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1
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Jiang M, Bianchi F, van den Bogaart G. Protonophore activity of short-chain fatty acids induces their intracellular accumulation and acidification. FEBS Lett 2025. [PMID: 40325954 DOI: 10.1002/1873-3468.70064] [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: 01/21/2025] [Revised: 03/27/2025] [Accepted: 04/13/2025] [Indexed: 05/07/2025]
Abstract
Short-chain fatty acids (SCFAs), produced by dietary fiber fermentation in the colon, play essential roles in cellular metabolism, with butyrate notably modulating immune responses and epigenetic regulation. Their production contributes to an acidic colonic environment where protonated SCFAs permeate membranes, leading to intracellular acidification and SCFA accumulation. Using our method to measure intracellular pH, we investigated how extracellular pH influences butyrate-induced acidification and immunomodulatory effects in human macrophages. Our data show that butyrate accumulates and acidifies cells at acidic extracellular pH due to the permeability of its protonated form. While inflammatory cytokine production was mildly influenced by extracellular pH, butyrate-induced histone acetylation exhibited a pH dependence, underscoring the importance of considering extracellular pH when assessing the SCFA's functions.
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Affiliation(s)
- Muwei Jiang
- Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands
| | - Frans Bianchi
- Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands
| | - Geert van den Bogaart
- Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands
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2
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Oliver A, Alkan Z, Stephensen CB, Newman JW, Kable ME, Lemay DG. Diet, Microbiome, and Inflammation Predictors of Fecal and Plasma Short-Chain Fatty Acids in Humans. J Nutr 2024; 154:3298-3311. [PMID: 39173973 PMCID: PMC11600052 DOI: 10.1016/j.tjnut.2024.08.012] [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: 05/22/2024] [Revised: 07/29/2024] [Accepted: 08/13/2024] [Indexed: 08/24/2024] Open
Abstract
BACKGROUND Gut microbes produce short-chain fatty acids (SCFAs), which are associated with broad health benefits. However, it is not fully known how diet and/or the gut microbiome could be modulated to improve SCFA production. OBJECTIVES The objective of this study was to identify dietary, inflammatory, and/or microbiome predictors of SCFAs in a cohort of healthy adults. METHODS SCFAs were measured in fecal and plasma samples from 359 healthy adults in the United States Department of Agriculture Nutritional Phenotyping Study. Habitual and recent diet was assessed using a Food Frequency Questionnaire and Automated Self-Administered 24-h Dietary Assesment Tool dietary recalls. Markers of systemic and gut inflammation were measured in fecal and plasma samples. The gut microbiome was assessed using shotgun metagenomics. Using statistics and machine learning, we determined how the abundance and composition of SCFAs varied with measures of diet, inflammation, and the gut microbiome. RESULTS We show that fecal pH may be a good proxy for fecal SCFA abundance. A higher Healthy Eating Index for a habitual diet was associated with a compositional increase in fecal butyrate relative to acetate and propionate. SCFAs were associated with markers of subclinical gastrointestinal (GI) inflammation. Fecal SCFA abundance was inversely related to plasma lipopolysaccharide-binding protein. When we analyzed hierarchically organized diet and microbiome data with taxonomy-aware algorithms, we observed that diet and microbiome features were far more predictive of fecal SCFA abundances compared to plasma SCFA abundances. The top diet and microbiome predictors of fecal butyrate included potatoes and the thiamine biosynthesis pathway, respectively. CONCLUSIONS These results suggest that resistant starch in the form of potatoes and microbially produced thiamine provide a substrate and essential cofactor, respectively, for butyrate synthesis. Thiamine may be a rate-limiting nutrient for butyrate production in adults. Overall, these findings illustrate the complex biology underpinning SCFA production in the gut. This trial was registered at clinicaltrials.gov as NCT02367287.
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Affiliation(s)
- Andrew Oliver
- USDA-Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA, United States
| | - Zeynep Alkan
- USDA-Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA, United States
| | - Charles B Stephensen
- USDA-Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA, United States; Department of Nutrition, University of California, Davis, Davis, CA, United States
| | - John W Newman
- USDA-Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA, United States; Department of Nutrition, University of California, Davis, Davis, CA, United States; Genome Center, University of California, Davis, CA, United States
| | - Mary E Kable
- USDA-Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA, United States; Department of Nutrition, University of California, Davis, Davis, CA, United States
| | - Danielle G Lemay
- USDA-Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA, United States; Department of Nutrition, University of California, Davis, Davis, CA, United States; Genome Center, University of California, Davis, CA, United States.
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3
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Saadh MJ, Mustafa AN, Mustafa MA, S RJ, Dabis HK, Prasad GVS, Mohammad IJ, Adnan A, Idan AH. The role of gut-derived short-chain fatty acids in Parkinson's disease. Neurogenetics 2024; 25:307-336. [PMID: 39266892 DOI: 10.1007/s10048-024-00779-3] [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: 06/21/2024] [Accepted: 08/29/2024] [Indexed: 09/14/2024]
Abstract
The emerging function of short-chain fatty acids (SCFAs) in Parkinson's disease (PD) has been investigated in this article. SCFAs, which are generated via the fermentation of dietary fiber by gut microbiota, have been associated with dysfunction of the gut-brain axis and, neuroinflammation. These processes are integral to the development of PD. This article examines the potential therapeutic implications of SCFAs in the management of PD, encompassing their capacity to modulate gastrointestinal permeability, neuroinflammation, and neuronal survival, by conducting an extensive literature review. As a whole, this article emphasizes the potential therapeutic utility of SCFAs as targets for the management and treatment of PD.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan.
| | | | - Mohammed Ahmed Mustafa
- School of Pharmacy-Adarsh Vijendra Institute of Pharmaceutical Sciences, Shobhit University, Gangoh, Uttar Pradesh, 247341, India
- Department of Pharmacy, Arka Jain University, Jamshedpur, Jharkhand, 831001, India
| | - Renuka Jyothi S
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | | | - G V Siva Prasad
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra, Pradesh-531162, India
| | - Imad Jassim Mohammad
- College of Health and Medical Technology, National University of Science and Technology, Dhi Qar, 64001, Iraq
| | - Ahmed Adnan
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
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Cuervo L, McAlpine PL, Olano C, Fernández J, Lombó F. Low-Molecular-Weight Compounds Produced by the Intestinal Microbiota and Cardiovascular Disease. Int J Mol Sci 2024; 25:10397. [PMID: 39408727 PMCID: PMC11477366 DOI: 10.3390/ijms251910397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/20/2024] [Accepted: 09/24/2024] [Indexed: 10/20/2024] Open
Abstract
Cardiovascular disease is the main cause of mortality in industrialized countries, with over 500 million people affected worldwide. In this work, the roles of low-molecular-weight metabolites originating from the gut microbiome, such as short-chain fatty acids, hydrogen sulfide, trimethylamine, phenylacetic acid, secondary bile acids, indoles, different gases, neurotransmitters, vitamins, and complex lipids, are discussed in relation to their CVD-promoting or preventing activities. Molecules of mixed microbial and human hepatic origin, such as trimethylamine N-oxide and phenylacetylglutamine, are also presented. Finally, dietary agents with cardioprotective effects, such as probiotics, prebiotics, mono- and poly-unsaturated fatty acids, carotenoids, and polyphenols, are also discussed. A special emphasis is given to their gut microbiota-modulating properties.
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Affiliation(s)
- Lorena Cuervo
- Research Group BIOMIC (Biosynthesis of Antitumor Molecules), Departamento de Biología Funcional, Área de Microbiología, Universidad de Oviedo, 33006 Oviedo, Spain; (L.C.); (C.O.)
- IUOPA (Instituto Universitario de Oncología del Principado de Asturias), 33006 Oviedo, Spain
- ISPA (Instituto de Investigación Sanitaria del Principado de Asturias), 33006 Oviedo, Spain
| | - Patrick L. McAlpine
- IUOPA (Instituto Universitario de Oncología del Principado de Asturias), 33006 Oviedo, Spain
- ISPA (Instituto de Investigación Sanitaria del Principado de Asturias), 33006 Oviedo, Spain
- Research Group BIONUC (Biotechnology of Nutraceuticals and Bioactive Compounds), Departamento de Biología Funcional, Área de Microbiología, Universidad de Oviedo, 33006 Oviedo, Spain
| | - Carlos Olano
- Research Group BIOMIC (Biosynthesis of Antitumor Molecules), Departamento de Biología Funcional, Área de Microbiología, Universidad de Oviedo, 33006 Oviedo, Spain; (L.C.); (C.O.)
- IUOPA (Instituto Universitario de Oncología del Principado de Asturias), 33006 Oviedo, Spain
- ISPA (Instituto de Investigación Sanitaria del Principado de Asturias), 33006 Oviedo, Spain
| | - Javier Fernández
- IUOPA (Instituto Universitario de Oncología del Principado de Asturias), 33006 Oviedo, Spain
- ISPA (Instituto de Investigación Sanitaria del Principado de Asturias), 33006 Oviedo, Spain
- Research Group BIONUC (Biotechnology of Nutraceuticals and Bioactive Compounds), Departamento de Biología Funcional, Área de Microbiología, Universidad de Oviedo, 33006 Oviedo, Spain
| | - Felipe Lombó
- IUOPA (Instituto Universitario de Oncología del Principado de Asturias), 33006 Oviedo, Spain
- ISPA (Instituto de Investigación Sanitaria del Principado de Asturias), 33006 Oviedo, Spain
- Research Group BIONUC (Biotechnology of Nutraceuticals and Bioactive Compounds), Departamento de Biología Funcional, Área de Microbiología, Universidad de Oviedo, 33006 Oviedo, Spain
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Singh S, Kriti M, Catanzaro R, Marotta F, Malvi M, Jain A, Verma V, Nagpal R, Tiwari R, Kumar M. Deciphering the Gut–Liver Axis: A Comprehensive Scientific Review of Non-Alcoholic Fatty Liver Disease. LIVERS 2024; 4:435-454. [DOI: 10.3390/livers4030032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant global health issue. The condition is closely linked to metabolic dysfunctions such as obesity and type 2 diabetes. The gut–liver axis, a bidirectional communication pathway between the liver and the gut, plays a crucial role in the pathogenesis of NAFLD. This review delves into the mechanisms underlying the gut–liver axis, exploring the influence of gut microbiota, intestinal permeability, and inflammatory pathways. This review also explores the potential therapeutic strategies centered on modulating gut microbiota such as fecal microbiota transplantation; phage therapy; and the use of specific probiotics, prebiotics, and postbiotics in managing NAFLD. By understanding these interactions, we can better comprehend the development and advancement of NAFLD and identify potential therapeutic targets.
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Affiliation(s)
- Samradhi Singh
- ICMR-National Institute for Research in Environmental Health, Bhopal Bypass Road, Bhauri, Bhopal 462030, India
| | - Mona Kriti
- ICMR-National Institute for Research in Environmental Health, Bhopal Bypass Road, Bhauri, Bhopal 462030, India
| | - Roberto Catanzaro
- Internal Medicine Unit, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology Service, University Hospital Policlinico “G. Rodolico”, University of Catania, 95123 Catania, Italy
| | | | - Mustafa Malvi
- Choithram Hospital and Research Centre Indore, Indore 452014, India
| | - Ajay Jain
- Choithram Hospital and Research Centre Indore, Indore 452014, India
| | - Vinod Verma
- Stem Cell Research Centre, Department of Hematology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Ravinder Nagpal
- Department of Nutrition & Integrative Physiology, College of Health & Human Sciences, Florida State University, Tallahassee, FL 32306, USA
| | - Rajnarayan Tiwari
- ICMR-National Institute for Research in Environmental Health, Bhopal Bypass Road, Bhauri, Bhopal 462030, India
| | - Manoj Kumar
- ICMR-National Institute for Research in Environmental Health, Bhopal Bypass Road, Bhauri, Bhopal 462030, India
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De Vos WM, Nguyen Trung M, Davids M, Liu G, Rios-Morales M, Jessen H, Fiedler D, Nieuwdorp M, Bui TPN. Phytate metabolism is mediated by microbial cross-feeding in the gut microbiota. Nat Microbiol 2024; 9:1812-1827. [PMID: 38858593 DOI: 10.1038/s41564-024-01698-7] [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: 08/25/2023] [Accepted: 04/04/2024] [Indexed: 06/12/2024]
Abstract
Dietary intake of phytate has various reported health benefits. Previous work showed that the gut microbiota can convert phytate to short-chain fatty acids (SCFAs), but the microbial species and metabolic pathway are unclear. Here we identified Mitsuokella jalaludinii as an efficient phytate degrader, which works synergistically with Anaerostipes rhamnosivorans to produce the SCFA propionate. Analysis of published human gut taxonomic profiles revealed that Mitsuokella spp., in particular M. jalaludinii, are prevalent in human gut microbiomes. NMR spectroscopy using 13C-isotope labelling, metabolomic and transcriptomic analyses identified a complete phytate degradation pathway in M. jalaludinii, including production of the intermediate Ins(2)P/myo-inositol. The major end product, 3-hydroxypropionate, was converted into propionate via a synergistic interaction with Anaerostipes rhamnosivorans both in vitro and in mice. Upon [13C6]phytate administration, various 13C-labelled components were detected in mouse caecum in contrast with the absence of [13C6] InsPs or [13C6]myo-inositol in plasma. Caco-2 cells incubated with co-culture supernatants exhibited improved intestinal barrier integrity. These results suggest that the microbiome plays a major role in the metabolism of this phytochemical and that its fermentation to propionate by M. jalaludinii and A. rhamnosivorans may contribute to phytate-driven health benefits.
