Yadav H, Layden BT. Intestinal FFA3 mediates obesogenic effects in mice on a Western diet. Am J Physiol Endocrinol Metab 2022; 323:E290-E306. [PMID: 35858247 PMCID: PMC9448285 DOI: 10.1152/ajpendo.00016.2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 07/07/2022] [Accepted: 07/11/2022] [Indexed: 01/05/2023]
Abstract
Free fatty acid receptor 3 (FFA3) is a recently-deorphanized G-protein-coupled receptor. Its ligands are short-chain fatty acids (SCFAs), which are key nutrients derived from the gut microbiome fermentation process that play diverse roles in the regulation of metabolic homeostasis and glycemic control. FFA3 is highly expressed within the intestine, where its role and its effects on physiology and metabolism are unclear. Previous in vivo studies involving this receptor have relied on global knockout mouse models, making it difficult to isolate intestine-specific roles of FFA3. To overcome this challenge, we generated an intestine-specific knockout mouse model for FFA3, Villin-Cre-FFA3 (Vil-FFA3). Model validation and general metabolic assessment of male mice fed a standard chow diet revealed no major congenital defects. Because dietary changes are known to alter gut microbial composition, and thereby SCFA production, an obesogenic challenge was performed on male Vil-FFA3 mice and their littermate controls to probe for a phenotype on a high-fat, high-sugar "Western diet" (WD) compared with a low-fat control diet (CD). Vil-FFA3 mice versus FFA3fl/fl controls on WD, but not CD, were protected from the development of diet-induced obesity and exhibited significantly less fat mass as well as smaller adipose depositions and adipocytes. Although overall glycemic control was unchanged in the WD-fed Vil-FFA3 group, fasted glucose levels trended lower. Intestinal inflammation was significantly reduced in the WD-fed Vil-FFA3 mice, supporting protection from obesogenic effects. Furthermore, we observed lower levels of gastric inhibitory protein (GIP) in the WD-fed Vil-FFA3 mice, which may contribute to phenotypic changes. Our findings suggest a novel role of intestinal FFA3 in promoting the metabolic consequences of a WD, including the development of obesity and inflammation. Moreover, these data support an intestine-specific role of FFA3 in whole body metabolic homeostasis and in the development of adiposity.NEW & NOTEWORTHY Here, we generated a novel intestine-specific knockout mouse model for FFA3 (Vil-FFA3) and performed a comprehensive metabolic characterization of mice in response to an obesogenic challenge. We found that Vil-FFA3 mice fed with a Western diet were largely protected from obesity, exhibiting significantly lower levels of fat mass, lower intestinal inflammation, and altered expression of intestinal incretin hormones. Results support an important role of intestinal FFA3 in contributing to metabolism and in the development of diet-induced obesity.
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Affiliation(s)
- Kristen R Lednovich
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Chioma Nnyamah
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Sophie Gough
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Medha Priyadarshini
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Kai Xu
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Barton Wicksteed
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Sidharth Mishra
- USF Center for Microbiome Research, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Shalini Jain
- USF Center for Microbiome Research, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Joseph L Zapater
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
- Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Hariom Yadav
- USF Center for Microbiome Research, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Brian T Layden
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
- Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
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Menees KB, Otero BA, Tansey MG. Microbiome influences on neuro-immune interactions in neurodegenerative disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2022; 167:25-57. [PMID: 36427957 DOI: 10.1016/bs.irn.2022.07.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Mounting evidence points to a role for the gut microbiome in a wide range of central nervous system diseases and disorders including depression, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and autism spectrum disorder. Moreover, immune system involvement has also been implicated in these diseases, specifically with inflammation being central to their pathogenesis. In addition to the reported changes in gut microbiome composition and altered immune states in many neurological diseases, how the microbiome and the immune system interact to influence disease onset and progression has recently garnered much attention. This chapter provides a review of the literature related to gut microbiome influences on neuro-immune interactions with a particular focus on neurological diseases. Gut microbiome-derived mediators, including short-chain fatty acids and other metabolites, lipopolysaccharide, and neurotransmitters, and their impact on neuro-immune interactions as well as routes by which these interactions may occur are also discussed.
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Affiliation(s)
- Kelly B Menees
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Brittney A Otero
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Malú Gámez Tansey
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, United States; Norman Fixel Institute for Neurological Diseases, University of Florida Health, Gainesville, FL, United States.
