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Yang J, Guo M, Wu J, Li F, Xu S, Wang J, Wu F. Assessment of cardiotoxicity induced by PFOS exposure and mechanism research via untarget metabolomics. Drug Chem Toxicol 2025; 48:303-313. [PMID: 39113645 DOI: 10.1080/01480545.2024.2387807] [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: 12/13/2023] [Revised: 07/21/2024] [Accepted: 07/29/2024] [Indexed: 02/25/2025]
Abstract
Perfluorooctane sulfonate (PFOS), widely used in various industrial and commercial materials, can accumulate in the human body due to its high environmental stability, and thus potentially has cardiotoxicity. We assess cardiotoxicity through rat exposure to PFOS by intraperitoneal injection. Untargeted metabolomic analysis was used to explore the potential cardiotoxicity mechanism of PFOS. In vivo, PFOS exposure increases pro-inflammatory factors TNF-α and IL-1β and decreases anti-inflammatory factors IL-10 and TGF-β. PFOS exposure causes pathological changes in cardiac tissue and increases cardiac injury markers brain natriuretic peptide (BNP), lactate dehydrogenase (LDH), C-reactive protein (CRP) in serum and triglyceride (TG), total cholesterol (TC) and ox-LDL in plasma. Increased expression of plasminogen activator inhibitor-1 (PAI-1) and CD36 indicates that PFOS exacerbates cardiac fibrosis. Untargeted metabolites analysis revealed 414 small molecule metabolites and 33 metabolites that differed after PFOS exposure, and identified 3 potential metabolic pathways. In conclusion, our study shows the inflammatory reactions involved in PFOS cardiotoxicity, and identifies potential pathways and differential metabolites involved in PFOS toxicity.
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Affiliation(s)
- Jie Yang
- Department of Cardiology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou City, Zhejiang, China
| | - Ming Guo
- Department of Cardiology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou City, Zhejiang, China
| | - Jijun Wu
- Department of Cardiology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou City, Zhejiang, China
| | - Fuling Li
- Department of Cardiology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou City, Zhejiang, China
| | - Shimeng Xu
- Department of Cardiology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou City, Zhejiang, China
| | - Jialin Wang
- Department of Cardiology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou City, Zhejiang, China
| | - Feifei Wu
- Department of Cardiology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou City, Zhejiang, China
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Kabisch S, Hajir J, Sukhobaevskaia V, Weickert MO, Pfeiffer AFH. Impact of Dietary Fiber on Inflammation in Humans. Int J Mol Sci 2025; 26:2000. [PMID: 40076626 PMCID: PMC11900212 DOI: 10.3390/ijms26052000] [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: 01/06/2025] [Revised: 02/17/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Cohort studies consistently show that a high intake of cereal fiber and whole-grain products is associated with a decreased risk of type 2 diabetes (T2DM), cancer, and cardiovascular diseases. Similar findings are also reported for infectious and chronic inflammatory disorders. All these disorders are at least partially caused by inflammaging, a chronic state of inflammation associated with aging and Metabolic Syndrome. Surprisingly, insoluble (cereal) fiber intake consistently shows stronger protective associations with most long-term health outcomes than soluble fiber. Most humans consume soluble fiber mainly from sweet fruits, which usually come with high levels of sugar, counteracting the potentially beneficial effects of fiber. In both observational and interventional studies, high-fiber diets show a beneficial impact on inflammation, which can be attributed to a variety of nutrients apart from dietary fiber. These confounders need to be considered when evaluating the effects of fiber as part of complex dietary patterns. When assessing specific types of fiber, inulin and resistant starch clearly elicit anti-inflammatory short-term effects, while results for pectins, beta-glucans, or psyllium turn out to be less convincing. For insoluble fiber, promising but sparse data have been published so far. Hypotheses on putative mechanisms of anti-inflammatory fiber effects include a direct impact on immune cells (e.g., for pectin), fermentation to pleiotropic short-chain fatty acids (for fermentable fiber only), modulation of the gut microbiome towards higher levels of diversity, changes in bile acid metabolism, a differential release of gut hormones (such as the glucose-dependent insulinotropic peptide (GIP)), and an improvement of insulin resistance via the mTOR/S6K1 signaling cascade. Moreover, the contribution of phytate-mediated antioxidative and immune-modulatory means of action needs to be considered. In this review, we summarize the present knowledge on the impact of fiber-rich diets and dietary fiber on the human inflammatory system. However, given the huge heterogeneity of study designs, cohorts, interventions, and outcomes, definite conclusions on which fiber to recommend to whom cannot yet be drawn.