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Affiliation(s)
- Willem M De Vos
- Laboratory of Microbiology, Wageningen University, Wageningen, the Netherlands
| | - Minh Nguyen Trung
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
- Institute of Chemistry, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Mark Davids
- Departments of Internal and Experimental Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, the Netherlands
| | - Guizhen Liu
- Institute of Organic Chemistry & Centre for Integrative Biological Signaling Studies (CIBSS), University of Freiburg, Freiburg, Germany
| | - Melany Rios-Morales
- Departments of Internal and Experimental Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, the Netherlands
| | - Henning Jessen
- Institute of Organic Chemistry & Centre for Integrative Biological Signaling Studies (CIBSS), University of Freiburg, Freiburg, Germany
| | - Dorothea Fiedler
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
- Institute of Chemistry, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Max Nieuwdorp
- Departments of Internal and Experimental Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, the Netherlands
- Department of Surgery, Spaarne Hospital, Hoofddorp, the Netherlands
| | - Thi Phuong Nam Bui
- Laboratory of Microbiology, Wageningen University, Wageningen, the Netherlands.
- Departments of Internal and Experimental Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, the Netherlands.
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7
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Ndou SP, Kiarie E, de Lange CF, Nyachoti CM. Interactive Effects of Dietary Fiber and Lipid Types Modulate the Predicted Production and Absorption of Cecal and Colorectal Short-Chain Fatty Acids in Growing Pigs. J Nutr 2024; 154:2042-2052. [PMID: 38795744 PMCID: PMC11282492 DOI: 10.1016/j.tjnut.2024.05.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 05/10/2024] [Accepted: 05/18/2024] [Indexed: 05/28/2024] Open
Abstract
BACKGROUND High-fiber diets are supplemented with lipids to meet the required energy content, but data on the interactions between dietary fiber (DF) and lipid types on gastrointestinal fermentation in pigs are scant. OBJECTIVES This study aimed to use a combination of in vivo and in vitro fermentation methodologies to determine the interactive effects of DF and lipid types on short-chain fatty acid (SCFA) production and absorption and organic matter (OM) fermentability in the cecum and colorectal tract of pigs. METHODS Eight ileal- and cecal-cannulated Yorkshire barrows were fed either pectin- or cellulose-containing diets that were supplemented with either corn oil or beef tallow in 2 independent Youden squares with a 2 × 2 factorial arrangement of treatments (n = 6). Ileal and cecal digesta were collected, freeze-dried, and fermented using inoculum from fresh cecal digesta and feces, respectively, to determine individual SCFA production and absorption and fermentability of OM. RESULTS Interactions (P < 0.001) between DF and lipid types were observed in which the addition of beef tallow decreased the quantity of cecal and colorectal acetic acid production and cecal acetic absorption, cecal butyric production, predicted cecal OM fermentability, and predicted colorectal propionic acid in pectin diets, but the effects were not observed for cellulose diets. The addition of beef tallow increased (P < 0.001) the production of cecal butyric and propionic acids during in vitro fermentation in cellulose diets and apparent total tract digestibility (ATTD) of OM in pectin diets. CONCLUSIONS The interactions between DF and lipids on gastrointestinal fermentation largely depend on the degree of saturation of fatty acids in dietary lipids. The addition of beef tallow selectively decreased the production and absorption of individual SCFAs in pectin and cellulose diets but increased cecal butyric and propionic acid production in cellulose diets and the ATTD of OM in pectin diets.
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Affiliation(s)
- Saymore P Ndou
- Department of Animal Science, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Elijah Kiarie
- Department of Animal Science, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Animal Biosciences, University of Guelph, Guelph, Ontario, Canada
| | | | - Charles M Nyachoti
- Department of Animal Science, University of Manitoba, Winnipeg, Manitoba, Canada.
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Xu C, Aqib AI, Fatima M, Muneer S, Zaheer T, Peng S, Ibrahim EH, Li K. Deciphering the Potential of Probiotics in Vaccines. Vaccines (Basel) 2024; 12:711. [PMID: 39066349 PMCID: PMC11281421 DOI: 10.3390/vaccines12070711] [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: 04/15/2024] [Revised: 06/13/2024] [Accepted: 06/18/2024] [Indexed: 07/28/2024] Open
Abstract
The demand for vaccines, particularly those prepared from non-conventional sources, is rising due to the emergence of drug resistance around the globe. Probiotic-based vaccines are a wise example of such vaccines which represent new horizons in the field of vaccinology in providing an enhanced and diversified immune response. The justification for incorporating probiotics into vaccines lies in the fact that that they hold the capacity to regulate immune function directly or indirectly by influencing the gastrointestinal microbiota and related pathways. Several animal-model-based studies have also highlighted the efficacy of these vaccines. The aim of this review is to collect and summarize the trends in the recent scientific literature regarding the role of probiotics in vaccines and vaccinology, along with their impact on target populations.
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Affiliation(s)
- Chang Xu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Amjad Islam Aqib
- Department of Medicine, Cholistan University of Veterinary and Animal Sciences, Bahawalpur 63100, Pakistan
| | - Mahreen Fatima
- Faculty of Biosciences, Cholistan University of Veterinary and Animal Sciences, Bahawalpur 63100, Pakistan;
| | - Sadia Muneer
- Institute of Microbiology, University of Agriculture Faisalabad, Faisalabad 38000, Pakistan
| | - Tean Zaheer
- Department of Parasitology, University of Agriculture Faisalabad, Faisalabad 38000, Pakistan;
| | - Song Peng
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China;
| | - Essam H. Ibrahim
- Biology Department, Faculty of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia
| | - Kun Li
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
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Shimshoni E, Solomonov I, Sagi I, Ghini V. Integrated Metabolomics and Proteomics of Symptomatic and Early Presymptomatic States of Colitis. J Proteome Res 2024; 23:1420-1432. [PMID: 38497760 DOI: 10.1021/acs.jproteome.3c00860] [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: 03/19/2024]
Abstract
Colitis has a multifactorial pathogenesis with a strong cross-talk among microbiota, hypoxia, and tissue metabolism. Here, we aimed to characterize the molecular signature of the disease in symptomatic and presymptomatic stages of the inflammatory process at the tissue and fecal level. The study is based on two different murine models for colitis, and HR-MAS NMR on "intact" colon tissues and LC-MS/MS on colon tissue extracts were used to derive untargeted metabolomics and proteomics information, respectively. Solution NMR was used to derive metabolomic profiles of the fecal extracts. By combining metabolomic and proteomic analyses of the tissues, we found increased anaerobic glycolysis, accompanied by an altered citric acid cycle and oxidative phosphorylation in inflamed colons; these changes associate with inflammation-induced hypoxia taking place in colon tissues. Different colitis states were also characterized by significantly different metabolomic profiles of fecal extracts, attributable to both the dysbiosis characteristic of colitis as well as the dysregulated tissue metabolism. Strong and distinctive tissue and fecal metabolomic signatures can be detected before the onset of symptoms. Therefore, untargeted metabolomics of tissues and fecal extracts provides a comprehensive picture of the changes accompanying the disease onset already at preclinical stages, highlighting the diagnostic potential of global metabolomics for inflammatory diseases.
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Affiliation(s)
- Elee Shimshoni
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Inna Solomonov
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Irit Sagi
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Veronica Ghini
- Department of Chemistry, University of Florence, Sesto Fiorentino, Florence 50019, Italy
- Center of Magnetic Resonance (CERM), University of Florence, Sesto Fiorentino, Florence 50019, Italy
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10
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Jackson R, Yao T, Bulut N, Cantu-Jungles TM, Hamaker BR. Protein combined with certain dietary fibers increases butyrate production in gut microbiota fermentation. Food Funct 2024; 15:3186-3198. [PMID: 38441170 DOI: 10.1039/d3fo04187e] [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: 03/19/2024]
Abstract
The modern diet delivers nearly equal amounts of carbohydrates and protein into the colon representing an important protein increase compared to past higher fiber diets. At the same time, plant-based protein foods have become increasingly popular, and these sources of protein are generally less digestible than animal protein sources. As a result, a significant amount of protein is expected to reach the colon and be available for fermentation by gut microbiota. While studies on diet-microbiota interventions have mainly focused on carbohydrate fermentation, limited attention has been given to the role of protein or protein-fiber mixtures as fermentation substrates for the colonic microbiota. In this study, we aimed to investigate: (1) how changing the ratio of protein to fiber substrates affects the types and quantities of gut microbial metabolites and bacteria; and (2) how the specific fermentation characteristics of different types of fiber might influence the utilization of protein by gut microbes to produce beneficial short chain fatty acids. Our results revealed that protein fermentation in the gut plays a crucial role in shaping the overall composition of microbiota communities and their metabolic outputs. Surprisingly, butyrate production was maintained or increased when fiber and protein were combined, and even when pure protein samples were used as substrates. These findings suggest that indigestible protein in fiber-rich substrates may promote the production of microbial butyrate perhaps including the later stages of fermentation in the large intestine.
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Affiliation(s)
- Rachel Jackson
- Whistler Center for Carbohydrate Research, Department of Food Science, Purdue University, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA.
| | - Tianming Yao
- Whistler Center for Carbohydrate Research, Department of Food Science, Purdue University, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA.
| | - Nuseybe Bulut
- Whistler Center for Carbohydrate Research, Department of Food Science, Purdue University, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA.
| | - Thaisa M Cantu-Jungles
- Whistler Center for Carbohydrate Research, Department of Food Science, Purdue University, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA.
| | - Bruce R Hamaker
- Whistler Center for Carbohydrate Research, Department of Food Science, Purdue University, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA.
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11
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Steinert RE, Mueller M, Serra M, Lehner-Sigrist S, Frost G, Gero D, Gerber PA, Bueter M. Effect of inulin on breath hydrogen, postprandial glycemia, gut hormone release, and appetite perception in RYGB patients: a prospective, randomized, cross-over pilot study. Nutr Diabetes 2024; 14:9. [PMID: 38448413 PMCID: PMC10918168 DOI: 10.1038/s41387-024-00267-5] [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: 07/10/2023] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 03/08/2024] Open
Abstract
BACKGROUND AND OBJECTIVE Large intestinal fermentation of dietary fiber may control meal-related glycemia and appetite via the production of short-chain fatty acids (SCFA) and the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). We investigated whether this mechanism contributes to the efficacy of the Roux-en-Y gastric bypass (RYGB) by assessing the effect of oligofructose-enriched inulin (inulin) vs. maltodextrin (MDX) on breath hydrogen (a marker of intestinal fermentation), plasma SCFAs, gut hormones, insulin and blood glucose concentrations as well as appetite in RYGB patients. METHOD Eight RYGB patients were studied on two occasions before and ~8 months after surgery using a cross-over design. Each patient received 300 ml orange juice containing 25 g inulin or an equicaloric load of 15.5 g MDX after an overnight fast followed by a fixed portion snack served 3 h postprandially. Blood samples were collected over 5 h and breath hydrogen measured as well as appetite assessed using visual analog scales. RESULTS Surgery increased postprandial secretion of GLP-1 and PYY (P ≤ 0.05); lowered blood glucose and plasma insulin increments (P ≤ 0.05) and reduced appetite ratings in response to both inulin and MDX. The effect of inulin on breath hydrogen was accelerated after surgery with an increase that was earlier in onset (2.5 h vs. 3 h, P ≤ 0.05), but less pronounced in magnitude. There was, however, no effect of inulin on plasma SCFAs or plasma GLP-1 and PYY after the snack at 3 h, neither before nor after surgery. Interestingly, inulin appeared to further potentiate the early-phase glucose-lowering and second-meal (3-5 h) appetite-suppressive effect of surgery with the latter showing a strong correlation with early-phase breath hydrogen concentrations. CONCLUSION RYGB surgery accelerates large intestinal fermentation of inulin, however, without measurable effects on plasma SCFAs or plasma GLP-1 and PYY. The glucose-lowering and appetite-suppressive effects of surgery appear to be potentiated with inulin.