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Abstract
The interaction between the metabolic activities of the intestinal microbiome and its host forms an important part of health. The basis of this interaction is in part mediated by the release of microbially-derived metabolites that enter the circulation. These products of microbial metabolism thereby interface with the immune, metabolic, or nervous systems of the host to influence physiology. Here, we review the interactions between the metabolic activities of the microbiome and the systemic metabolism of the host. The concept that the endocrine system includes more than just the eukaryotic host component enables the rational design of exogenous interventions that shape human metabolism. An improved mechanistic understanding of the metabolic microbiome-host interaction may therefore pioneer actionable microbiota-based diagnostics or therapeutics that allow the control of host systemic metabolism via the microbiome.
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Affiliation(s)
- Timothy O Cox
- Microbiology Department, Institute for Immunology, and Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Patrick Lundgren
- Microbiology Department, Institute for Immunology, and Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kirti Nath
- Microbiology Department, Institute for Immunology, and Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Christoph A Thaiss
- Microbiology Department, Institute for Immunology, and Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Changes of Short-Chain Fatty Acids and Their Receptors in an Obese Rat Model After Sleeve Gastrectomy. Obes Surg 2022; 32:2649-2657. [PMID: 35648365 DOI: 10.1007/s11695-022-06130-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 05/16/2022] [Accepted: 05/25/2022] [Indexed: 01/19/2023]
Abstract
BACKGROUND Short-chain fatty acids (SCFAs) and gut microbiota have health-related effects and are associated with a wide range of disorders. However, the changes of SCFAs and their receptors after sleeve gastrectomy (SG) remain unclear. This study aimed to examine changes of SCFAs and their receptors after SG in an obese rat model. METHODS Thirty obese Sprague-Dawley rats eating a high-energy diet for 6 weeks were divided into three groups: sham-operated (SO) control, pair-fed (PF) control, and SG group. Six weeks after the surgery, metabolic parameters, SCFA levels in the blood and stool, mRNA and protein expression of SCFA receptors in the ileum and epididymal fat, and gut microbiota were examined. RESULTS Metabolic parameters in the SG group were significantly improved compared with the SO group. Acetic acid levels in the blood and stool were significantly higher in the SG group than the PF group. The butyric acid level in the stool was also significantly higher in the SG group than in the PF group. In the ileum and epididymal fat, mRNA and protein expression of GPR41 was significantly higher in the SG group than in the other two groups, and mRNA and protein expression of GPR43 was significantly higher in the SG group than in the PF group. Increases in the genera Enterococcus, Lactobacillus, Lactococcus, and Clostridium were observed in the stool after SG. CONCLUSIONS SG may activate SCFA pathways through a change in gut microbiota.
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Yang Y, Jiang X, Cai X, Zhang L, Li W, Che L, Fang Z, Feng B, Lin Y, Xu S, Li J, Zhao X, Wu D, Zhuo Y. Deprivation of Dietary Fiber Enhances Susceptibility of Piglets to Lung Immune Stress. Front Nutr 2022; 9:827509. [PMID: 35223957 PMCID: PMC8867169 DOI: 10.3389/fnut.2022.827509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 01/07/2022] [Indexed: 12/12/2022] Open
Abstract
Growing evidence suggests that dietary fiber enhances short-chain fatty acid (SCFA) producing gut microbes, improving lung immunity against invading pathogens via the gut–lung axis. This study investigated the effects of dietary fiber on lung immune stress after challenge with complete Freund's adjuvant (CFA) containing killed Mycobacterium tuberculosis. Thirty-six healthy hybrid Duroc, Landrace, and Yorkshire male piglets (9.7 ± 1.07 kg, 35 ± 3 days) were randomly fed a low fiber (LF) diet formulated with semipurified corn starch, soy protein concentrate, and fishmeal or a high fiber (HF) diet composed of 1,000 g LF diet plus 20 g inulin, and 100 g cellulose. Piglets were housed individually in the metabolism cages with eighteen replicates per group, with one pig per cage. All the piglets received similar levels of digestible energy and lysine and had similar weight gain. After dietary treatment for 28 days, nine piglets per group were intravenously administered CFA (0.4 mg/kg) or an equivalent amount of sterile saline in a 2 × 2 factorial arrangement. In piglets fed the LF diet, CFA caused lung damage and elevated serum C-reactive protein and relative mRNA expression of genes related to lung inflammation (NLRP3, Casp1, ASC, IL1β, IL18, Bax). Compared with the LF diet, the HF diet increased bacterial diversity and Deferribacteres (p = 0.01) in the phylum level and unidentified_Ruminococcaceae (p = 0.03) and Catenisphaera (p < 0.01) in the genus level. The HF diet improved increased short-chain fatty acids in feces, blood, cecal, and colonic digesta; reduced lung damage; and promoted lung recovery. Overall, dietary fiber deprivation enhanced the risk of piglets to lung immune stress, demonstrating the importance of dietary fiber in gut–lung health.