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Affiliation(s)
- Stefan Kabisch
- Department of Endocrinology and Metabolism, Campus Benjamin Franklin, Charité University Medicine, Hindenburgdamm 30, 12203 Berlin, Germany
- Deutsches Zentrum für Diabetesforschung e.V., Geschäftsstelle am Helmholtz-Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
| | - Jasmin Hajir
- Department of Endocrinology and Metabolism, Campus Benjamin Franklin, Charité University Medicine, Hindenburgdamm 30, 12203 Berlin, Germany
- Deutsches Zentrum für Diabetesforschung e.V., Geschäftsstelle am Helmholtz-Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
| | - Varvara Sukhobaevskaia
- Department of Endocrinology and Metabolism, Campus Benjamin Franklin, Charité University Medicine, Hindenburgdamm 30, 12203 Berlin, Germany
- Deutsches Zentrum für Diabetesforschung e.V., Geschäftsstelle am Helmholtz-Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
| | - Martin O. Weickert
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism; The ARDEN NET Centre, ENETS CoE; University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Centre of Applied Biological & Exercise Sciences (ABES), Faculty of Health & Life Sciences, Coventry University, Coventry CV1 5FB, UK
- Translational & Experimental Medicine, Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Andreas F. H. Pfeiffer
- Department of Endocrinology and Metabolism, Campus Benjamin Franklin, Charité University Medicine, Hindenburgdamm 30, 12203 Berlin, Germany
- Deutsches Zentrum für Diabetesforschung e.V., Geschäftsstelle am Helmholtz-Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
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Michalopoulou E, Thymis J, Lampsas S, Pavlidis G, Katogiannis K, Vlachomitros D, Katsanaki E, Kostelli G, Pililis S, Pliouta L, Kountouri A, Papanikolaou IS, Lambadiari V, Ikonomidis I. The Triad of Risk: Linking MASLD, Cardiovascular Disease and Type 2 Diabetes; From Pathophysiology to Treatment. J Clin Med 2025; 14:428. [PMID: 39860434 PMCID: PMC11765821 DOI: 10.3390/jcm14020428] [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: 11/29/2024] [Revised: 12/30/2024] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health concern, and it is not only the keystone precursor of eventual liver-related morbidity, but it also places patients at considerably higher cardiovascular risk, which is still a leading cause of death in these patients. The most important common underlying pathophysiological mechanisms in these diseases are primarily related to insulin resistance, chronic inflammation and oxidative stress. The presence of MASLD with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) elevates the risk for poor outcomes, thus this review highlights a method to the therapeutic approaches. Given the intertwined nature of MASLD, T2DM, and CVD, there is an urgent need for therapeutic strategies that address all three conditions. Although lifestyle changes are important as treatment, medication plays a crucial role in managing hyperglycemia, enhancing liver function and lowering cardiovascular risk. The onset and progression of MASLD should be addressed through a multifaceted therapeutic approach, targeting inflammatory, immune, metabolic, oxidative stress, hormonal and gutaxis pathways, alongside the treatment strategies for T2DM. In this review, we discuss the effects of antidiabetic drugs with an impact on both liver outcomes and cardiovascular risk in patients affected by MASLD, T2DM and CDV.
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Affiliation(s)
- Eleni Michalopoulou
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - John Thymis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Stamatios Lampsas
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - George Pavlidis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Konstantinos Katogiannis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Dimitrios Vlachomitros
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Eleni Katsanaki
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Gavriella Kostelli
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Sotirios Pililis
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Loukia Pliouta
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Aikaterini Kountouri
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Ioannis S. Papanikolaou
- Hepatogastroenterology Unit, Second Department of Internal Medicine-Propaedeutic, Attikon University Hospital, Rimini 1, Chaidari, 12462 Athens, Greece;
| | - Vaia Lambadiari
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Ignatios Ikonomidis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
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Parisse S, Carnevale S, Damato E, Ferri F, Mischitelli M, Corona M, Lucatelli P, Cantafora A, De Santis A, Alvaro D, Muscaritoli M, Ginanni Corradini S. Effect of Daily Fiber Intake Among Cirrhotic Patients With and Without Portosystemic Shunts. Curr Dev Nutr 2025; 9:104527. [PMID: 39896732 PMCID: PMC11787017 DOI: 10.1016/j.cdnut.2024.104527] [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: 05/17/2024] [Revised: 11/18/2024] [Accepted: 12/11/2024] [Indexed: 02/04/2025] Open
Abstract
Background A diet rich in fiber, especially soluble fiber, causes cholestatic liver damage and fibrosis in animal models with intestinal dysbiosis, high serum bile acid concentrations, and congenital portosystemic shunts (PSs), but no data on patients with cirrhosis (CIRs) are available. Objectives To investigate whether dietary fiber consumption was associated with clinical outcomes of CIRs and whether their effect differed according to the presence of PSs. Methods Daily soluble and insoluble fiber intake was extrapolated from 3-d food diaries in 25 patients with chronic hepatitis (CH) and 80 CIRs outpatient liver transplant candidates abstinent from alcohol and nonviremic for ≥6 mo. In CIRs, the presence of PSs was verified by computed tomography, and the model for end-stage liver disease (MELD) score was calculated at enrollment and after 6 mo. Results PSs were present in 48 (60%) CIRs. The MELD score after 6 mo, compared with enrollment, had improved in 19 and 10 CIRs with and without PSs, respectively. By adjusting for confounders in logistic regression models we found that improvement in MELD over time was inversely associated with insoluble fiber consumption expressed in milligrams per kilogram (mg/kg) body weight in CIRs without PSs [odds ratio (OR): 0.968; 95% confidence interval (CI): 0.939, 0.997; P = 0.005] but with soluble fiber consumption in CIRs with PSs [OR: 0.946; 95% CI: 0.912, 0.982; P = 0.001]. In CIRs with PSs, soluble fiber consumption was inversely associated with normal serum alkaline phosphatase values at enrollment [OR: 0.964; 95% CI: 0.963, 0.993; P = 0.010]. CHs with normal serum alanine transaminase consumed significantly more soluble fiber (p=0.015) than those with abnormal alanine transaminase. Conclusions The clinical impact of dietary fiber changes from beneficial to harmful as the stage of chronic liver disease progresses. In particular, in the advanced cirrhosis stage with PSs, soluble fiber intake appears to significantly influence disease progression and should be kept low.