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Affiliation(s)
- R E Steinert
- Department of Surgery and Transplantation, University Hospital Zurich (USZ) and University of Zurich (UZH), Zürich, Switzerland.
| | - M Mueller
- Department of Surgery and Transplantation, University Hospital Zurich (USZ) and University of Zurich (UZH), Zürich, Switzerland
| | - M Serra
- Department of Surgery and Transplantation, University Hospital Zurich (USZ) and University of Zurich (UZH), Zürich, Switzerland
| | - S Lehner-Sigrist
- Department of Surgery and Transplantation, University Hospital Zurich (USZ) and University of Zurich (UZH), Zürich, Switzerland
| | - G Frost
- Section for Nutrition Research, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - D Gero
- Department of Surgery and Transplantation, University Hospital Zurich (USZ) and University of Zurich (UZH), Zürich, Switzerland
| | - P A Gerber
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zürich, Switzerland
| | - M Bueter
- Department of Surgery and Transplantation, University Hospital Zurich (USZ) and University of Zurich (UZH), Zürich, Switzerland
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12
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Thammayon N, Wongdee K, Teerapornpuntakit J, Panmanee J, Chanpaisaeng K, Charoensetakul N, Srimongkolpithak N, Suntornsaratoon P, Charoenphandhu N. Enhancement of intestinal calcium transport by short-chain fatty acids: roles of Na +/H + exchanger 3 and transient receptor potential vanilloid subfamily 6. Am J Physiol Cell Physiol 2024; 326:C317-C330. [PMID: 38073487 DOI: 10.1152/ajpcell.00330.2023] [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: 07/21/2023] [Revised: 12/01/2023] [Accepted: 12/02/2023] [Indexed: 01/18/2024]
Abstract
Small organic molecules in the intestinal lumen, particularly short-chain fatty acids (SCFAs) and glucose, have long been postulated to enhance calcium absorption. Here, we used 45Ca radioactive tracer to determine calcium fluxes across the rat intestine after exposure to glucose and SCFAs. Confirming previous reports, glucose was found to increase the apical-to-basolateral calcium flux in the cecum. Under apical glucose-free conditions, SCFAs (e.g., butyrate) stimulated the cecal calcium fluxes by approximately twofold, while having no effect on proximal colon. Since SCFAs could be absorbed into the circulation, we further determined whether basolateral SCFA exposure rendered some positive actions. It was found that exposure of duodenum and cecum on the basolateral side to acetate or butyrate increased calcium fluxes. Under butyrate-rich conditions, cecal calcium transport was partially diminished by Na+/H+ exchanger 3 (NHE3) inhibitor (tenapanor) and nonselective transient receptor potential vanilloid subfamily 6 (TRPV6) inhibitor (miconazole). To confirm the contribution of TRPV6 to SCFA-stimulated calcium transport, we synthesized another TRPV6 inhibitor that was demonstrated by in silico molecular docking and molecular dynamics to occlude TRPV6 pore and diminish the glucose- and butyrate-induced calcium fluxes. Therefore, besides corroborating the importance of luminal molecules in calcium absorption, our findings provided foundation for development of more effective calcium-rich nutraceuticals in combination with various absorptive enhancers, e.g., glucose and SCFAs.NEW & NOTEWORTHY Organic molecules in the intestinal lumen, e.g., glucose and short-chain fatty acids (SCFAs), the latter of which are normally produced by microfloral fermentation, can stimulate calcium absorption dependent on transient receptor potential vanilloid subfamily 6 (TRPV6) and Na+/H+ exchanger 3 (NHE3). A selective TRPV6 inhibitor synthesized and demonstrated by in silico docking and molecular dynamics to specifically bind to the pore domain of TRPV6 was used to confirm a significant contribution of this channel. Our findings corroborate physiological significance of nutrients and SCFAs in enhancing calcium absorption.
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Affiliation(s)
- Nithipak Thammayon
- Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Kannikar Wongdee
- Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand
- Faculty of Allied Health Sciences, Burapha University, Chonburi, Thailand
| | - Jarinthorn Teerapornpuntakit
- Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand
- Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Jiraporn Panmanee
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - Krittikan Chanpaisaeng
- Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand
- National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Netnapa Charoensetakul
- National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Nitipol Srimongkolpithak
- National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Panan Suntornsaratoon
- Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Narattaphol Charoenphandhu
- Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
- Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
- The Academy of Science, The Royal Society of Thailand, Bangkok, Thailand
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13
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Cheng J, Zhou J. Unraveling the gut health puzzle: exploring the mechanisms of butyrate and the potential of High-Amylose Maize Starch Butyrate (HAMSB) in alleviating colorectal disturbances. Front Nutr 2024; 11:1285169. [PMID: 38304546 PMCID: PMC10830644 DOI: 10.3389/fnut.2024.1285169] [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: 08/29/2023] [Accepted: 01/02/2024] [Indexed: 02/03/2024] Open
Abstract
Colorectal disturbances encompass a variety of disorders that impact the colon and rectum, such as colitis and colon cancer. Butyrate, a short-chain fatty acid, plays a pivotal role in supporting gut health by nourishing colonocytes, promoting barrier function, modulating inflammation, and fostering a balanced microbiome. Increasing colorectal butyrate concentration may serve as a critical strategy to improve colon function and reduce the risk of colorectal disturbances. Butyrylated high-amylose maize starch (HAMSB) is an edible ingredient that efficiently delivers butyrate to the colon. HAMSB is developed by esterifying a high-amylose starch backbone with butyric anhydride. With a degree of substitution of 0.25, each hydroxy group of HAMSB is substituted by a butyryl group in every four D-glucopyranosyl units. In humans, the digestibility of HAMSB is 68% (w/w), and 60% butyrate molecules attached to the starch backbone is absorbed by the colon. One clinical trial yielded two publications, which showed that HAMSB significantly reduced rectal O6-methyl-guanine adducts and epithelial proliferation induced by the high protein diet. Fecal microbial profiles were assessed in three clinical trials, showing that HAMSB supplementation was consistently linked to increased abundance of Parabacteroides distasonis. In animal studies, HAMSB was effective in reducing the risk of diet- or AOM-induced colon cancer by reducing genetic damage, but the mechanisms differed. HAMSB functioned through affecting cecal ammonia levels by modulating colon pH in diet-induced cancer, while it ameliorated chemical-induced colon cancer through downregulating miR19b and miR92a expressions and subsequently activating the caspase-dependent apoptosis. Furthermore, animal studies showed that HAMSB improved colitis via regulating the gut immune modulation by inhibiting histone deacetylase and activating G protein-coupled receptors, but its role in bacteria-induced colon colitis requires further investigation. In conclusion, HAMSB is a food ingredient that may deliver butyrate to the colon to support colon health. Further clinical trials are warranted to validate earlier findings and determine the minimum effective dose of HAMSB.
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Affiliation(s)
- Junrui Cheng
- Global Scientific and Regulatory Department, Ingredion Incorporated, Bridgewater, NJ, United States
| | - Jing Zhou
- Global Scientific and Regulatory Department, Ingredion Incorporated, Bridgewater, NJ, United States
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14
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Hays KE, Pfaffinger JM, Ryznar R. The interplay between gut microbiota, short-chain fatty acids, and implications for host health and disease. Gut Microbes 2024; 16:2393270. [PMID: 39284033 PMCID: PMC11407412 DOI: 10.1080/19490976.2024.2393270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/19/2024] Open
Abstract
Short-chain fatty acids (SCFAs) - acetate, propionate, and butyrate - are important bacterial fermentation metabolites regulating many important aspects of human physiology. Decreases in the concentrations of any or multiple SCFAs are associated with various detrimental effects to the host. Previous research has broadly focused on gut microbiome produced SCFAs as a group, with minimal distinction between acetate, propionate, and butyrate independently, each with significantly different host effects. In this review, we comprehensively delineate the roles of these SCFAs with emphasis on receptor affinity, signaling pathway involvement, and net host physiologic effects. Butyrate is highlighted due to its unique role in gastrointestinal-associated functions, especially maintaining gut barrier integrity. Butyrate functions by promoting epithelial tight junctions, serving as fuel for colonocyte ATP production, and modulating the immune system. Interaction with the immune system occurs locally in the gastrointestinal tract and systemically in the brain. Investigation into research conducted on butyrate production pathways and specific bacterial players involved highlights a unique risk associated with use of gram-positive targeted antibiotics. We review and discuss evidence showing the relationship between the butyrate-producing gram-positive genus, Roseburia, and susceptibility to commonly prescribed, widely used gram-positive antibiotics. Considering gut microbiome implications when choosing antibiotic therapy may benefit health outcomes in patients.
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Affiliation(s)
- Kallie E Hays
- Doctor of Osteopathic Medicine Program, Rocky Vista University College of Osteopathic Medicine, Englewood, CO, USA
| | - Jacob M Pfaffinger
- Doctor of Osteopathic Medicine Program, Rocky Vista University College of Osteopathic Medicine, Englewood, CO, USA
| | - Rebecca Ryznar
- Department of Biomedical Sciences, Rocky Vista University College of Osteopathic Medicine, Englewood, CO, USA
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15
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Carlsen H, Pajari AM. Dietary fiber - a scoping review for Nordic Nutrition Recommendations 2023. Food Nutr Res 2023; 67:9979. [PMID: 37920675 PMCID: PMC10619389 DOI: 10.29219/fnr.v67.9979] [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: 10/30/2022] [Revised: 08/27/2023] [Accepted: 08/30/2023] [Indexed: 11/04/2023] Open
Abstract
Dietary fiber is a term crudely defined as carbohydrates (CHOs) that escape digestion and uptake in the small intestine. Lignin, which is not a CHO, is also a part of the dietary fiber definition. Dietary fibers come in different sizes and forms, with a variety of combinations of monomeric units. Health authorities worldwide have for many years recommended a diet rich in dietary fibers based on consistent findings that dietary fibers are associated with reduced incidences of major non-communicable diseases, including obesity, type 2 diabetes, cardiovascular disease, and colorectal cancer. Most fibers come from common edible foods from the plant kingdom, but fibers are also found in food additives, supplements, and breast milk. The recommended intake in Nordic Nutrition Recommendations 2012 (NNR2012) is 25 g/d for women and 35 g/d for men, whereas the actual intake is significantly lower, ranging from 16 g/d to 22 g/d in women and 18 g/d to 26 g/d in men. New studies since NNR2012 confirm the current view that dietary fiber is beneficial for health, advocating intakes of at least 25 g/day.
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Affiliation(s)
- Harald Carlsen
- Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås, Norway
| | - Anne-Maria Pajari
- Department of Food and Nutrition, University of Helsinki, Helsinki, Finland
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16
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Notting F, Pirovano W, Sybesma W, Kort R. The butyrate-producing and spore-forming bacterial genus Coprococcus as a potential biomarker for neurological disorders. GUT MICROBIOME (CAMBRIDGE, ENGLAND) 2023; 4:e16. [PMID: 39295905 PMCID: PMC11406416 DOI: 10.1017/gmb.2023.14] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 07/28/2023] [Accepted: 08/10/2023] [Indexed: 09/21/2024]
Abstract
The host-intestinal microbiome interaction has gained much scientific attention in the past two decades, boosted by advances in DNA sequencing and cultivation techniques. An accumulating amount of evidence shows that gut microbes play crucial roles in gut homeostasis, immune system education, and are associated with quality-of-life indicators. Beneficial health factors are associated with the digestion of dietary fibres in the colon and the subsequent production of short-chain fatty acids, including acetate, propionate, and butyrate. Coprococcus is a butyrate-producing genus in the phylum Firmicutes, and its abundance is inversely correlated with several neuropsychological and neurodegenerative disorders. Case-control studies provide strong evidence of decreased abundance of Coprococcus spp. in depressed individuals. The species Coprococcus eutactus has the unique capacity to use two separate pathways for butyrate synthesis and has been found to be depleted in children with delayed language development and adults with Parkinson's disease. The combined literature on Coprococcus and the gut microbiota-brain axis points towards enhanced butyrate production and reduced colonisation of pathogenic clades as factors explaining its association with health effects. The genus Coprococcus is a promising candidate for a mental health biomarker and an interesting lead for novel dietary-based preventive therapies for specific neurological disorders.
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Affiliation(s)
- Fleur Notting
- Amsterdam Institute for Life and Environment, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Walter Pirovano
- Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | | | - Remco Kort
- Amsterdam Institute for Life and Environment, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- ARTIS-Micropia, Amsterdam, The Netherlands
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17
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Zamani M, Nikbaf-Shandiz M, Aali Y, Rasaei N, Zarei M, Shiraseb F, Asbaghi O. The effects of acarbose treatment on cardiovascular risk factors in impaired glucose tolerance and diabetic patients: a systematic review and dose-response meta-analysis of randomized clinical trials. Front Nutr 2023; 10:1084084. [PMID: 37599681 PMCID: PMC10433190 DOI: 10.3389/fnut.2023.1084084] [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: 10/29/2022] [Accepted: 06/27/2023] [Indexed: 08/22/2023] Open
Abstract
Acarbose (ACB) seems to be an effective drug in the management of cardiovascular risk factors. However, no previous meta-analysis of randomized controlled trials (RCTs) has been done to evaluate the effects of ACB on cardiovascular risk factors on impaired glucose tolerance (IGT), type 2 diabetes mellitus (T2D), and type 1 diabetes mellitus (T1D). We comprehensively searched electronic databases including Scopus, Web of Science, and PubMed for RCTs for related keywords up to September 2022. A random-effects model was used to estimate the weighted mean difference (WMD) and 95% confidence interval (CI). The pooled analysis demonstrated that ACB treatment had a significant effect on fasting blood glucose (FBG) (WMD = -3.55 mg/dL; 95%CI: -6.29, -0.81; p = 0.011), fasting insulin (WMD = -6.73 pmoL/L; 95%CI: -10.37, -3.10; p < 0.001), HbA1c [WMD = -0.32%; 95%CI: -0.45, -0.20; p < 0.001], body weight (WMD = -1.25 kg; 95%CI: -1.79, -0.75; p < 0.001), body mass index (BMI) (WMD = -0.64 kg/m2; 95%CI: -0.92, -0.37; p < 0.001), tumor necrosis factor-alpha (TNF-α) (WMD = -2.70 pg/mL, 95%CI: -5.25, -0.16; p = 0.037), leptin (WMD = -1.58 ng/mL; 95%CI: -2.82, -0.35; p = 0.012), alanine transaminase (ALT) (WMD = 0.71 U/L; 95%CI: -0.31, 1.85; p = 0.164), triglyceride (TG) (WMD = -13.89 mg/dL; 95%CI: -20.69, -7.09; p < 0.001), total cholesterol (TC) (WMD = -2.26 mg/dL; 95%CI: -4.18, -0.34; p = 0.021), systolic blood pressure (SBP) (WMD = -1.29 mmHg; 95%CI: -2.44, -0.15; p = 0.027), and diastolic blood pressure (DBP) (WMD = 0.02 mmHg; 95%CI: -0.41, 0.45; p = 0.925) in an intervention group, compared with a placebo group. The non-linear dose-response analysis showed that ACB reduces the TC in trial duration by >50 weeks, and 180 mg/day is more effective for the decrement of CRP. ACB can improve lipid profiles, glycemic indices, anthropometric indices, and inflammatory markers in T2D, T1D, and IGT patients.