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Affiliation(s)
- Yi Yang
- State Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Xuemei Jiang
- State Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Xuelin Cai
- State Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Lijia Zhang
- State Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Wentao Li
- State Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Lianqiang Che
- State Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Zhengfeng Fang
- State Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Bin Feng
- State Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Yan Lin
- State Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Shengyu Xu
- State Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Jian Li
- State Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Xilun Zhao
- State Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - De Wu
- State Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Yong Zhuo
- State Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
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Huang C, Du W, Ni Y, Lan G, Shi G. The effect of short-chain fatty acids on M2 macrophages polarization in vitro and in vivo. Clin Exp Immunol 2022; 207:53-64. [PMID: 35020860 PMCID: PMC8802183 DOI: 10.1093/cei/uxab028] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/16/2021] [Accepted: 12/01/2021] [Indexed: 12/19/2022] Open
Abstract
Alternatively activated macrophages (M2 polarization) play an important role in asthma. Short-chain fatty acids (SCFAs) possessed immune-regulatory functions, but their effects on M2 polarization of alveolar macrophages and its underlying mechanisms are still unclear. In our study, murine alveolar macrophage MH-S cell line and human monocyte-derived macrophages were used to polarize to M2 subset with interleukin-4 (IL-4) treatment. The underlying mechanisms involved were investigated using molecule inhibitors/agonists. In vivo, female C57BL/6 mice were divided into five groups: CON group, ovalbumin (OVA) asthma group, OVA+Acetate group, OVA+Butyrate group, and OVA+Propionate group. Mice were fed with or without SCFAs (Acetate, Butyrate, Propionate) in drinking water for 20 days before developing OVA-induced asthma model. In MH-S, SCFAs inhibited IL-4-incuced protein or mRNA expressions of M2-associated genes in a dose-dependent manner. G-protein-coupled receptor 43 (GPR43) agonist 4-CMTB and histone deacetylase (HDAC) inhibitor (trichostatin A, TSA), but not GPR41 agonist AR420626 could inhibit the protein or mRNA expressions M2-associated genes. 4-CMTB, but not TSA, had no synergistic role in the inhibitory effect of SCFAs on M2 polarization. In vivo study indicated Butyrate and Propionate, but not Acetate, attenuated OVA-induced M2 polarization in the lung and airway inflammation. We also found the inhibitory effect of SCFAs on M2 polarization in human-derived macrophages. Therefore, SCFAs inhibited M2 polarization in MH-S likely through GPR43 activation and/or HDAC inhibition. Butyrate and Propionate but not Acetate could inhibit M2 polarization and airway inflammation in asthma model. SCFAs also abrogated M2 polarization in human-derived macrophages.
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Affiliation(s)
- Chunrong Huang
- Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai, People's Republic of China
| | - Wei Du
- Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai, People's Republic of China
| | - Yingmeng Ni
- Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai, People's Republic of China
| | - Gelei Lan
- Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai, People's Republic of China
| | - Guochao Shi
- Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai, People's Republic of China
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Yang X, Liu X, Song F, Wei H, Gao F, Zhang H, Han Y, Weng Q, Yuan Z. Seasonal expressions of GPR41 and GPR43 in the colon of the wild ground squirrels ( Spermophilus dauricus). Eur J Histochem 2022; 66. [PMID: 35057584 PMCID: PMC8847768 DOI: 10.4081/ejh.2022.3351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 01/02/2022] [Indexed: 11/22/2022] Open
Abstract
G-protein-coupled receptor 41 (GPR41) and G-protein-coupled receptor 43 (GPR43) are important short-chain fatty acids (SCFAs) receptors. Previous studies indicated that GPR41 and GPR43 are involved in the secretion of gastrointestinal peptides, and glucose and lipid metabolism, and are closely related to obesity and type II diabetes, and other diseases. The purpose of the study was to explore the relationship between the GPR41 and GPR43 and seasonal breeding, and provide new prospects for further exploring the nutritional needs of breeding. We identified the localization and expression levels of GPR41 and GPR43 in the colon of the wild ground squirrels (Spermophilus dauricus) both in the breeding season and non-breeding season. The histological results revealed that the lumen diameter of the colon had obvious seasonal changes, and the diameter of the colonic lumen in the non-breeding season was larger than that in the breeding season. Immunohistochemical staining suggested GPR41 and GPR43 have expressed in the simple layer columnar epithelium. In addition, compared with the breeding season, the mRNA and protein expression levels of GPR41 and GPR43 in the colon were higher during the non-breeding season. In general, these results indicated GPR41 and GPR43 might play a certain role in regulating seasonal breeding.