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Affiliation(s)
- Simona Parisse
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Elio Damato
- Department of Radiological, Oncological and Anatomopathological Sciences, Sapienza University of Rome, Rome, Italy
| | - Flaminia Ferri
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Monica Mischitelli
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Mario Corona
- Department of Radiological, Oncological and Anatomopathological Sciences, Sapienza University of Rome, Rome, Italy
| | - Pierleone Lucatelli
- Department of Radiological, Oncological and Anatomopathological Sciences, Sapienza University of Rome, Rome, Italy
| | - Alfredo Cantafora
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Adriano De Santis
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Maurizio Muscaritoli
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
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Lei P, Li X, Jiang L, Yu H, Zhang P, Han L, Jiang M. Alisma plantago-aquatica polysaccharides ameliorate acetaminophen-induced acute liver injury by regulating hepatic metabolic profiles and modulating gut microbiota. Int J Biol Macromol 2024; 285:138345. [PMID: 39631232 DOI: 10.1016/j.ijbiomac.2024.138345] [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: 03/14/2024] [Revised: 11/21/2024] [Accepted: 12/02/2024] [Indexed: 12/07/2024]
Abstract
Acetaminophen (APAP) has emerged as a predominant contributor to acute liver failure (ALF) in United States. Alismatis rhizoma, a commonly used traditional herbal medicine, contains small molecular components with extensive hepatoprotective activity. However, the specific role of Alismatis rhizoma polysaccharide (ARP) in liver protection remains unclear. ARP50 and ARP70, derived through graded alcohol precipitation and refinement, predominantly consisted of varying proportions of glucose, galactose, and arabinose. In vitro experiments on free radical scavenging demonstrated notable antioxidant capabilities of ARP50 and ARP70. To investigate the hepatoprotective effects, an APAP-induced acute liver injury (ALI) model was established in mice. ARP50 and ARP70 exerted dose-dependent therapeutic effects on APAP-induced liver injury. Further analysis of liver metabolites revealed that ARPs facilitated the reconstruction of the liver antioxidant system by modulating the metabolism network centered on l-glutamine. In addition, the abundance of gut microbiota was altered under the influence of ARPs. ARP50 significantly reduced the levels of Pseudarthrobacter and markedly increased the levels of Faecalibacterium，At the same time, ARP50 could increase the levels of acetic acid in the liver and serum. Meanwhile, ARP70 significantly increased the abundance of Dubosiella, Muribaculum, Ileibacterium, and Prevotellaceae UCG 001, while reducing the abundance of Escherichia Shigella and Pseudarthrobacter. The results indicated that ARPs could exert a protective effect against APAP-induced acute liver injury by reshaping the liver metabolic profile and modulating the gut microbiota.
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Affiliation(s)
- Peng Lei
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaoge Li
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Lei Jiang
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Heshui Yu
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Peng Zhang
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Lifeng Han
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Miaomiao Jiang
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin, China.
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Ataollahi Eshkoor S, Fanijavadi S. Dysbiosis-epigenetics-immune system interaction and ageing health problems. J Med Microbiol 2024; 73. [PMID: 39606883 DOI: 10.1099/jmm.0.001921] [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: 11/29/2024] Open
Abstract
Background. The growing interest in microbiota-epigenetics-immune system research stems from the understanding that microbiota, a group of micro-organisms colonized in the human body, can influence the gene expression through epigenetic mechanisms and interaction with the immune system. Epigenetics refers to changes in gene activity that are not caused by the alteration in the DNA sequence itself.Discussion. The clinical significance of this research lies in the potential to develop new therapies for diseases linked to the imbalance of these microbial species (dysbiosis), such as cancer and neurodegenerative diseases. The intricate interaction between microbiota and epigenetics involves the production of metabolites and signalling molecules that can impact our health by influencing immune responses, metabolism and inflammation. Understanding these interactions could lead to novel therapeutic strategies targeting microbiota-epigenetic pathways to improve health outcomes.Conclusion. In this context, we aim to review and emphasize the current knowledge and key concepts that link the microbiota to epigenetics and immune system function, exploring their relevance to the development and maintenance of homeostasis and susceptibility to different diseases later in life. We aim to elucidate key concepts concerning the interactions and potential effects among the human gut microbiota, epigenetics, the immune system and ageing diseases linked to dysbiosis.
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Kwan SY, Sabotta CM, Cruz LR, Wong MC, Ajami NJ, McCormick JB, Fisher-Hoch SP, Beretta L. Gut phageome in Mexican Americans: a population at high risk for metabolic dysfunction-associated steatotic liver disease and diabetes. mSystems 2024; 9:e0043424. [PMID: 39166873 PMCID: PMC11406975 DOI: 10.1128/msystems.00434-24] [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: 03/25/2024] [Accepted: 07/19/2024] [Indexed: 08/23/2024] Open
Abstract
Mexican Americans are disproportionally affected by metabolic dysfunction-associated steatotic liver disease (MASLD), which often co-occurs with diabetes. Despite extensive evidence on the causative role of the gut microbiome in MASLD, studies determining the involvement of the gut phageome are scarce. In this cross-sectional study, we characterized the gut phageome in Mexican Americans of South Texas by stool shotgun metagenomic sequencing of 340 subjects, concurrently screened for liver steatosis by transient elastography. Inter-individual variations in the phageome were associated with gender, country of birth, diabetes, and liver steatosis. The phage signatures for diabetes and liver steatosis were subsequently determined. Enrichment of Inoviridae was associated with both diabetes and liver steatosis. Diabetes was further associated with the enrichment of predominantly temperate Escherichia phages, some of which possessed virulence factors. Liver steatosis was associated with the depletion of Lactococcus phages r1t and BK5-T, and enrichment of the globally prevalent Crassvirales phages, including members of genus cluster IX (Burzaovirus coli, Burzaovirus faecalis) and VI (Kahnovirus oralis). The Lactococcus phages showed strong correlations and co-occurrence with Lactococcus lactis, while the Crassvirales phages, B. coli, B. faecalis, and UAG-readthrough crAss clade correlated and co-occurred with Prevotella copri. In conclusion, we identified the gut phageome signatures for two closely linked metabolic diseases with significant global burden. These phage signatures may have utility in risk modeling and disease prevention in this high-risk population, and identification of potential bacterial targets for phage therapy.IMPORTANCEPhages influence human health and disease by shaping the gut bacterial community. Using stool samples from a high-risk Mexican American population, we provide insights into the gut phageome changes associated with diabetes and liver steatosis, two closely linked metabolic diseases with significant global burden. Common to both diseases was an enrichment of Inoviridae, a group of phages that infect bacterial hosts chronically without lysis, allowing them to significantly influence bacterial growth, virulence, motility, biofilm formation, and horizontal gene transfer. Diabetes was additionally associated with the enrichment of Escherichia coli-infecting phages, some of which contained virulence factors. Liver steatosis was additionally associated with the depletion of Lactococcus lactis-infecting phages, and enrichment of Crassvirales phages, a group of virulent phages with high global prevalence and persistence across generations. These phageome signatures may have utility in risk modeling, as well as identify potential bacterial targets for phage therapy.