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Affiliation(s)
- Mohammad Zamani
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Yasaman Aali
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Niloufar Rasaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mahtab Zarei
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Farideh Shiraseb
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Omid Asbaghi
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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18
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Zhang D, He J, Cui J, Wang R, Tang Z, Yu H, Zhou M. Oral Microalgae-Nano Integrated System against Radiation-Induced Injury. ACS NANO 2023; 17:10560-10576. [PMID: 37253200 DOI: 10.1021/acsnano.3c01502] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
The increasing applications of ionizing radiation in society raise the risk of radiation-induced intestinal and whole-body injury. Astaxanthin is a powerful antioxidant to reduce the reactive oxygen generated from radiation and the subsequent damage. However, the oral administration of astaxanthin remains challenging owing to its low solubility and poor bioavailability. Herein, we facilely construct an orally used microalgae-nano integrated system (SP@ASXnano) against radiation-induced intestinal and whole-body injury, combining natural microalgae Spirulina platensis (SP) with astaxanthin nanoparticles (ASXnano). SP and ASXnano show complementation in drug delivery to improve distribution in the intestine and blood. SP displays limited gastric drug loss, prolonged intestinal retention, constant ASXnano release, and progressive degradation. ASXnano improves drug solubility, gastric stability, cell uptake, and intestinal absorption. SP and ASXnano have synergy in many aspects such as anti-inflammation, microbiota protection, and fecal short-chain fatty acid up-regulation. In addition, the system is ensured with biosafety for long-term administration. The system organically combines the properties of microalgae and nanoparticles, which was expected to expand the medical application of SP as a versatile drug delivery platform.
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Affiliation(s)
- Dongxiao Zhang
- Department of Surgery, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, 322000, China
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, 314400, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Jian He
- Department of Surgery, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, 322000, China
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, 314400, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Jiarong Cui
- Institute of Translational Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Ruoxi Wang
- Institute of Translational Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Zhe Tang
- Department of Surgery, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, 322000, China
| | - Hongyu Yu
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Min Zhou
- Department of Surgery, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, 322000, China
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, 314400, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou, 310009, China
- Cancer Center, Zhejiang University, Hangzhou, 310058, China
- Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou, 310053, China
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19
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Colangeli L, Escobar Marcillo DI, Simonelli V, Iorio E, Rinaldi T, Sbraccia P, Fortini P, Guglielmi V. The Crosstalk between Gut Microbiota and White Adipose Tissue Mitochondria in Obesity. Nutrients 2023; 15:nu15071723. [PMID: 37049562 PMCID: PMC10097238 DOI: 10.3390/nu15071723] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/19/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Adipose tissue (AT) dysregulation is a key process in the pathophysiology of obesity and its cardiometabolic complications, but even if a growing body of evidence has been collected over recent decades, the underlying molecular basis of adiposopathy remains to be fully understood. In this context, mitochondria, the intracellular organelles that orchestrate energy production and undergo highly dynamic adaptive changes in response to changing environments, have emerged as crucial regulators of both white (WAT) and brown adipose tissue (BAT) metabolism and function. Given that the gut microbiota and its metabolites are able to regulate host metabolism, adipogenesis, WAT inflammation, and thermogenesis, we hypothesize that their frequently observed dysregulation in obesity could affect AT metabolism by exerting direct and indirect effects on AT mitochondria. By collecting and revising the current evidence on the connections between gut microbiota and AT mitochondria in obesity, we gained insights into the molecular biology of their hitherto largely unexplored crosstalk, tracing how gut microbiota may regulate AT mitochondrial function.
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20
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Chuppava B, Siebert DC, Visscher C, Kamphues J, Abd El-Wahab A. Impact of Animal By-Products on Diet Digestibility and Fecal Quality in Beagle Dogs. Life (Basel) 2023; 13:life13030850. [PMID: 36984005 PMCID: PMC10052969 DOI: 10.3390/life13030850] [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: 01/17/2023] [Revised: 03/11/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
In animal feeds and pet food, meat industry rendered by-products as a source of high-quality protein are commonly used. Among all rendered protein sources, poultry carcasses and neck meal are frequently used as ingredients in commercial pet foods due to their agreeable fatty acid and amino acid profiles, and they have no impact on the palatability of the diet. Nonetheless, it is unclear how poultry by-product meal affects companion animals regarding diet digestibility and fecal quality. This study either aimed to provide information on poultry by-product meal, including coarsely, finely, or very finely ground varieties, regarding their nutrient digestibility and characteristics of feces in dogs. One type of animal by-product meal was used in the three aforementioned particle sizes. Beagle dogs (n = 6; body weight, 16.6 kg ± 2.03) participated in a crossover experiment design. Each trial consisted of a five day adaptation period to the diet, and five days of fecal samples were collected and measured for individual apparent nutritional digestibility and fecal scores. The animal by-product supplementation in the diet of dogs was well accepted, with an acceptable percentage of apparent nutrient digestibility. Different particle sizes had no significant effect on the organic matter, crude protein, and crude fat digestibility as well as the fecal fatty acid concentrations. In addition, feces remained firm and well-formed and increased fecal dry matter. This indicates that poultry by-products should be taken into account as a potential dietary protein source in dog food.
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Affiliation(s)
- Bussarakam Chuppava
- Institute for Animal Nutrition, University of Veterinary Medicine Hannover, Foundation, 30173 Hannover, Germany
| | - Diana-Christin Siebert
- Institute for Animal Nutrition, University of Veterinary Medicine Hannover, Foundation, 30173 Hannover, Germany
| | - Christian Visscher
- Institute for Animal Nutrition, University of Veterinary Medicine Hannover, Foundation, 30173 Hannover, Germany
| | - Josef Kamphues
- Institute for Animal Nutrition, University of Veterinary Medicine Hannover, Foundation, 30173 Hannover, Germany
| | - Amr Abd El-Wahab
- Institute for Animal Nutrition, University of Veterinary Medicine Hannover, Foundation, 30173 Hannover, Germany
- Department of Nutrition and Nutritional Deficiency Diseases, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt
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Luo Y, Wu J, Liu Y, Shen Y, Zhu F, Wu J, Hu Y. Metabolomics Study of Shaoyao Plants Decoction on the Proximal and Distal Colon in Mice with Dextran Sulfate Sodium-Induced Colitis by UPLC-Q-TOF-MS. Drug Des Devel Ther 2022; 16:4343-4364. [PMID: 36583115 PMCID: PMC9792814 DOI: 10.2147/dddt.s384607] [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: 09/15/2022] [Accepted: 12/09/2022] [Indexed: 12/24/2022] Open
Abstract
Purpose Shaoyao decoction (SYD) is a traditional Chinese medicine used to treat ulcerative colitis (UC). The exact mechanism of action of SYD in UC treatment is still unclear. Here, we examined the therapeutic effects of SYD in mice with dextran sulfate sodium (DSS)-induced colitis and explored the underlying mechanism. Methods The experimental group was divided into normal control, UC, and SYD treatment groups. The UC model of C57BL/6 mice was induced using 3% (w/v) DSS for 7 days. SYD was orally administered for 7 days. The proximal and distal colonic metabolic profiles were detected using quadrupole-time-of-flight mass spectrometry-based untargeted metabolomics. Results SYD significantly increased weight, reduced disease activity index scores, and ameliorated colon length shortening and pathological damage in mice. In the distal colon, SYD increased the abundance of phosphatidic acid and lysophosphatidylethanolamine and decreased the abundance of lactosylceramide, erythrodiol 3-palmitate, and lysophosphatidylcholine. In the proximal colon, SYD increased the abundance of palmitic acid, cyclonormammein, monoacylglyceride, 13S-hydroxyoctadecadienoic acid, and ceanothine C and decreased the abundance of tetracosahexaenoic acid, phosphatidylserine, and diglyceride. Conclusion Our findings revealed that SYD could alleviate UC by regulating metabolic dysfunction, which provides a reference for further studies on SYD.
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Affiliation(s)
- Yiting Luo
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
| | - Jin Wu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
| | - Yingchao Liu
- Academic Affairs Office, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
| | - Yan Shen
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
| | - Fangyuan Zhu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
| | - Jiaqian Wu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
| | - Yuyao Hu
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China,Correspondence: Yuyao Hu, The Second Affiliated Hospital of Zhejiang Chinese Medical University, 318 Chaowang Road, Hangzhou, People’s Republic of China, Email
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22
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Kircher B, Woltemate S, Gutzki F, Schlüter D, Geffers R, Bähre H, Vital M. Predicting butyrate- and propionate-forming bacteria of gut microbiota from sequencing data. Gut Microbes 2022; 14:2149019. [PMID: 36416760 PMCID: PMC9704393 DOI: 10.1080/19490976.2022.2149019] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The bacteria-derived short-chain fatty acids (SCFAs) butyrate and propionate play important (distinct) roles in health and disease, and understanding the ecology of respective bacteria on a community-wide level is a top priority in microbiome research. Applying sequence data (metagenomics and 16S rRNA gene) to predict SCFAs production in vitro and in vivo, a clear split between butyrate- and propionate-forming bacteria was detected with only very few taxa exhibiting pathways for the production of both SCFAs. After in vitro growth of fecal communities from distinct donors (n = 8) on different substrates (n = 7), abundances of bacteria exhibiting pathways correlated with respective SCFA concentrations, in particular in the case of butyrate. For propionate, correlations were weaker, indicating that its production is less imprinted into the core metabolism compared with butyrate-forming bacteria. Longitudinal measurements in vivo (n = 5 time-points from 20 subjects) also revealed a correlation between abundances of pathway-carrying bacteria and concentrations of the two SCFAs. Additionally, lower bacterial cell concentrations, together with higher stool moisture, promoted overall bacterial activity (measured by flow cytometry and coverage patterns of metagenome-assembled genomes) that led to elevated SCFA concentrations with over-proportional levels of butyrate. Predictions on pathway abundances based on 16S rRNA gene data using our in-house database worked well, yielding similar results as metagenomic-based analyses. Our study indicates that stimulating growth of butyrate- and propionate-producing bacteria directly leads to more production of those compounds, which is governed by two functionally distinct bacterial groups facilitating the development of precision intervention strategies targeting either metabolite.
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Affiliation(s)
- Berenike Kircher
- Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Sabrina Woltemate
- Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Frank Gutzki
- Research Core Unit Metabolomics, Hannover Medical School, Hannover, Germany
| | - Dirk Schlüter
- Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Robert Geffers
- Genomics Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Heike Bähre
- Genomics Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Marius Vital
- Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany,CONTACT Marius Vital Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, OE5210, Carl-Neuberg-Str. 1, 30625Hannover, Germany
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23
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Zhong C, Bai X, Chen Q, Ma Y, Li J, Zhang J, Luo Q, Cai K. Gut microbial products valerate and caproate predict renal outcome among the patients with biopsy-confirmed diabetic nephropathy. Acta Diabetol 2022; 59:1469-1477. [PMID: 35947193 DOI: 10.1007/s00592-022-01948-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/20/2022] [Indexed: 11/30/2022]
Abstract
AIMS Valerate and caproate are two subtypes of short-chain fatty acids produced by gut microbiota. We aimed to measure the serum valerate and caproate levels and analyze the associations between them and renal prognosis of diabetic nephropathy (DN). METHODS The serum samples of patients with biopsy-confirmed diagnosis of DN were collected in the First Affiliated Hospital of Zhejiang University, from April 1, 2013, to March 31, 2018. One hundred patients were included and divided into an early DN group (eGFR ≥ 60 ml/min, n = 42) and an advanced DN group (eGFR < 60 ml/min, n = 58). The valerate and caproate were measured using gas chromatography-mass spectrometry. Participants were followed up until the cutoff date of August 31, 2018, or if they met the primary endpoint of end-stage renal disease (ESRD). RESULTS There were 71 males and 29 females in this study, and 29 patients developed ESRD. We observed a significant lower concentration of valerate and caproate in the advanced DN group. There were negative correlations between valerate and glomerular classification (r = - 0.20, P = 0.03) and between caproate and interstitial fibrosis and tubular atrophy (IFTA) (r = - 0.24, P = 0.01). And there were positive correlations between valerate or caproate and eGFR (r = 0.22, P = 0.02; r = 0.38, P < 0.01). Multivariate Cox analysis revealed higher levels of valerate and caproate were negatively related to progression to ESRD (HR = 0.024, P = 0.016; HR = 0.543, P = 0.030). The area under the curve values of valerate and caproate levels were 0.66 and 0.63, respectively, in predicting progression to ESRD. CONCLUSION This study showed alterations in serum valerate and caproate in DN and demonstrates lower valerate and caproate levels with progression of DN to ESRD.
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Affiliation(s)
- Chenyu Zhong
- Department of Nephrology, HwaMei Hospital, University of Chinese Academy of Sciences, 41 Xibei Street, Ningbo, 315010, Zhejiang Province, People's Republic of China
| | - Xu Bai
- Department of Nephrology, HwaMei Hospital, University of Chinese Academy of Sciences, 41 Xibei Street, Ningbo, 315010, Zhejiang Province, People's Republic of China
| | - Qinghuo Chen
- Department of Nephrology, HwaMei Hospital, University of Chinese Academy of Sciences, 41 Xibei Street, Ningbo, 315010, Zhejiang Province, People's Republic of China
| | - Yanhong Ma
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China
| | - Jianhui Li
- Department of Endocrinology, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang Province, People's Republic of China
| | - Jie Zhang
- Department of Endocrinology, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang Province, People's Republic of China
| | - Qun Luo
- Department of Nephrology, HwaMei Hospital, University of Chinese Academy of Sciences, 41 Xibei Street, Ningbo, 315010, Zhejiang Province, People's Republic of China
| | - Kedan Cai
- Department of Nephrology, HwaMei Hospital, University of Chinese Academy of Sciences, 41 Xibei Street, Ningbo, 315010, Zhejiang Province, People's Republic of China.