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Mirzaei R, Dehkhodaie E, Bouzari B, Rahimi M, Gholestani A, Hosseini-Fard SR, Keyvani H, Teimoori A, Karampoor S. Dual role of microbiota-derived short-chain fatty acids on host and pathogen. Biomed Pharmacother 2022; 145:112352. [PMID: 34840032 DOI: 10.1016/j.biopha.2021.112352] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 10/15/2021] [Accepted: 10/19/2021] [Indexed: 12/12/2022] Open
Abstract
A growing body of documents shows microbiota produce metabolites such as short-chain fatty acids (SCFAs) as crucial executors of diet-based microbial influence the host and bacterial pathogens. The production of SCFAs depends on the metabolic activity of intestinal microflora and is also affected by dietary changes. SCFAs play important roles in maintaining colonic health as an energy source, as a regulator of gene expression and cell differentiation, and as an anti-inflammatory agent. Additionally, the regulated expression of virulence genes is critical for successful infection by an intestinal pathogen. Bacteria rely on sensing environmental signals to find preferable niches and reach the infectious state. This review will present data supporting the diverse functional roles of microbiota-derived butyrate, propionate, and acetate on host cellular activities such as immune modulation, energy metabolism, nervous system, inflammation, cellular differentiation, and anti-tumor effects, among others. On the other hand, we will discuss and summarize data about the role of these SCFAs on the virulence factor of bacterial pathogens. In this regard, receptors and signaling routes for SCFAs metabolites in host and pathogens will be introduced.
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Affiliation(s)
- Rasoul Mirzaei
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
| | - Elahe Dehkhodaie
- Department of Biology, Science and Research Branch, Islamic Azad University Tehran, Iran
| | - Behnaz Bouzari
- Department of Pathology, Firouzgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mandana Rahimi
- Department of Pathology, School of Medicine, Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, Iran
| | - Abolfazl Gholestani
- Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Reza Hosseini-Fard
- Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Keyvani
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Ali Teimoori
- Department of Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Piotrowska M, Binienda A, Fichna J. The role of fatty acids in Crohn's disease pathophysiology - An overview. Mol Cell Endocrinol 2021; 538:111448. [PMID: 34480991 DOI: 10.1016/j.mce.2021.111448] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 08/30/2021] [Indexed: 12/14/2022]
Abstract
Crohn's disease (CD) is an inflammatory bowel disease (IBD) which is characterized by chronic and relapsing inflammation of the gastrointestinal (GI) tract. The etiology of CD is unknown, but factors such as epithelial barrier dysfunction, immune system imbalance, microbiota dysbiosis and environmental influences are thought to be involved in its pathogenesis. Recent studies have shown that short chain fatty acids (SCFAs) and long chain fatty acids (LCFAs) play a vital role in pathophysiology and development of CD by various mechanisms affecting pro- and anti-inflammatory mediators, and maintaining the intestinal homeostasis and regulation of gene expression. SCFAs and LCFAs activate signaling cascades that control immune functions through interaction with cell surface free fatty acid receptors (FFARs), i.e. FFAR1, FFAR2, FFAR3, and FFAR4. This review highlights the role of fatty acids in maintenance of intestinal and immune homeostasis and supports the supplementation of fatty acids as a promising adjunctive treatment for CD.
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Affiliation(s)
- Marta Piotrowska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215, Lodz, Poland.
| | - Agata Binienda
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215, Lodz, Poland.
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215, Lodz, Poland.