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Affiliation(s)
- Suet-Ying Kwan
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Caroline M. Sabotta
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Lorenzo R. Cruz
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Matthew C. Wong
- The Platform for Innovative Microbiome and Translational Research (PRIME-TR), Moon Shots Program, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Nadim J. Ajami
- The Platform for Innovative Microbiome and Translational Research (PRIME-TR), Moon Shots Program, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Joseph B. McCormick
- School of Public Health, University of Texas Health Science Center at Houston, Brownsville Regional Campus, Brownsville, Texas, USA
| | - Susan P. Fisher-Hoch
- School of Public Health, University of Texas Health Science Center at Houston, Brownsville Regional Campus, Brownsville, Texas, USA
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Mei EH, Yao C, Chen YN, Nan SX, Qi SC. Multifunctional role of oral bacteria in the progression of non-alcoholic fatty liver disease. World J Hepatol 2024; 16:688-702. [PMID: 38818294 PMCID: PMC11135273 DOI: 10.4254/wjh.v16.i5.688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 02/26/2024] [Accepted: 04/07/2024] [Indexed: 05/22/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders of varying severity, ultimately leading to fibrosis. This spectrum primarily consists of NAFL and non-alcoholic steatohepatitis. The pathogenesis of NAFLD is closely associated with disturbances in the gut microbiota and impairment of the intestinal barrier. Non-gut commensal flora, particularly bacteria, play a pivotal role in the progression of NAFLD. Notably, Porphyromonas gingivalis, a principal bacterium involved in periodontitis, is known to facilitate lipid accumulation, augment immune responses, and induce insulin resistance, thereby exacerbating fibrosis in cases of periodontitis-associated NAFLD. The influence of oral microbiota on NAFLD via the "oral-gut-liver" axis is gaining recognition, offering a novel perspective for NAFLD management through microbial imbalance correction. This review endeavors to encapsulate the intricate roles of oral bacteria in NAFLD and explore underlying mechanisms, emphasizing microbial control strategies as a viable therapeutic avenue for NAFLD.
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Affiliation(s)
- En-Hua Mei
- Shanghai Medical College, Fudan University, Shanghai 200000, China
- Department of Prothodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200000, China
- Shanghai Key Laboratory of Craniomaxiofacial Development and Diseases, Fudan University, Shanghai 200000, China
| | - Chao Yao
- Department of Prothodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200000, China
- Shanghai Key Laboratory of Craniomaxiofacial Development and Diseases, Fudan University, Shanghai 200000, China
| | - Yi-Nan Chen
- Shanghai Medical College, Fudan University, Shanghai 200000, China
| | - Shun-Xue Nan
- Shanghai Medical College, Fudan University, Shanghai 200000, China
| | - Sheng-Cai Qi
- Department of Prothodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200000, China
- Shanghai Key Laboratory of Craniomaxiofacial Development and Diseases, Fudan University, Shanghai 200000, China.
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Ming Z, Ruishi X, Linyi X, Yonggang Y, Haoming L, Xintian L. The gut-liver axis in fatty liver disease: role played by natural products. Front Pharmacol 2024; 15:1365294. [PMID: 38686320 PMCID: PMC11056694 DOI: 10.3389/fphar.2024.1365294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 02/01/2024] [Indexed: 05/02/2024] Open
Abstract
Fatty liver disease, a condition characterized by fatty degeneration of the liver, mainly classified as non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD), has become a leading cause of cirrhosis, liver cancer and death. The gut-liver axis is the bidirectional relationship between the gut and its microbiota and its liver. The liver can communicate with the gut through the bile ducts, while the portal vein transports the products of the gut flora to the liver. The intestinal flora and its metabolites directly and indirectly regulate hepatic gene expression, leading to an imbalance in the gut-liver axis and thus contributing to the development of liver disease. Utilizing natural products for the prevention and treatment of various metabolic diseases is a prevalent practice, and it is anticipated to represent the forthcoming trend in the development of drugs for combating NAFLD/ALD. This paper discusses the mechanism of the enterohepatic axis in fatty liver, summarizes the important role of plant metabolites in natural products in fatty liver treatment by regulating the enterohepatic axis, and provides a theoretical basis for the subsequent development of new drugs and clinical research.