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24
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Cao Y, Aquino-Martinez R, Hutchison E, Allayee H, Lusis AJ, Rey FE. Role of gut microbe-derived metabolites in cardiometabolic diseases: Systems based approach. Mol Metab 2022; 64:101557. [PMID: 35870705 PMCID: PMC9399267 DOI: 10.1016/j.molmet.2022.101557] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/30/2022] [Accepted: 07/18/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The gut microbiome influences host physiology and cardiometabolic diseases by interacting directly with intestinal cells or by producing molecules that enter the host circulation. Given the large number of microbial species present in the gut and the numerous factors that influence gut bacterial composition, it has been challenging to understand the underlying biological mechanisms that modulate risk of cardiometabolic disease. SCOPE OF THE REVIEW Here we discuss a systems-based approach that involves simultaneously examining individuals in populations for gut microbiome composition, molecular traits using "omics" technologies, such as circulating metabolites quantified by mass spectrometry, and clinical traits. We summarize findings from landmark studies using this approach and discuss future applications. MAJOR CONCLUSIONS Population-based integrative approaches have identified a large number of microbe-derived or microbe-modified metabolites that are associated with cardiometabolic traits. The knowledge gained from these studies provide new opportunities for understanding the mechanisms involved in gut microbiome-host interactions and may have potentially important implications for developing novel therapeutic approaches.
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Affiliation(s)
- Yang Cao
- Departments of Medicine, Human Genetics, and Microbiology, Immunology, & Molecular Genetics, David Geffen School of Medicine of UCLA, Los Angeles, CA 90095, USA
| | - Ruben Aquino-Martinez
- Department of Bacteriology, University of Wisconsin, Madison, Madison, WI 53706, USA
| | - Evan Hutchison
- Department of Bacteriology, University of Wisconsin, Madison, Madison, WI 53706, USA
| | - Hooman Allayee
- Departments of Population & Public Health Sciences and Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Aldons J Lusis
- Departments of Medicine, Human Genetics, and Microbiology, Immunology, & Molecular Genetics, David Geffen School of Medicine of UCLA, Los Angeles, CA 90095, USA.
| | - Federico E Rey
- Department of Bacteriology, University of Wisconsin, Madison, Madison, WI 53706, USA
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25
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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: 47] [Impact Index Per Article: 15.7] [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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26
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Frolova MS, Suvorova IA, Iablokov SN, Petrov SN, Rodionov DA. Genomic reconstruction of short-chain fatty acid production by the human gut microbiota. Front Mol Biosci 2022; 9:949563. [PMID: 36032669 PMCID: PMC9403272 DOI: 10.3389/fmolb.2022.949563] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 07/19/2022] [Indexed: 12/04/2022] Open
Abstract
Short-chain fatty acids (SCFAs) including acetate, formate, propionate, and butyrate are the end products of dietary fiber and host glycan fermentation by the human gut microbiota (HGM). SCFAs produced in the column are of utmost importance for host physiology and health. Butyrate and propionate improve gut health and play a key role in the neuroendocrine and immune systems. Prediction of HGM metabolic potential is important for understanding the influence of diet and HGM-produced metabolites on human health. We conducted a detailed metabolic reconstruction of pathways for the synthesis of SCFAs and L- and D-lactate, as additional fermentation products, in a reference set of 2,856 bacterial genomes representing strains of >800 known HGM species. The reconstructed butyrate and propionate pathways included four and three pathway variants, respectively, that start from different metabolic precursors. Altogether, we identified 48 metabolic enzymes, including five alternative enzymes in propionate pathways, and propagated their occurrences across all studied genomes. We established genomic signatures for reconstructed pathways and classified genomes according to their simplified binary phenotypes encoding the ability ("1") or inability ("0") of a given organism to produce SCFAs. The resulting binary phenotypes combined into a binary phenotype matrix were used to assess the SCFA synthesis potential of HGM samples from several public metagenomic studies. We report baseline and variance for Community Phenotype Indices calculated for SCFAs production capabilities in 16S metagenomic samples of intestinal microbiota from two large national cohorts (American Gut Project, UK twins), the Hadza hunter-gatherers, and the young children cohort of infants with high-risk for type 1 diabetes. We further linked the predicted SCFA metabolic capabilities with available SCFA concentrations both for in vivo fecal samples and in vitro fermentation samples from previous studies. Finally, we analyzed differential representation of individual SCFA pathway genes across several WGS metagenomic datasets. The obtained collection of SCFA pathway genes and phenotypes enables the predictive metabolic phenotype profiling of HGM datasets and enhances the in silico methodology to study cross-feeding interactions in the gut microbiomes.
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Affiliation(s)
- Maria S. Frolova
- Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Russia
| | - Inna A. Suvorova
- A.A. Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia
| | - Stanislav N. Iablokov
- A.A. Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia
| | - Sergei N. Petrov
- Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia
| | - Dmitry A. Rodionov
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
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27
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Abd El-Wahab A, Chuppava B, Siebert DC, Visscher C, Kamphues J. Digestibility of a Lignocellulose Supplemented Diet and Fecal Quality in Beagle Dogs. Animals (Basel) 2022; 12:ani12151965. [PMID: 35953954 PMCID: PMC9367428 DOI: 10.3390/ani12151965] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/28/2022] [Accepted: 08/01/2022] [Indexed: 11/16/2022] Open
Abstract
Lignocellulose (LC) might be used as a substitute fiber source for dogs as a strategy to decrease energy density and enhance gastrointestinal functionality. The objective of the present study was to compare the effects of including different levels of LC on apparent nutrient digestibility and fecal parameters (dry matter (DM), fecal score, and daily fecal output), as well as fecal fatty acid concentrations. Four diets were tested: control diet (no supplementation of LC; LC0), and three control diets diluted with increasing levels of LC: 1, 2, and 4% (LC1, LC2, and LC4). Six Beagle dogs (BW 17.1 kg ± 1.22) participated in a crossover experimental design. Before each experimental period, five days were used as a wash-out period. The fecal consistency was scored based on a 5-point scale (1 = very hard; 2 = solid, well-formed “optimum”; 3 = soft, still formed; 4 = pasty, slushy; and 5 = watery diarrhea). The results demonstrated that the organic matter apparent digestibility (p = 0.01) and nitrogen-free extract (NFE) (p < 0.01) was significantly lower for dogs fed LC4 compared to those fed LC0. Dogs fed LC2 and LC4 had a lower fecal consistency score (2.39 and 2.18, respectively; p < 0.05). The fecal DM was significantly the highest (p < 0.01), and the daily fecal output on fresh matter was lower (p < 0.05) when dogs were fed the LC4 diet compared with the LC0 diet. Including LC at 1% in the diet resulted in significantly higher fecal acidic pH levels. However, no differences among treatments were noted regarding fecal fatty acid concentrations.
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Affiliation(s)
- Amr Abd El-Wahab
- Institute for Animal Nutrition, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, D-30173 Hannover, Germany; (A.A.E.-W.); (D.-C.S.); (C.V.); (J.K.)
- Department of Nutrition and Nutritional Deficiency Diseases, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Bussarakam Chuppava
- Institute for Animal Nutrition, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, D-30173 Hannover, Germany; (A.A.E.-W.); (D.-C.S.); (C.V.); (J.K.)
- Correspondence:
| | - Diana-Christin Siebert
- Institute for Animal Nutrition, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, D-30173 Hannover, Germany; (A.A.E.-W.); (D.-C.S.); (C.V.); (J.K.)
| | - Christian Visscher
- Institute for Animal Nutrition, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, D-30173 Hannover, Germany; (A.A.E.-W.); (D.-C.S.); (C.V.); (J.K.)
| | - Josef Kamphues
- Institute for Animal Nutrition, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, D-30173 Hannover, Germany; (A.A.E.-W.); (D.-C.S.); (C.V.); (J.K.)
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28
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Liu H, Liao C, Wu L, Tang J, Chen J, Lei C, Zheng L, Zhang C, Liu YY, Xavier J, Dai L. Ecological dynamics of the gut microbiome in response to dietary fiber. THE ISME JOURNAL 2022; 16:2040-2055. [PMID: 35597888 PMCID: PMC9296629 DOI: 10.1038/s41396-022-01253-4] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 05/05/2022] [Accepted: 05/11/2022] [Indexed: 12/19/2022]
Abstract
Dietary fibers are generally thought to benefit intestinal health. Their impacts on the composition and metabolic function of the gut microbiome, however, vary greatly across individuals. Previous research showed that each individual's response to fibers depends on their baseline gut microbiome, but the ecology driving microbiota remodeling during fiber intake remained unclear. Here, we studied the long-term dynamics of the gut microbiome and short-chain fatty acids (SCFAs) in isogenic mice with distinct microbiota baselines fed with the fermentable fiber inulin and resistant starch compared to the non-fermentable fiber cellulose. We found that inulin produced a generally rapid response followed by gradual stabilization to new equilibria, and those dynamics were baseline-dependent. We parameterized an ecology model from the time-series data, which revealed a group of bacteria whose growth significantly increased in response to inulin and whose baseline abundance and interspecies competition explained the baseline dependence of microbiome density and community composition dynamics. Fecal levels of SCFAs, such as propionate, were associated with the abundance of inulin responders, yet inter-individual variation of gut microbiome impeded the prediction of SCFAs by machine learning models. We showed that our methods and major findings were generalizable to dietary resistant starch. Finally, we analyzed time-series data of synthetic and natural human gut microbiome in response to dietary fiber and validated the inferred interspecies interactions in vitro. This study emphasizes the importance of ecological modeling to understand microbiome responses to dietary changes and the need for personalized interventions.
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Affiliation(s)
- Hongbin Liu
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Chen Liao
- Program for Computational and Systems Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Lu Wu
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Jinhui Tang
- Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Junyu Chen
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Chaobi Lei
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Linggang Zheng
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Chenhong Zhang
- State Key Laboratory of Microbial Metabolism, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Yang-Yu Liu
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Joao Xavier
- Program for Computational and Systems Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Lei Dai
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
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29
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Qian XH, Xie RY, Liu XL, Chen SD, Tang HD. Mechanisms of Short-Chain Fatty Acids Derived from Gut Microbiota in Alzheimer's Disease. Aging Dis 2022; 13:1252-1266. [PMID: 35855330 PMCID: PMC9286902 DOI: 10.14336/ad.2021.1215] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 12/15/2021] [Indexed: 12/11/2022] Open
Abstract
Short-chain fatty acids (SCFAs) are important metabolites derived from the gut microbiota through fermentation of dietary fiber. SCFAs participate a number of physiological and pathological processes in the human body, such as host metabolism, immune regulation, appetite regulation. Recent studies on gut-brain interaction have shown that SCFAs are important mediators of gut-brain interactions and are involved in the occurrence and development of many neurodegenerative diseases, including Alzheimer's disease. This review summarizes the current research on the potential roles and mechanisms of SCFAs in AD. First, we introduce the metabolic distribution, specific receptors and signaling pathways of SCFAs in human body. The concentration levels of SCFAs in AD patient/animal models are then summarized. In addition, we illustrate the effects and mechanisms of SCFAs on the cognitive level, pathological features (Aβ and tau) and neuroinflammation in AD. Finally, we analyze the translational value of SCFAs as potential therapeutic targets for the treatment of AD.
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Affiliation(s)
- Xiao-hang Qian
- Department of Neurology and Institute of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Ru-yan Xie
- Shanghai Guangci Memorial hospital, Shanghai 200025, China.
| | - Xiao-li Liu
- Department of Neurology, Shanghai Fengxian District Central Hospital, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital South Campus, Shanghai 201406, China.
| | - Sheng-di Chen
- Department of Neurology and Institute of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
- Correspondence should be addressed to: Dr. Sheng-di Chen () and Dr. Hui-dong Tang (), Department of Neurology and Institute of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hui-dong Tang
- Department of Neurology and Institute of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
- Correspondence should be addressed to: Dr. Sheng-di Chen () and Dr. Hui-dong Tang (), Department of Neurology and Institute of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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30
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An Improved Method to Quantify Short-Chain Fatty Acids in Biological Samples Using Gas Chromatography-Mass Spectrometry. Metabolites 2022; 12:metabo12060525. [PMID: 35736458 PMCID: PMC9228653 DOI: 10.3390/metabo12060525] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 05/27/2022] [Accepted: 06/01/2022] [Indexed: 02/01/2023] Open
Abstract
Gut microbial metabolites, short-chain fatty acids (SCFAs), are found at multiple locations in the host body and are identified as important metabolites in gut microbiome-associated diseases. Quantifying SCFAs in diverse biological samples is important to understand their roles in host health. This study developed an accurate SCFA quantification method by performing gas chromatography–mass spectrometry (GC/MS) in human plasma, serum, feces, and mouse cecum tissue. The samples were acidified with hydrochloric acid, and the SCFAs were extracted using methyl tert-butyl ether. In this method, distilled water was selected as a surrogate matrix for the quantification of SCFAs in target biological samples. The method was validated in terms of linearity, parallelism, precision, recovery, and matrix effect. The developed method was further applied in target biological samples. In conclusion, this optimized method can be used as a simultaneous SCFA quantification method in diverse biological samples.