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Shi H, Ge X, Ma X, Zheng M, Cui X, Pan W, Zheng P, Yang X, Zhang P, Hu M, Hu T, Tang R, Zheng K, Huang XF, Yu Y. A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites. MICROBIOME 2021; 9:223. [PMID: 34758889 PMCID: PMC8582174 DOI: 10.1186/s40168-021-01172-0] [Citation(s) in RCA: 135] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 10/06/2021] [Indexed: 05/11/2023]
Abstract
BACKGROUND Cognitive impairment, an increasing mental health issue, is a core feature of the aging brain and neurodegenerative diseases. Industrialized nations especially, have experienced a marked decrease in dietary fiber intake, but the potential mechanism linking low fiber intake and cognitive impairment is poorly understood. Emerging research reported that the diversity of gut microbiota in Western populations is significantly reduced. However, it is unknown whether a fiber-deficient diet (which alters gut microbiota) could impair cognition and brain functional elements through the gut-brain axis. RESULTS In this study, a mouse model of long-term (15 weeks) dietary fiber deficiency (FD) was used to mimic a sustained low fiber intake in humans. We found that FD mice showed impaired cognition, including deficits in object location memory, temporal order memory, and the ability to perform daily living activities. The hippocampal synaptic ultrastructure was damaged in FD mice, characterized by widened synaptic clefts and thinned postsynaptic densities. A hippocampal proteomic analysis further identified a deficit of CaMKIId and its associated synaptic proteins (including GAP43 and SV2C) in the FD mice, along with neuroinflammation and microglial engulfment of synapses. The FD mice also exhibited gut microbiota dysbiosis (decreased Bacteroidetes and increased Proteobacteria), which was significantly associated with the cognitive deficits. Of note, a rapid differentiating microbiota change was observed in the mice with a short-term FD diet (7 days) before cognitive impairment, highlighting a possible causal impact of the gut microbiota profile on cognitive outcomes. Moreover, the FD diet compromised the intestinal barrier and reduced short-chain fatty acid (SCFA) production. We exploit these findings for SCFA receptor knockout mice and oral SCFA supplementation that verified SCFA playing a critical role linking the altered gut microbiota and cognitive impairment. CONCLUSIONS This study, for the first time, reports that a fiber-deprived diet leads to cognitive impairment through altering the gut microbiota-hippocampal axis, which is pathologically distinct from normal brain aging. These findings alert the adverse impact of dietary fiber deficiency on brain function, and highlight an increase in fiber intake as a nutritional strategy to reduce the risk of developing diet-associated cognitive decline and neurodegenerative diseases. Video Abstract.
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Affiliation(s)
- Hongli Shi
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Xing Ge
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Xi Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Mingxuan Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Xiaoying Cui
- Queensland Brain Institute, The University of Queensland, St. Lucia, QLD, 4113, Australia
| | - Wei Pan
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Peng Zheng
- Illawarra Health and Medical Research Institute (IHMRI) and School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia
| | - Xiaoying Yang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Peng Zhang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Minmin Hu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Tao Hu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
| | - Xu-Feng Huang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
- Illawarra Health and Medical Research Institute (IHMRI) and School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia.
| | - Yinghua Yu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
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Zhang M, Wang Y, Zhao X, Liu C, Wang B, Zhou J. Mechanistic basis and preliminary practice of butyric acid and butyrate sodium to mitigate gut inflammatory diseases: a comprehensive review. Nutr Res 2021; 95:1-18. [PMID: 34757305 DOI: 10.1016/j.nutres.2021.08.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/19/2021] [Accepted: 08/26/2021] [Indexed: 01/02/2023]
Abstract
A key event featured in the early stage of chronic gut inflammatory diseases is the disordered recruitment and excess accumulation of immune cells in the gut lamina propria. This process is followed by the over-secretion of pro-inflammatory factors and the prolonged overactive inflammatory responses. Growing evidence has suggested that gut inflammatory diseases may be mitigated by butyric acid (BA) or butyrate sodium (NaB). Laboratory studies show that BA and NaB can enhance gut innate immune function through G-protein-mediated signaling pathways while mitigating the overactive inflammatory responses by inhibiting histone deacetylase. The regulatory effects may occur in both epithelial enterocytes and the immune cells in the lamina propria. Prior to further clinical trials, comprehensive literature reviews and rigid examination concerning the underlying mechanism are necessary. To this end, we collected and reviewed 197 published reports regarding the mechanisms, bioactivities, and clinical effects of BA and NaB to modulate gut inflammatory diseases. Our review found insufficient evidence to guarantee the safety of clinical practice of BA and NaB, either by anal enema or oral administration of capsule or tablet. The safety of clinical use of BA and NaB should be further evaluated. Alternatively, dietary patterns rich in "fruits, vegetables and beans" may be an effective and safe approach to prevent gut inflammatory disease, which elevates gut microbiota-dependent production of BA. Our review provides a comprehensive reference to future clinical trials of BA and NaB to treat gut inflammatory diseases.
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Affiliation(s)
- Mingbao Zhang
- Department of Gastroenterology and Hepatology, Second Hospital of Shandong University, Shandong University, 250012 China
| | - Yanan Wang
- Department of Gastroenterology and Hepatology, Second Hospital of Shandong University, Shandong University, 250012 China
| | - Xianqi Zhao
- School of Public Health, Cheeloo College of Medicine, Shandong University, 250012 China
| | - Chang Liu
- School of Public Health, Cheeloo College of Medicine, Shandong University, 250012 China
| | - Baozhen Wang
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 250012 China.
| | - Jun Zhou
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 250012 China.
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