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Affiliation(s)
- Zhu Ming
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Xie Ruishi
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Xu Linyi
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | | | - Luo Haoming
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Lan Xintian
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
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10
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Han J, Wu P, Xu Z, Liu C, Chen Q, Zhang F, Tao H, Luo D, Zhou L, Wang B, Gao Z, Shen T, Wen Y, Yu H. The anti-cholestatic effects of Coptis chinensis Franch. alone and combined with Tetradium ruticarpum (A. Jussieu) T. G. Hartley: dual effects on fecal metabolism and microbial diversity. Front Pharmacol 2024; 15:1372527. [PMID: 38523644 PMCID: PMC10957555 DOI: 10.3389/fphar.2024.1372527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 02/16/2024] [Indexed: 03/26/2024] Open
Abstract
Introduction: Drug dosages and combinations are the main factors that affect the efficacy of pleiotropic traditional Chinese medicine (TCM). Coptis chinensis Franch. (CF) is a representative TCM with multiple effects and is often combined with Tetradium ruticarpum (A. Jussieu) T. G. Hartley (TR) to treat cholestasis. The present study assessed the influence of CF dose and its combination with TR on the efficacy of CF in cholestasis treatment, including their effects on fecal metabolism and fecal microorganisms. Methods: Rats with α-naphthylisothiocyanate (ANIT, 50 mg/kg)-induced cholestasis were administered low (0.3 g/kg) and high (0.6 g/kg) doses of CF, as well as CF combined with TR at doses of 0.6 g/kg and 0.9 g/kg, respectively. The anti-cholestatic effects of these treatments were assessed by determining their anti-inflammatory, hypolipidemic, and anti-oxidative stress properties. Additionally, fecal metabolomics and fecal microorganisms were analyzed. Results: Low dose CF had a more potent hypolipidemic effect than high dose CF, whereas high dose CF had more potent anti-inflammatory and anti-oxidative stress effects. Combination with TR enhanced the hypolipidemic effect, but antagonized the anti-inflammatory effect, of CF. Analyses of fecal metabolomics and fecal microorganisms showed differences in the regulation of lipid- and amino acid metabolism-related pathways, including pathways of linoleic acid, tyrosine, and arachidonic acid metabolism, and amino acid biosynthesis between different doses of CF as well as between different doses of CF in combination with TR. These differences may contribute to differences in the anti-cholestatic effects of these preparations. Conclusion: CF dose influences its anti-cholestatic efficacy. The combination with TR had synergistic or antagonistic effects on the properties of CF, perhaps by altering fecal metabolism and fecal microbial homeostasis.
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Affiliation(s)
- Jun Han
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Peijie Wu
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zongying Xu
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chao Liu
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qian Chen
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fenghua Zhang
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Huan Tao
- Cangxi Traditional Chinese Medicine Hospital, Guangyuan, China
| | - Dan Luo
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Zhou
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Bo Wang
- School of Medicine and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhe Gao
- School of Medicine and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tao Shen
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yueqiang Wen
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Han Yu
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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11
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Groenen C, Nguyen TA, Paulusma C, van de Graaf S. Bile salt signaling and bile salt-based therapies in cardiometabolic disease. Clin Sci (Lond) 2024; 138:1-21. [PMID: 38180064 PMCID: PMC10767275 DOI: 10.1042/cs20230934] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 11/23/2023] [Accepted: 12/05/2023] [Indexed: 01/06/2024]
Abstract
Bile salts have an established role in the emulsification and intestinal absorption of dietary lipids, and their homeostasis is tightly controlled by various transporters and regulators in the enterohepatic circulation. Notably, emerging evidence points toward bile salts as major modulators of cardiometabolic disease (CMD), an umbrella disease of disorders affecting the heart and blood vessels that is caused by systemic metabolic diseases such as Type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD), the latter encompassing also metabolic dysfunction-associated steatohepatitis (MASH). The underlying mechanisms of protective effects of bile salts are their hormonal properties, enabling them to exert versatile metabolic effects by activating various bile salt-responsive signaling receptors with the nuclear farnesoid X receptor (FXR) and the Takeda G-protein-coupled receptor 5 (TGR5) as most extensively investigated. Activation of FXR and TGR5 is involved in the regulation of glucose, lipid and energy metabolism, and inflammation. Bile salt-based therapies directly targeting FXR and TGR5 signaling have been evaluated for their therapeutic potential in CMD. More recently, therapeutics targeting bile salt transporters thereby modulating bile salt localization, dynamics, and signaling, have been developed and evaluated in CMD. Here, we discuss the current knowledge on the contribution of bile salt signaling in the pathogenesis of CMD and the potential of bile salt-based therapies for the treatment of CMD.
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Affiliation(s)
- Claire C.J. Groenen
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Centers, The Netherlands
| | - Thuc-Anh Nguyen
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Centers, The Netherlands
| | - Coen C. Paulusma
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Centers, The Netherlands
| | - Stan F.J. van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Centers, The Netherlands
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12
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Wang W, Fan Z, Yan Q, Pan T, Luo J, Wei Y, Li B, Fang Z, Lu W. Gut microbiota determines the fate of dietary fiber-targeted interventions in host health. Gut Microbes 2024; 16:2416915. [PMID: 39418223 PMCID: PMC11487953 DOI: 10.1080/19490976.2024.2416915] [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: 04/07/2024] [Revised: 07/04/2024] [Accepted: 10/10/2024] [Indexed: 10/19/2024] Open
Abstract
Epidemiological investigation confirmed that the intake of dietary fiber (DF) is closely related to human health, and the most important factor affecting the physiological function of DF, besides its physicochemical properties, is the gut microbiota. This paper mainly summarizes the interaction between DF and gut microbiota, including the influence of DF on the colonization of gut microbiota based on its different physicochemical properties, and the physiological role of gut microbiota in destroying the complex molecular structure of DF by encoding carbohydrate-active enzymes, thus producing small molecular products that affect the metabolism of the host. Taking cardiovascular disease (Atherosclerosis and hypertension), liver disease, and immune diseases as examples, it is confirmed that some DF, such as fructo-oligosaccharide, galactooligosaccharide, xylo-oligosaccharide, and inulin, have prebiotic-like physiological effects. These effects are dependent on the metabolites produced by the gut microbiota. Therefore, this paper further explores how DF affects the gut microbiota's production of substances such as short-chain fatty acids, bile acids, and tryptophan metabolites, and provides a preliminary explanation of the mechanisms associated with their impact on host health. Finally, based on the structural properties of DF and the large heterogeneity in the composition of the population gut microbiota, it may be a future trend to utilize DF and the gut microbiota to correlate host health for precision nutrition by combining the information from population disease databases.