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A high-fibre personalised dietary advice given via a web tool reduces constipation complaints in adults. J Nutr Sci 2022; 11:e31. [PMID: 35573462 PMCID: PMC9066321 DOI: 10.1017/jns.2022.27] [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: 03/18/2022] [Revised: 03/28/2022] [Accepted: 04/01/2022] [Indexed: 11/07/2022] Open
Abstract
Constipation can greatly impact the quality of life (QoL), which can be relieved by dietary fibres; however, preserving a higher fibre intake remains a challenge. We investigated the effects of a personalised dietary advice (PDA) on fibre intake and mild constipation complaints. A total number of twenty-five adults with mild constipation complaints were included in a 4-week observation period followed by a 4-week personalised intervention. The PDA provided high-fibre alternatives via a web tool. In weeks 1, 4 and 8, dietary intake, constipation complaints and QoL were assessed. Furthermore, participants collected a faecal sample at weeks 1, 4 and 8 to determine microbiota diversity and composition, and short-chain fatty acids (SCFA). Participants completed questions daily for 8 weeks regarding abdominal complaints, stool frequency and stool consistency. Fibre intake in week 8 was significantly higher compared to week 1 (Δ = 5·7 ± 6·7 g, P < 0·001) and week 4 (Δ = 5·2 ± 6·4 g, P < 0·001). Constipation severity and QoL significantly improved at week 8 compared to the observation period (P < 0·001). A higher fibre intake significantly reduced constipation severity (β = -0·031 (-0·05; -0·01), P = 0·001) and the QoL (β = -0·022 (-0·04; -0·01), P = 0·009). Stool consistency (P = 0·040) and abdominal pain (P = 0·030) improved significantly during the intervention period (P = 0·040), but stool frequency did not. Average microbial alpha diversity and composition and SCFA concentrations did not change over time, but indicated individual-specific dynamics. Several SCFAs were associated with constipation complaints. To conclude, a PDA effectively increased fibre intake and subsequently reduced constipation complaints, indicating that guided dietary adjustments are important and feasible in the treatment of mild constipation complaints.
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Key Words
- BMI, body mass index
- Constipation
- Dietary fibre
- EMA, ecological momentary assessment
- FFQ, food frequency questionnaire
- Functional bowel disorders
- IBS-C, Irritable Bowel Syndrome constipation predominant
- MET, metabolic equivalent task
- PAC-QoL, Patient Assessment of Constipation Quality of Life
- PAC-SYM, Patient Assessment of Constipation Symptoms
- PDA, personalised dietary advice
- Personalised nutrition
- QoL, quality of life
- Quality of life
- SQUASH, short questionnaire to assess health-enhancing physical activity
- VAS, visual analogue scale
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Johnson WT, Dorn NC, Ogbonna DA, Bottini N, Shah NJ. Lipid-based regulators of immunity. Bioeng Transl Med 2022; 7:e10288. [PMID: 35600637 PMCID: PMC9115682 DOI: 10.1002/btm2.10288] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/29/2021] [Accepted: 12/14/2021] [Indexed: 11/22/2022] Open
Abstract
Lipids constitute a diverse class of molecular regulators with ubiquitous physiological roles in sustaining life. These carbon-rich compounds are primarily sourced from exogenous sources and may be used directly as structural cellular building blocks or as a substrate for generating signaling mediators to regulate cell behavior. In both of these roles, lipids play a key role in both immune activation and suppression, leading to inflammation and resolution, respectively. The simple yet elegant structural properties of lipids encompassing size, hydrophobicity, and molecular weight enable unique biodistribution profiles that facilitate preferential accumulation in target tissues to modulate relevant immune cell subsets. Thus, the structural and functional properties of lipids can be leveraged to generate new materials as pharmacological agents for potently modulating the immune system. Here, we discuss the properties of three classes of lipids: polyunsaturated fatty acids, short-chain fatty acids, and lipid adjuvants. We describe their immunoregulatory functions in modulating disease pathogenesis in preclinical models and in human clinical trials. We conclude with an outlook on harnessing the diverse and potent immune modulating properties of lipids for immunoregulation.
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Affiliation(s)
- Wade T. Johnson
- Department of NanoengineeringUniversity of California, San DiegoLa JollaCaliforniaUSA
| | - Nicholas C. Dorn
- Department of NanoengineeringUniversity of California, San DiegoLa JollaCaliforniaUSA
- Chemical Engineering ProgramUniversity of California, San DiegoLa JollaCaliforniaUSA
| | - Dora A. Ogbonna
- Department of NanoengineeringUniversity of California, San DiegoLa JollaCaliforniaUSA
- Chemical Engineering ProgramUniversity of California, San DiegoLa JollaCaliforniaUSA
| | - Nunzio Bottini
- Division of Rheumatology, Allergy and Immunology, Department of MedicineUniversity of California, San DiegoLa JollaCaliforniaUSA
- Program in ImmunologyUniversity of California, San DiegoLa JollaCaliforniaUSA
| | - Nisarg J. Shah
- Department of NanoengineeringUniversity of California, San DiegoLa JollaCaliforniaUSA
- Chemical Engineering ProgramUniversity of California, San DiegoLa JollaCaliforniaUSA
- Program in ImmunologyUniversity of California, San DiegoLa JollaCaliforniaUSA
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O'Riordan KJ, Collins MK, Moloney GM, Knox EG, Aburto MR, Fülling C, Morley SJ, Clarke G, Schellekens H, Cryan JF. Short chain fatty acids: Microbial metabolites for gut-brain axis signalling. Mol Cell Endocrinol 2022; 546:111572. [PMID: 35066114 DOI: 10.1016/j.mce.2022.111572] [Citation(s) in RCA: 220] [Impact Index Per Article: 73.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 01/07/2022] [Accepted: 01/11/2022] [Indexed: 02/08/2023]
Abstract
The role of the intestinal microbiota as a regulator of gut-brain axis signalling has risen to prominence in recent years. Understanding the relationship between the gut microbiota, the metabolites it produces, and the brain will be critical for the subsequent development of new therapeutic approaches, including the identification of novel psychobiotics. A key focus in this regard have been the short-chain fatty acids (SCFAs) produced by bacterial fermentation of dietary fibre, which include butyrate, acetate, and propionate. Ongoing research is focused on the entry of SCFAs into systemic circulation from the gut lumen, their migration to cerebral circulation and across the blood brain barrier, and their potential to exert acute and chronic effects on brain structure and function. This review aims to discuss our current mechanistic understanding of the direct and indirect influence that SCFAs have on brain function, behaviour and physiology, which will inform future microbiota-targeted interventions for brain disorders.
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Affiliation(s)
| | - Michael K Collins
- APC Microbiome Ireland, University College Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Ireland
| | - Gerard M Moloney
- APC Microbiome Ireland, University College Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Ireland
| | - Emily G Knox
- APC Microbiome Ireland, University College Cork, Ireland; School of Pharmacy, University College Cork, Ireland
| | - María R Aburto
- APC Microbiome Ireland, University College Cork, Ireland
| | | | - Shane J Morley
- APC Microbiome Ireland, University College Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Ireland, University College Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - Harriët Schellekens
- APC Microbiome Ireland, University College Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Ireland.
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Nutrient Digestibility and Fecal Quality in Beagle Dogs Fed Meat and Bone Meal Added to Dry Food. Vet Sci 2022; 9:vetsci9040164. [PMID: 35448662 PMCID: PMC9031195 DOI: 10.3390/vetsci9040164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/25/2022] [Accepted: 03/28/2022] [Indexed: 02/01/2023] Open
Abstract
Meat and bone meal (MBM) is one animal by-product used in pets. This study purposed to provide information on MBM including either coarsely (MBMc) or finely (MBMf) ground with regard to diet digestibility and fecal characteristics in dogs. Three different levels of MBM (6%, 12% and 24%) of each grinding form (MBM6, MBM12 and MBM24) were added to a basic diet. Six Beagle dogs (body weight 16.7 kg ± 0.42) participated in a Latin Square experiment. Each trial began with the animals adapting to the food for a five-day period, followed by five days of fecal collection. The feed particle size had no effect on the apparent digestibility of organic matter, crude protein and crude fat. The fecal score was significantly affected by the particle size × level interaction among treatments (p < 0.0001). It was noted that the different particle sizes or levels of MBM as main effects had no significant effect on the fecal fatty acid concentrations. These findings suggest that using coarse or fine grinding even including MBM up to 24% in dog diets does not affect the apparent digestibility of protein nor fecal quality negatively in our experimental study.
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McMurdie PJ, Stoeva MK, Justice N, Nemchek M, Sieber CMK, Tyagi S, Gines J, Skennerton CT, Souza M, Kolterman O, Eid J. Increased circulating butyrate and ursodeoxycholate during probiotic intervention in humans with type 2 diabetes. BMC Microbiol 2022; 22:19. [PMID: 34996347 PMCID: PMC8742391 DOI: 10.1186/s12866-021-02415-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 12/07/2021] [Indexed: 02/07/2023] Open
Abstract
Background An increasing body of evidence implicates the resident gut microbiota as playing a critical role in type 2 diabetes (T2D) pathogenesis. We previously reported significant improvement in postprandial glucose control in human participants with T2D following 12-week administration of a 5-strain novel probiotic formulation (‘WBF-011’) in a double-blind, randomized, placebo controlled setting (NCT03893422). While the clinical endpoints were encouraging, additional exploratory measurements were needed in order to link the motivating mechanistic hypothesis - increased short-chain fatty acids - with markers of disease. Results Here we report targeted and untargeted metabolomic measurements on fasting plasma (n = 104) collected at baseline and end of intervention. Butyrate and ursodeoxycholate increased among participants randomized to WBF-011, along with compelling trends between butyrate and glycated haemoglobin (HbA1c). In vitro monoculture experiments demonstrated that the formulation’s C. butyricum strain efficiently synthesizes ursodeoxycholate from the primary bile acid chenodeoxycholate during butyrogenic growth. Untargeted metabolomics also revealed coordinated decreases in intermediates of fatty acid oxidation and bilirubin, potential secondary signatures for metabolic improvement. Finally, improvement in HbA1c was limited almost entirely to participants not using sulfonylurea drugs. We show that these drugs can inhibit growth of formulation strains in vitro. Conclusion To our knowledge, this is the first description of an increase in circulating butyrate or ursodeoxycholate following a probiotic intervention in humans with T2D, adding support for the possibility of a targeted microbiome-based approach to assist in the management of T2D. The efficient synthesis of UDCA by C. butyricum is also likely of interest to investigators of its use as a probiotic in other disease settings. The potential for inhibitory interaction between sulfonylurea drugs and gut microbiota should be considered carefully in the design of future studies. Supplementary Information The online version contains supplementary material available at 10.1186/s12866-021-02415-8.
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Affiliation(s)
- Paul J McMurdie
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA.
| | - Magdalena K Stoeva
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
| | - Nicholas Justice
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
| | - Madeleine Nemchek
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
| | | | - Surabhi Tyagi
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
| | - Jessica Gines
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
| | | | - Michael Souza
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
| | - Orville Kolterman
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
| | - John Eid
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
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Fecal Microbiota Signatures Are Not Consistently Related to Symptom Severity in Irritable Bowel Syndrome. Dig Dis Sci 2022; 67:5137-5148. [PMID: 35624331 PMCID: PMC9587953 DOI: 10.1007/s10620-022-07543-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 03/01/2022] [Indexed: 01/05/2023]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is the most prevalent functional bowel disorder, but its pathophysiology is still unknown. Although a microbial signature associated with IBS severity has been suggested, its association with IBS severity still remains largely unknown. AIMS This study aims to assess longitudinal dynamics of fecal microbiota and short-chain fatty acids (SCFAs) in different IBS severity groups and study the association with stool pattern, diet, depression, anxiety, and quality of life (QoL). METHODS A longitudinal study was performed, including n = 91 IBS patients and n = 28 matched controls. All participants collected fecal samples for microbiota composition and SCFA analysis and completed validated questionnaires regarding IBS severity, stool pattern, depression, anxiety, and IBS-QoL at two timepoints with four weeks in-between. Diet was assessed at the first timepoint. RESULTS Over time, 36% of IBS patients changed in severity group, and 53% changed in predominant stool pattern. The largest proportion of microbiota variation was explained by the individual (R2 = 70.07%). Microbiota alpha diversity and composition, and SCFAs did not differ between IBS severity groups, nor between IBS and controls. Relative abundances of Bifidobacterium, Terrisporobacter, and Turicibacter consistently differed between IBS and controls, but not between IBS severity groups. Large dynamics over time were observed in the association of microbiota composition with questionnaire data where IBS symptom severity was associated at T1 but not at T2. CONCLUSIONS Fecal microbiota and SCFA signatures were not consistently associated with IBS severity over time, indicating the importance of repeated sampling in IBS research.
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Fujimori S. Humans have intestinal bacteria that degrade the plant cell walls in herbivores. World J Gastroenterol 2021; 27:7784-7791. [PMID: 34963741 PMCID: PMC8661373 DOI: 10.3748/wjg.v27.i45.7784] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/22/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
The cell walls of plants are mainly made of cellulose and contain a large number of calories. However, the main component, cellulose, is an indigestible plant fiber that is thought to be difficult for humans to use as energy. Herbivores acquire energy through the degradation of cell wall-derived dietary fiber by microorganisms in the digestive tract. Herbivores, especially horses, have a highly developed cecum and large intestine, and plants are fermented for their efficient use with the help of microorganisms. Humans also have an intestinal tract with a wide lumen on the proximal side of the large intestine, in which fermentation occurs. The digestive process of horses is similar to that of humans, and many of the intestinal bacteria found in horses that degrade plants are also found in humans. Therefore, it is thought that humans also obtain a certain amount of energy from cell wall-derived dietary fiber. However, the intake of dietary fiber by modern humans is low; thus, the amount of calories derived from indigestible plant fiber is considered to be very low. Cellulose in the plant cell wall is often accompanied by hemicellulose, pectin, lignin, suberin, and other materials. These materials are hard to degrade, and cellulose is therefore difficult for animals to utilize. If the cell wall can be degraded to some extent by cooking, it is thought that humans can obtain calories from cell wall-derived dietary fiber. If humans can use the calories from the cell wall for their diet, it may compensate for human food shortages.