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Affiliation(s)
- Wenjing Wang
- School of Food Science and Technology, Shihezi University, Shihezi, China
| | - Zhexin Fan
- School of Food Science and Technology, Shihezi University, Shihezi, China
- Key Laboratory of Characteristics Agricultural Product Processing and Quality Control (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
- Key Laboratory for Food Nutrition and Safety Control of Xinjiang Production and Construction Corps, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
| | - Qingqing Yan
- School of Food Science and Technology, Shihezi University, Shihezi, China
| | - Tong Pan
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Jing Luo
- School of Food Science and Technology, Shihezi University, Shihezi, China
| | - Yijiang Wei
- School of Food Science and Technology, Shihezi University, Shihezi, China
| | - Baokun Li
- School of Food Science and Technology, Shihezi University, Shihezi, China
- Key Laboratory of Characteristics Agricultural Product Processing and Quality Control (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
- Key Laboratory for Food Nutrition and Safety Control of Xinjiang Production and Construction Corps, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
| | - Zhifeng Fang
- School of Food Science and Technology, Shihezi University, Shihezi, China
- Key Laboratory of Characteristics Agricultural Product Processing and Quality Control (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
- Key Laboratory for Food Nutrition and Safety Control of Xinjiang Production and Construction Corps, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science and Technology, Shihezi University, Shihezi, Xinjiang, China
| | - Wenwei Lu
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, China
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13
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Zhai T, Wang J, Chen Y. Honokiol affects the composition of gut microbiota and the metabolism of lipid and bile acid in methionine-choline deficiency diet-induced NASH mice. Sci Rep 2023; 13:15203. [PMID: 37709801 PMCID: PMC10502053 DOI: 10.1038/s41598-023-42358-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 09/08/2023] [Indexed: 09/16/2023] Open
Abstract
Honokiol (HNK), one of the main active components of Magnolia officinalis, has a positive effect on non-alcoholic steatohepatitis (NASH). However, the effects of HNK on the composition of serum lipids and bile acids (BAs) and gut microbiota (GM) of NASH mice are still unknown.C57BL/6 mice were fed with methionine-choline deficiency (MCD) diet and gavaged with HNK (20 mg/kg/d) for 8 weeks, then the serum lipids and BAs were detected by LC-MS, the composition of ileum microflora and the mRNA expression of hepatic BAs homeostasis related genes were analyzed by 16S rDNA sequencing and RT-qPCR, respectively. HNK treatment decreased the degree of hepatic lipid drops, inflammatory cell infiltration and fibrosis. Meantime, the serum levels of 34 lipids and 4 BAs in MCD mice were significantly altered by HNK treatment, as well as the increased abundance of Ruminococcaceae, Caulobacteraceae and Brevundimonas, and the decreased abundance of Firmicutes and Dubosiella. Besides, HNK treatment increased the hepatic mRNA expression of Oatp1b2 in MCD mice. The ameliorating effect of HNK on NASH may be partly related to its correction on the disorders of GM, serum lipids and BAs of MCD mice.
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Affiliation(s)
- Ting Zhai
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, 430062, China
| | - Junjun Wang
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, 430062, China
| | - Yong Chen
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, 430062, China.
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14
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Huang C, Mei S, Zhang X, Tian X. Inflammatory Milieu Related to Dysbiotic Gut Microbiota Promotes Tumorigenesis of Hepatocellular Carcinoma. J Clin Gastroenterol 2023; 57:782-788. [PMID: 37406184 DOI: 10.1097/mcg.0000000000001883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is an invasive primary liver cancer caused by multiple pathogenic factors and is a significant global health concern. With few effective therapeutic options, HCC is a heterogeneous carcinoma that typically arises in an inflammatory environment. Recent studies have suggested that dysbiotic gut microbiota is involved in hepatocarcinogenesis via multiple mechanisms. In this review, we discuss the effects of gut microbiota, microbial components, and microbiota-derived metabolites on the promotion and progression of HCC by feeding a persistent inflammatory milieu. In addition, we discuss the potential therapeutic modalities for HCC targeting the inflammatory status induced by gut microbiota. A better understanding of the correlation between the inflammatory milieu and gut microbiota in HCC may be beneficial for developing new therapeutic strategies and managing the disease.
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Affiliation(s)
- Caizhi Huang
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine
- Department of Laboratory Medicine, Hunan Children's Hospital
| | - Si Mei
- Department of Physiology, Hunan University of Chinese Medicine
| | - Xue Zhang
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention & Treatment, Hunan University of Chinese Medicine
| | - Xuefei Tian
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention & Treatment, Hunan University of Chinese Medicine
- Hunan Province University Key Laboratory of Oncology of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
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15
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Wu H, Wu Z, Qiu Y, Zhao F, Liao M, Zhong Z, Chen J, Zeng Y, Liu R. Supplementing a specific synbiotic suppressed the incidence of AOM/DSS-induced colorectal cancer in mice. iScience 2023; 26:106979. [PMID: 37378327 PMCID: PMC10291512 DOI: 10.1016/j.isci.2023.106979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 04/11/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
In this study, we evaluated the effect of a specific synbiotic on CAC (AOM/DSS-induced colitis-associated cancer). We confirmed that the synbiotic intervention was able to protect the intestinal barrier and inhibit CAC occurrence via upregulating tight junction proteins and anti-inflammatory cytokines, and downregulating pro-inflammatory cytokines. Moreover, the synbiotic significantly improved the disorder of the colonic microbiota of CAC mice, promoted the formation of SCFAs and the production of secondary bile acids, and alleviated the accumulation of primary bile acids in the CAC mice. Meanwhile, the synbiotic could significantly inhibit the abnormal activation of the intestinal Wnt/β-catenin signaling pathway significantly related to IL-23. In a word, the synbiotic can inhibit the occurrence and development of colorectal tumors and it may be a functional food to prevent inflammation-related colon tumors, and the research also provided a theoretical basis for improving the intestinal microecological environment through diet therapy.
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Affiliation(s)
- Huixia Wu
- Department of Medical Laboratory, School of Medicine, Hunan Normal University, Changsha 410013, China
| | - Zhengchun Wu
- Department of Hepatobiliary and Intestinal Surgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Yilan Qiu
- School of Life Science, Hunan Normal University, Changsha 410018, China
- Changsha Tianan Biotechnology Co., Ltd., Changsha 410018, China
| | - Fangjian Zhao
- Medical Laboratory, The First Affiliated Hospital of Hunan Normal University, Changsha 410018, China
| | - Minjing Liao
- Department of Medical Laboratory, School of Medicine, Hunan Normal University, Changsha 410013, China
| | - Zhihong Zhong
- Department of Medical Laboratory, School of Medicine, Hunan Normal University, Changsha 410013, China
| | - Jian Chen
- Medical Laboratory, The First Affiliated Hospital of Hunan Normal University, Changsha 410018, China
| | - Yiliang Zeng
- Shaoshan Changbaitong Biological Technology Co., Ltd., Shaoshan 411100, China
| | - Rushi Liu
- Department of Medical Laboratory, School of Medicine, Hunan Normal University, Changsha 410013, China
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16
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Buchynskyi M, Kamyshna I, Oksenych V, Zavidniuk N, Kamyshnyi A. The Intersection of COVID-19 and Metabolic-Associated Fatty Liver Disease: An Overview of the Current Evidence. Viruses 2023; 15:v15051072. [PMID: 37243158 DOI: 10.3390/v15051072] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 04/23/2023] [Accepted: 04/26/2023] [Indexed: 05/28/2023] Open
Abstract
The global population is currently experiencing the impact of the SARS-CoV-2 coronavirus, which has caused the Coronavirus Disease 2019 (COVID-19) pandemic. With our profound comprehension of COVID-19, encompassing the involvement sequence of the respiratory tract, gastrointestinal system, and cardiovascular apparatus, the multiorgan symptoms of this infectious disease have been discerned. Metabolic-associated fatty liver disease (MAFLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a pervasive public health concern intricately linked with metabolic dysregulation and estimated to afflict one-fourth of the global adult population. The burgeoning focus on the association between COVID-19 and MAFLD is justified by the potential role of the latter as a risk factor for both SARS-CoV-2 infection and the subsequent emergence of severe COVID-19 symptoms. Investigations have suggested that changes in both innate and adaptive immune responses among MAFLD patients may play a role in determining the severity of COVID-19. The remarkable similarities observed in the cytokine pathways implicated in both diseases imply the existence of shared mechanisms governing the chronic inflammatory responses characterizing these conditions. The effect of MAFLD on the severity of COVID-19 illness remains uncertain, as indicated by conflicting results in cohort investigations.
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Affiliation(s)
- Mykhailo Buchynskyi
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, 46001 Ternopil, Ukraine
| | - Iryna Kamyshna
- Department of Medical Rehabilitation, I. Horbachevsky Ternopil National Medical University, 46001 Ternopil, Ukraine
| | - Valentyn Oksenych
- Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7028 Trondheim, Norway
| | - Nataliia Zavidniuk
- Department of Infectious Diseases with Epidemiology, Dermatology and Venerology, I. Horbachevsky Ternopil National Medical University, 46001 Ternopil, Ukraine
| | - Aleksandr Kamyshnyi
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, 46001 Ternopil, Ukraine
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17
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Gao X, Lin X, Xin Y, Zhu X, Li X, Chen M, Huang Z, Guo H. Dietary cholesterol drives the development of non-alcoholic steatohepatitis by altering gut microbiota mediated bile acid metabolism in high-fat diet fed mice. J Nutr Biochem 2023; 117:109347. [PMID: 37031879 DOI: 10.1016/j.jnutbio.2023.109347] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 03/27/2023] [Accepted: 04/03/2023] [Indexed: 04/11/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most widespread chronic liver disorder globally. Unraveling the pathogenesis of simple fatty liver to non-alcoholic steatohepatitis (NASH) has important clinical significance for improving the prognosis of NAFLD. Here, we explored the role of a high-fat diet alone or combined with high cholesterol in causing NASH progression. Our results demonstrated that high dietary cholesterol intakes accelerate the progression of spontaneous NAFLD and induces liver inflammation in mice. An elevation of hydrophobic unconjugated bile acids cholic acid (CA), deoxycholic acid (DCA), muricholic acid and chenodeoxycholic acid, was observed in high-fat and high-cholesterol diet fed mice. Full-length sequencing of the 16S rRNA gene of gut microbiota revealed a significant increase in the abundance of Bacteroides, Clostridium and Lactobacillus that possess bile salt hydrolase activity. Furthermore, the relative abundance of these bacterial species was positively correlated with content of unconjugated bile acids in liver. Moreover, the expression of genes related to bile acid reabsorption (organic anion-transporting polypeptides, Na+-taurocholic acid cotransporting polypeptide, apical sodium dependent bile acid transporter and organic solute transporter β) was found to be increased in mice with a high-cholesterol diet. Lastly, we observed that hydrophobic bile acids CA and DCA induce an inflammatory response in free fatty acids-induced steatotic HepG2 cells. In conclusion, high dietary cholesterol promotes the development of NASH by altering gut microbiota composition and abundance and thereby influencing with bile acid metabolism.
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Affiliation(s)
- Xuebin Gao
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan 523808, China; Department of Science and Education, Yuebei People's Hospital, Shaoguan 512026, China
| | - Xiaozhuan Lin
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Yan Xin
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Xuan Zhu
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Xiang Li
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Ming Chen
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Zhigang Huang
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Honghui Guo
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan 523808, China; Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China.