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Affiliation(s)
- Shunji Fujimori
- Department of Gastroenterology, Chiba Hokusoh Hospital, Nippon Medical School, Chiba 270-1694, Japan
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38
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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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Gut Microbiome Alteration after Reboxetine Administration in Type-1 Diabetic Rats. Microorganisms 2021; 9:microorganisms9091948. [PMID: 34576843 PMCID: PMC8465486 DOI: 10.3390/microorganisms9091948] [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: 06/30/2021] [Revised: 08/25/2021] [Accepted: 09/07/2021] [Indexed: 11/16/2022] Open
Abstract
Antidepressants are drugs commonly used in clinical settings. However, there are very limited studies on the effects of these drugs on the gut microbiota. Herein, we evaluated the effect of reboxetine (RBX), a selective norepinephrine (noradrenaline) reuptake inhibitor (NRI), on gut microbiota in both diabetic and non-diabetic rats. This is the first report of relation between reboxetine use and the gut microbiota to our knowledge. In this study, type-1 diabetes induced by using streptozotocin (STZ) and RBX was administered to diabetic rats and healthy controls for 14 days. At the end of the treatment, stool samples were collected. Following DNA extraction, amplicon libraries for the V3-V4 region were prepared and sequenced with the Illumina Miseq platform. QIIME was used for preprocessing and analysis of the data. As a result, RBX had a significant effect on gut microbiota structure and composition in diabetic and healthy rats. For example, RBX exposure had a pronounced microbial signature in both groups, with a low Firmicutes/Bacteroidetes ratio and low Lactobacillus levels. While another abundance phylum after exposure to RBX was Proteabacteria, other notable taxa in the diabetic group included Flavobacterium, Desulfovibrionaceae, Helicobacteriaceae, Campylobacterales, and Pasteurellacae when compared to the untreated group.
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40
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Zaky A, Glastras SJ, Wong MYW, Pollock CA, Saad S. The Role of the Gut Microbiome in Diabetes and Obesity-Related Kidney Disease. Int J Mol Sci 2021; 22:9641. [PMID: 34502562 PMCID: PMC8431784 DOI: 10.3390/ijms22179641] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetic kidney disease (DKD) is a progressive disorder, which is increasing globally in prevalence due to the increased incidence of obesity and diabetes mellitus. Despite optimal clinical management, a significant number of patients with diabetes develop DKD. Hence, hitherto unrecognized factors are likely to be involved in the initiation and progression of DKD. An extensive number of studies have demonstrated the role of microbiota in health and disease. Dysregulation in the microbiota resulting in a deficiency of short chain fatty acids (SCFAs) such as propionate, acetate, and butyrate, by-products of healthy gut microbiota metabolism, have been demonstrated in obesity, type 1 and type 2 diabetes. However, it is not clear to date whether such changes in the microbiota are causative or merely associated with the diseases. It is also not clear which microbiota have protective effects on humans. Few studies have investigated the centrality of reduced SCFA in DKD development and progression or the potential therapeutic effects of supplemental SCFAs on insulin resistance, inflammation, and metabolic changes. SCFA receptors are expressed in the kidneys, and emerging data have demonstrated that intestinal dysbiosis activates the renal renin-angiotensin system, which contributes to the development of DKD. In this review, we will summarize the complex relationship between the gut microbiota and the kidney, examine the evidence for the role of gut dysbiosis in diabetes and obesity-related kidney disease, and explore the mechanisms involved. In addition, we will describe the role of potential therapies that modulate the gut microbiota to prevent or reduce kidney disease progression.
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Affiliation(s)
- Amgad Zaky
- Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW 2065, Australia; (A.Z.); (S.J.G.); (M.Y.W.W.); (C.A.P.)
| | - Sarah J. Glastras
- Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW 2065, Australia; (A.Z.); (S.J.G.); (M.Y.W.W.); (C.A.P.)
- Royal North Shore Hospital, St. Leonards, NSW 2065, Australia
| | - May Y. W. Wong
- Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW 2065, Australia; (A.Z.); (S.J.G.); (M.Y.W.W.); (C.A.P.)
- Royal North Shore Hospital, St. Leonards, NSW 2065, Australia
| | - Carol A. Pollock
- Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW 2065, Australia; (A.Z.); (S.J.G.); (M.Y.W.W.); (C.A.P.)
- Royal North Shore Hospital, St. Leonards, NSW 2065, Australia
| | - Sonia Saad
- Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW 2065, Australia; (A.Z.); (S.J.G.); (M.Y.W.W.); (C.A.P.)
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Gurry T, Nguyen LTT, Yu X, Alm EJ. Functional heterogeneity in the fermentation capabilities of the healthy human gut microbiota. PLoS One 2021; 16:e0254004. [PMID: 34288919 PMCID: PMC8294568 DOI: 10.1371/journal.pone.0254004] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 06/17/2021] [Indexed: 12/12/2022] Open
Abstract
The human gut microbiota is known for its highly heterogeneous composition across different individuals. However, relatively little is known about functional differences in its ability to ferment complex polysaccharides. Through ex vivo measurements from healthy human donors, we show that individuals vary markedly in their microbial metabolic phenotypes (MMPs), mirroring differences in their microbiota composition, and resulting in the production of different quantities and proportions of Short Chain Fatty Acids (SCFAs) from the same inputs. We also show that aspects of these MMPs can be predicted from composition using 16S rRNA sequencing. From experiments performed using the same dietary fibers in vivo, we demonstrate that an ingested bolus of fiber is almost entirely consumed by the microbiota upon passage. We leverage our ex vivo data to construct a model of SCFA production and absorption in vivo, and argue that inter-individual differences in quantities of absorbed SCFA are directly related to differences in production. Though in vivo studies are required to confirm these data in the context of the gut, in addition to in vivo read outs of SCFAs produced in response to specific fiber spike-ins, these data suggest that optimizing SCFA production in a given individual through targeted fiber supplementation requires quantitative understanding of their MMP.
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Affiliation(s)
- Thomas Gurry
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States of America
- Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, United States of America
- The Broad Institute of MIT and Harvard, Cambridge, MA, United States of America
- Institute for Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland
| | - Le Thanh Tu Nguyen
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States of America
- Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, United States of America
- The Broad Institute of MIT and Harvard, Cambridge, MA, United States of America
| | - Xiaoqian Yu
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States of America
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, United States of America
| | - Eric J. Alm
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States of America
- Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, United States of America
- The Broad Institute of MIT and Harvard, Cambridge, MA, United States of America
- * E-mail:
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Fianchi F, Liguori A, Gasbarrini A, Grieco A, Miele L. Nonalcoholic Fatty Liver Disease (NAFLD) as Model of Gut-Liver Axis Interaction: From Pathophysiology to Potential Target of Treatment for Personalized Therapy. Int J Mol Sci 2021; 22:6485. [PMID: 34204274 PMCID: PMC8233936 DOI: 10.3390/ijms22126485] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 06/13/2021] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide, affecting both adults and children and will result, in the near future, as the leading cause of end-stage liver disease. Indeed, its prevalence is rapidly increasing, and NAFLD is becoming a major public health concern. For this reason, great efforts are needed to identify its pathogenetic factors and new therapeutic approaches. In the past decade, enormous advances understanding the gut-liver axis-the complex network of cross-talking between the gut, microbiome and liver through the portal circulation-have elucidated its role as one of the main actors in the pathogenesis of NAFLD. Indeed, evidence shows that gut microbiota is involved in the development and progression of liver steatosis, inflammation and fibrosis seen in the context of NAFLD, as well as in the process of hepatocarcinogenesis. As a result, gut microbiota is currently emerging as a non-invasive biomarker for the diagnosis of disease and for the assessment of its severity. Additionally, to its enormous diagnostic potential, gut microbiota is currently studied as a therapeutic target in NAFLD: several different approaches targeting the gut homeostasis such as antibiotics, prebiotics, probiotics, symbiotics, adsorbents, bariatric surgery and fecal microbiota transplantation are emerging as promising therapeutic options.
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Affiliation(s)
- Francesca Fianchi
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.F.); (A.L.); (A.G.); (A.G.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, 00168 Rome, Italy
| | - Antonio Liguori
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.F.); (A.L.); (A.G.); (A.G.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.F.); (A.L.); (A.G.); (A.G.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, 00168 Rome, Italy
| | - Antonio Grieco
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.F.); (A.L.); (A.G.); (A.G.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, 00168 Rome, Italy
| | - Luca Miele
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.F.); (A.L.); (A.G.); (A.G.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, 00168 Rome, Italy
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Olsson A, Gustavsen S, Nguyen TD, Nyman M, Langkilde AR, Hansen TH, Sellebjerg F, Oturai AB, Bach Søndergaard H. Serum Short-Chain Fatty Acids and Associations With Inflammation in Newly Diagnosed Patients With Multiple Sclerosis and Healthy Controls. Front Immunol 2021; 12:661493. [PMID: 34025661 PMCID: PMC8134701 DOI: 10.3389/fimmu.2021.661493] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/16/2021] [Indexed: 12/14/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic immune-mediated disease characterized by demyelination and neuroaxonal damage in the central nervous system. The etiology is complex and is still not fully understood. Accumulating evidence suggests that our gut microbiota and its metabolites influence the MS pathogenesis. Short-chain fatty acids (SCFAs), such as acetate, propionate and butyrate, are metabolites produced by gut microbiota through fermentation of indigestible carbohydrates. SCFAs and kynurenine metabolites have been shown to have important immunomodulatory properties, and propionate supplementation in MS patients has been associated with long-term clinical improvement. However, the underlying mechanisms of action and its importance in MS remain incompletely understood. We analyzed serum levels of SCFAs and performed targeted metabolomics in relation to biomarkers of inflammation, and clinical and MRI measures in newly diagnosed patients with relapsing-remitting MS before their first disease modifying therapy and healthy controls (HCs). We demonstrated that serum acetate levels were nominally reduced in MS patients compared with HCs. The ratios of acetate/butyrate and acetate/(propionate + butyrate) were significantly lower in MS patients in a multivariate analysis (orthogonal partial least squares discriminant analysis; OPLS-DA). The mentioned ratios and acetate levels correlated negatively with the pro-inflammatory biomarker IFNG, indicating an inverse relation between acetate and inflammation. In contrast, the proportion of butyrate was found higher in MS patients in the multivariate analysis, and both butyrate and valerate correlated positively with proinflammatory cytokines (IFNG and TNF), suggesting complex bidirectional regulatory properties of SCFAs. Branched SCFAs were inversely correlated with clinical disability, at a nominal significance level. Otherwise SCFAs did not correlate with clinical variables or MRI measures. There were signs of an alteration of the kynurenine pathway in MS, and butyrate was positively correlated with the immunomodulatory metabolite 3-hydroxyanthranilic acid. Other variables that influenced the separation between MS and HCs were NfL, ARG1 and IL1R1, D-ribose 5-phosphate, pantothenic acid and D-glucuronic acid. In conclusion, we provide novel results in this rapidly evolving field, emphasizing the complexity of the interactions between SCFAs and inflammation; therefore, further studies are required to clarify these issues before supplementation of SCFAs can be widely recommended.
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Affiliation(s)
- Anna Olsson
- Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark
| | - Stefan Gustavsen
- Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark
| | - Thao Duy Nguyen
- Department of Food Technology, Engineering and Nutrition, Kemicentrum, Lund University, Lund, Sweden
| | - Margareta Nyman
- Department of Food Technology, Engineering and Nutrition, Kemicentrum, Lund University, Lund, Sweden
| | - Annika R Langkilde
- Department of Radiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Tue H Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Finn Sellebjerg
- Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark
| | - Annette B Oturai
- Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark
| | - Helle Bach Søndergaard
- Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark
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44
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Gut Dysbiosis and Its Associations with Gut Microbiota-Derived Metabolites in Dogs with Myxomatous Mitral Valve Disease. mSystems 2021; 6:6/2/e00111-21. [PMID: 33879495 PMCID: PMC8546968 DOI: 10.1128/msystems.00111-21] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Gut dysbiosis and gut microbiota-derived metabolites, including bile acid (BA), short-chain fatty acid, and trimethylamine N-oxide (TMAO), are associated with cardiovascular disease. Canine myxomatous mitral valve disease (MMVD) is a model for human MMVD. The aim of the study is to evaluate gut microbial dysbiosis and its relationship with gut-produced metabolites in dogs with MMVD. Fecal samples from 92 privately owned dogs, including 17 healthy, 23 and 27 asymptomatic MMVD dogs without (stage B1) and with (stage B2) secondary cardiac enlargement, respectively, and 25 MMVD dogs with history of congestive heart failure (stage C or D), were analyzed by 16S rRNA sequencing. Alpha and beta diversities were different between healthy and MMVD dogs (adjusted P < 0.05). The average dysbiosis indexes were −1.48, −0.6, 0.01, and 1.47 for healthy, B1, B2, and C/D dogs, respectively (P = 0.07). Dysbiosis index was negatively correlated with Clostridium hiranonis (P < 0.0001, r = −0.79). Escherichia coli, capable of trimethylamine production in the gut, had an increased abundance (adjusted P < 0.05) and may be responsible for the increased circulating TMAO levels in stage B2 and C/D MMVD dogs. Primary and secondary BAs showed opposite associations with C. hiranonis, a key BA converter (P < 0.0001 for both, r = −0.94 and 0.95, respectively). Secondary BAs appeared to promote the growth of Fusobacterium and Faecalibacterium but inhibit that of E. coli. Multivariate analysis revealed significant but weak associations between gut microbiota and several circulating metabolites, including short-chain acylcarnitines and TMAO. IMPORTANCE Our study expands the current “gut hypothesis” to include gut dysbiosis at the preclinical stage, prior to the onset of heart failure. Gut dysbiosis index increases in proportion to the severity of myxomatous mitral valve disease (MMVD) and is inversely associated with Clostridium hiranonis, a key bile acid (BA) converter in the gut. Secondary BAs appear to promote the growth of beneficial bacteria but inhibit that of harmful ones. An intricate interplay between gut microbiota, gut microbiota-produced metabolites, and MMVD pathophysiological progression is implicated.
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45
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Withrow D, Bowers SJ, Depner CM, González A, Reynolds AC, Wright KP. Sleep and Circadian Disruption and the Gut Microbiome-Possible Links to Dysregulated Metabolism. CURRENT OPINION IN ENDOCRINE AND METABOLIC RESEARCH 2021; 17:26-37. [PMID: 34805616 PMCID: PMC8597978 DOI: 10.1016/j.coemr.2020.11.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Insufficient sleep and circadian misalignment are associated with adverse metabolic health outcomes. Alterations in gut microbial diversity occur with insufficient sleep and circadian misalignment, which can lead to modifications in microbial structure and function. Changes in microbially produced and modified metabolites such as short chain fatty acids and secondary bile acids may contribute to chronic inflammation, positive energy balance and endocrine changes, and represent potential mechanisms linking insufficient sleep and circadian misalignment with metabolic dysregulation. Literature primarily from the last two years is reviewed here, examining the impact of sleep and circadian rhythms and their disruption on the gut microbiome in human and non-human models, with an emphasis on the hypothesis that the altered gut microbiome may be one pathway by which insufficient sleep and circadian misalignment dysregulate metabolism.
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Affiliation(s)
- Dana Withrow
- Sleep and Chronobiology Laboratory, Department of Integrative Physiology, University of Colorado-Boulder, Boulder, CO, USA
| | - Samuel J. Bowers
- Center for Sleep and Circadian Biology, Northwestern University, Evanston, IL, USA
| | - Christopher M. Depner
- Sleep and Chronobiology Laboratory, Department of Integrative Physiology, University of Colorado-Boulder, Boulder, CO, USA
- Department of Health and Kinesiology, University of Utah, Salt Lake City, UT, USA
| | - Antonio González
- Department of Pediatrics, University of California at San Diego, La Jolla, CA, USA
| | - Amy C. Reynolds
- The Appleton Institute, CQUniversity Australia, Adelaide, Australia
| | - Kenneth P. Wright
- Sleep and Chronobiology Laboratory, Department of Integrative Physiology, University of Colorado-Boulder, Boulder, CO, USA
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46
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Vornhagen J, Bassis CM, Ramakrishnan S, Hein R, Mason S, Bergman Y, Sunshine N, Fan Y, Holmes CL, Timp W, Schatz MC, Young VB, Simner PJ, Bachman MA. A plasmid locus associated with Klebsiella clinical infections encodes a microbiome-dependent gut fitness factor. PLoS Pathog 2021; 17:e1009537. [PMID: 33930099 PMCID: PMC8115787 DOI: 10.1371/journal.ppat.1009537] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 05/12/2021] [Accepted: 04/07/2021] [Indexed: 02/07/2023] Open
Abstract
Klebsiella pneumoniae (Kp) is an important cause of healthcare-associated infections, which increases patient morbidity, mortality, and hospitalization costs. Gut colonization by Kp is consistently associated with subsequent Kp disease, and patients are predominantly infected with their colonizing strain. Our previous comparative genomics study, between disease-causing and asymptomatically colonizing Kp isolates, identified a plasmid-encoded tellurite (TeO3-2)-resistance (ter) operon as strongly associated with infection. However, TeO3-2 is extremely rare and toxic to humans. Thus, we used a multidisciplinary approach to determine the biological link between ter and Kp infection. First, we used a genomic and bioinformatic approach to extensively characterize Kp plasmids encoding the ter locus. These plasmids displayed substantial variation in plasmid incompatibility type and gene content. Moreover, the ter operon was genetically independent of other plasmid-encoded virulence and antibiotic resistance loci, both in our original patient cohort and in a large set (n = 88) of publicly available ter operon-encoding Kp plasmids, indicating that the ter operon is likely playing a direct, but yet undescribed role in Kp disease. Next, we employed multiple mouse models of infection and colonization to show that 1) the ter operon is dispensable during bacteremia, 2) the ter operon enhances fitness in the gut, 3) this phenotype is dependent on the colony of origin of mice, and 4) antibiotic disruption of the gut microbiota eliminates the requirement for ter. Furthermore, using 16S rRNA gene sequencing, we show that the ter operon enhances Kp fitness in the gut in the presence of specific indigenous microbiota, including those predicted to produce short chain fatty acids. Finally, administration of exogenous short-chain fatty acids in our mouse model of colonization was sufficient to reduce fitness of a ter mutant. These findings indicate that the ter operon, strongly associated with human infection, encodes factors that resist stress induced by the indigenous gut microbiota during colonization. This work represents a substantial advancement in our molecular understanding of Kp pathogenesis and gut colonization, directly relevant to Kp disease in healthcare settings.
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Affiliation(s)
- Jay Vornhagen
- Department of Pathology, University of Michigan, Ann Arbor, MI, United States of America
- Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI, United States of America
| | - Christine M. Bassis
- Department of Internal Medicine/Infectious Diseases Division, University of Michigan, Ann Arbor, MI, United States of America
| | - Srividya Ramakrishnan
- Department of Computer Science, Johns Hopkins University, Baltimore, MD, United States of America
| | - Robert Hein
- Department of Internal Medicine/Infectious Diseases Division, University of Michigan, Ann Arbor, MI, United States of America
| | - Sophia Mason
- Department of Pathology, University of Michigan, Ann Arbor, MI, United States of America
| | - Yehudit Bergman
- Division of Medical Microbiology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Nicole Sunshine
- Department of Pathology, University of Michigan, Ann Arbor, MI, United States of America
| | - Yunfan Fan
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States of America
| | - Caitlyn L. Holmes
- Department of Pathology, University of Michigan, Ann Arbor, MI, United States of America
- Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI, United States of America
| | - Winston Timp
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States of America
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
- Department of Medicine, Division of Infectious Disease, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Michael C. Schatz
- Department of Computer Science, Johns Hopkins University, Baltimore, MD, United States of America
- Department of Biology, Johns Hopkins University, Baltimore, MD, United States of America
- Simons Center for Quantitative Biology, Cold Spring Harbor, NY, United States of America
| | - Vincent B. Young
- Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI, United States of America
- Department of Internal Medicine/Infectious Diseases Division, University of Michigan, Ann Arbor, MI, United States of America
| | - Patricia J. Simner
- Division of Medical Microbiology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Michael A. Bachman
- Department of Pathology, University of Michigan, Ann Arbor, MI, United States of America
- Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI, United States of America
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47
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Untargeted fecal metabolomics revealed biochemical mechanisms of the blood lipid-lowering effect of koumiss treatment in patients with hyperlipidemia. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104355] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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48
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Yip W, Hughes MR, Li Y, Cait A, Hirst M, Mohn WW, McNagny KM. Butyrate Shapes Immune Cell Fate and Function in Allergic Asthma. Front Immunol 2021; 12:628453. [PMID: 33659009 PMCID: PMC7917140 DOI: 10.3389/fimmu.2021.628453] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 01/25/2021] [Indexed: 12/19/2022] Open
Abstract
The microbiome plays a fundamental role in how the immune system develops and how inflammatory responses are shaped and regulated. The “gut-lung axis” is a relatively new term that highlights a crucial biological crosstalk between the intestinal microbiome and lung. A growing body of literature suggests that dysbiosis, perturbation of the gut microbiome, is a driving force behind the development, and severity of allergic asthma. Animal models have given researchers new insights into how gut microbe-derived components and metabolites, such as short-chain fatty acids (SCFAs), influence the development of asthma. While the full understanding of how SCFAs influence allergic airway disease remains obscure, a recurring theme of epigenetic regulation of gene expression in several immune cell compartments is emerging. This review will address our current understanding of how SCFAs, and specifically butyrate, orchestrates cell behavior, and epigenetic changes and will provide a detailed overview of the effects of these modifications on immune cells in the context of allergic airway disease.
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Affiliation(s)
- William Yip
- School of Biomedical Engineering, The University of British Columbia, Vancouver, BC, Canada.,The Biomedical Research Centre, The University of British Columbia, Vancouver, BC, Canada
| | - Michael R Hughes
- School of Biomedical Engineering, The University of British Columbia, Vancouver, BC, Canada.,The Biomedical Research Centre, The University of British Columbia, Vancouver, BC, Canada
| | - Yicong Li
- The Biomedical Research Centre, The University of British Columbia, Vancouver, BC, Canada
| | - Alissa Cait
- Life Sciences Institute, The University of British Columbia, Vancouver, BC, Canada.,Department of Microbiology and Immunology, The University of British Columbia, Vancouver, BC, Canada
| | - Martin Hirst
- Department of Microbiology and Immunology, The University of British Columbia, Vancouver, BC, Canada.,Michael Smith Laboratories, The University of British Columbia, Vancouver, BC, Canada
| | - William W Mohn
- Life Sciences Institute, The University of British Columbia, Vancouver, BC, Canada.,Department of Microbiology and Immunology, The University of British Columbia, Vancouver, BC, Canada
| | - Kelly M McNagny
- School of Biomedical Engineering, The University of British Columbia, Vancouver, BC, Canada.,The Biomedical Research Centre, The University of British Columbia, Vancouver, BC, Canada.,Department of Medical Genetics, The University of British Columbia, Vancouver, BC, Canada
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49
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Nogal A, Valdes AM, Menni C. The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health. Gut Microbes 2021; 13:1-24. [PMID: 33764858 PMCID: PMC8007165 DOI: 10.1080/19490976.2021.1897212] [Citation(s) in RCA: 413] [Impact Index Per Article: 103.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/29/2021] [Accepted: 02/15/2021] [Indexed: 02/04/2023] Open
Abstract
The gut microbiota plays an important role in cardio-metabolic diseases with diet being among the strongest modulators of gut microbiota composition and function. Resistant dietary carbohydrates are fermented to short-chain fatty acids (SCFAs) by the gut bacteria. Fiber and omega-3 rich diets increase SCFAs production and abundance of SCFA-producing bacteria. Likewise, SCFAs can improve gut barrier integrity, glucose, and lipid metabolism, regulate the immune system, the inflammatory response, and blood pressure. Therefore, targeting the gut microbiota with dietary strategies leading to increased SCFA production may benefit cardio-metabolic health. In this review, we provide an overview of the association between diet, SCFAs produced by the gut microbiota and cardio-metabolic diseases. We first discuss the association between the human gut microbiota and cardio-metabolic diseases, then investigate the role of SCFAs and finally explore the beneficial effects of specific dietary interventions that can improve cardio-metabolic outcomes through boosting the SCFA production.
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Affiliation(s)
- Ana Nogal
- Department of Twin Research, King’s College London, St Thomas’ Hospital Campus, London, UK
| | - Ana M. Valdes
- Department of Twin Research, King’s College London, St Thomas’ Hospital Campus, London, UK
- School of Medicine, Nottingham City Hospital, Nottingham, UK
- NIHR Nottingham Biomedical Research Centre, Nottingham, UK
| | - Cristina Menni
- Department of Twin Research, King’s College London, St Thomas’ Hospital Campus, London, UK
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50
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Bai J, Li Y, Zhang W, Fan M, Qian H, Zhang H, Qi X, Wang L. Effects of cereal fibers on short-chain fatty acids in healthy subjects and patients: a meta-analysis of randomized clinical trials. Food Funct 2021; 12:7040-7053. [PMID: 34152334 DOI: 10.1039/d1fo00858g] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Short-chain fatty acids (SCFAs) are involved in the regulation of a wide array of diseases. However, the effect of cereal dietary fibers on SCFA production remains unclear. We reviewed relevant clinical studies between 1950 and 2021 and aimed to evaluate the effect of cereal fiber consumption on SCFA production in healthy subjects and patients. PubMed, Web of Science, and the Cochrane Library databases were used for systematically searching published relevant trials with adults and a minimum intervention duration of 2 weeks. The effect size was estimated using standardized mean difference (SMD) and 95% confidence interval (CI). Of the 555 identified studies, 14 intervention groups involving 205 participants aged between 20 and 69 years are eligible. The results of meta-analysis revealed that cereal fiber supplementation significantly increased acetate [SMD: 0.86, 95% CI (0.46, 1.25), p < 0.0001], propionate [SMD: 0.48, 95% CI: (0.15, 0.81), p = 0.004], butyrate [SMD: 0.61, 95% CI: (0.20, 1.01), p = 0.003], and total SCFA [SMD, 0.96, 95% CI: (0.54, 1.39), p < 0.00001] concentrations. Subgroup analysis suggested that a long intervention duration (>4 weeks) significantly promoted acetate and propionate production, whereas a short intervention duration (≤4 weeks) significantly facilitated butyrate production. Cereal fiber supplementation had a more significant impact on overweight and obese subjects with body mass index (BMI) >29 kg m-2 than on individuals with BMI ≤29 kg m-2. Furthermore, we found that cereal fibers and wheat/rye arabinoxylan oligosaccharides, rather than wheat bran fibers, barley fibers, and barley β-glucan, could significantly elevate the SCFA concentration. Overall, our meta-analysis demonstrated that cereal fiber supplementation is helpful in increasing the SCFA concentration, which provided strong proof for the beneficial role of cereal fibers.
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Affiliation(s)
- Junying Bai
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
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