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18
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Che W, Zhao M, Li X, Li C, Cho WC, Yu S. Current insights in molecular characterization of non-alcoholic fatty liver disease and treatment. Front Endocrinol (Lausanne) 2022; 13:1002916. [PMID: 36523601 PMCID: PMC9744925 DOI: 10.3389/fendo.2022.1002916] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/14/2022] [Indexed: 11/30/2022] Open
Abstract
There is a continuously rising incidence of non-alcoholic fatty liver disease (NAFLD) around the world, which parallels the increasing incidence of metabolic diseases. NAFLD is a range of liver conditions that contains simple non-alcoholic fatty liver and advanced non-alcoholic steatohepatitis. In serious cases, NAFLD may develop into cirrhosis or even liver cancer. NAFLD has an intense relationship with metabolic syndrome, type 2 diabetes mellitus. It is known that gut microbiota, and functional molecules such as adenosine monophosphate-activated protein kinase JNK, and peroxisome proliferator-activated receptors (PPARs) in progressing and treating NAFLD. Traditionally, the conventional and effective therapeutic strategy is lifestyle intervention. Nowadays, new medicines targeting specific molecules, such as farnesoid X receptor, PPARs, and GLP-1 receptor, have been discovered and shown beneficial effects on patients with NAFLD. In this article, we focus on the molecular mechanisms and therapeutic approaches to NAFLD.
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Affiliation(s)
- Wensheng Che
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ming Zhao
- Chengdu Medical College, Chengdu, China
- Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Xiaoqing Li
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chunlong Li
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong SAR, China
| | - Shan Yu
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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19
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Arifuzzaman M, Won TH, Li TT, Yano H, Digumarthi S, Heras AF, Zhang W, Parkhurst CN, Kashyap S, Jin WB, Putzel GG, Tsou AM, Chu C, Wei Q, Grier A, Worgall S, Guo CJ, Schroeder FC, Artis D. Inulin fibre promotes microbiota-derived bile acids and type 2 inflammation. Nature 2022; 611:578-584. [PMID: 36323778 PMCID: PMC10576985 DOI: 10.1038/s41586-022-05380-y] [Citation(s) in RCA: 95] [Impact Index Per Article: 31.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 09/22/2022] [Indexed: 11/05/2022]
Abstract
Dietary fibres can exert beneficial anti-inflammatory effects through microbially fermented short-chain fatty acid metabolites<sup>1,2</sup>, although the immunoregulatory roles of most fibre diets and their microbiota-derived metabolites remain poorly defined. Here, using microbial sequencing and untargeted metabolomics, we show that a diet of inulin fibre alters the composition of the mouse microbiota and the levels of microbiota-derived metabolites, notably bile acids. This metabolomic shift is associated with type 2 inflammation in the intestine and lungs, characterized by IL-33 production, activation of group 2 innate lymphoid cells and eosinophilia. Delivery of cholic acid mimics inulin-induced type 2 inflammation, whereas deletion of the bile acid receptor farnesoid X receptor diminishes the effects of inulin. The effects of inulin are microbiota dependent and were reproduced in mice colonized with human-derived microbiota. Furthermore, genetic deletion of a bile-acid-metabolizing enzyme in one bacterial species abolishes the ability of inulin to trigger type 2 inflammation. Finally, we demonstrate that inulin enhances allergen- and helminth-induced type 2 inflammation. Taken together, these data reveal that dietary inulin fibre triggers microbiota-derived cholic acid and type 2 inflammation at barrier surfaces with implications for understanding the pathophysiology of allergic inflammation, tissue protection and host defence.
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Affiliation(s)
- Mohammad Arifuzzaman
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Tae Hyung Won
- Boyce Thompson Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA
| | - Ting-Ting Li
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Hiroshi Yano
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Sreehaas Digumarthi
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Andrea F Heras
- Gale and Ira Drukier Institute for Children's Health, Department of Pediatrics, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Wen Zhang
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Christopher N Parkhurst
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Sanchita Kashyap
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Wen-Bing Jin
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Gregory Garbès Putzel
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Amy M Tsou
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Weill Cornell Medicine, New York, NY, USA
| | - Coco Chu
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Qianru Wei
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Alex Grier
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Stefan Worgall
- Gale and Ira Drukier Institute for Children's Health, Department of Pediatrics, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Chun-Jun Guo
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA.
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
| | - Frank C Schroeder
- Boyce Thompson Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA.
| | - David Artis
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA.
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
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20
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Zhang YL, Li ZJ, Gou HZ, Song XJ, Zhang L. The gut microbiota–bile acid axis: A potential therapeutic target for liver fibrosis. Front Cell Infect Microbiol 2022; 12:945368. [PMID: 36189347 PMCID: PMC9519863 DOI: 10.3389/fcimb.2022.945368] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 09/01/2022] [Indexed: 11/15/2022] Open
Abstract
Liver fibrosis involves the proliferation and deposition of extracellular matrix on liver tissues owing to various etiologies (including viral, alcohol, immune, and metabolic factors), ultimately leading to structural and functional abnormalities in the liver. If not effectively treated, liver fibrosis, a pivotal stage in the path to chronic liver disease, can progress to cirrhosis and eventually liver cancer; unfortunately, no specific clinical treatment for liver fibrosis has been established to date. In liver fibrosis cases, both the gut microbiota and bile acid metabolism are disrupted. As metabolites of the gut microbiota, bile acids have been linked to the progression of liver fibrosis via various pathways, thus implying that the gut microbiota–bile acid axis might play a critical role in the progression of liver fibrosis and could be a target for its reversal. Therefore, in this review, we examined the involvement of the gut microbiota–bile acid axis in liver fibrosis progression to the end of discovering new targets for the prevention, diagnosis, and therapy of chronic liver diseases, including liver fibrosis.
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Affiliation(s)
- Yu-Lin Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Zhen-Jiao Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Hong-Zhong Gou
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xiao-Jing Song
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Lei Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
- *Correspondence: Lei Zhang,
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21
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Dietary Inulin Supplementation Affects Specific Plasmalogen Species in the Brain. Nutrients 2022; 14:nu14153097. [PMID: 35956273 PMCID: PMC9370380 DOI: 10.3390/nu14153097] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/23/2022] [Accepted: 07/24/2022] [Indexed: 11/29/2022] Open
Abstract
Plasmalogens (Pls) are glycerophospholipids that play critical roles in the brain. Evidence supports the role of diet and that of the gut microbiota in regulating brain lipids. We investigated the impact of dietary intake of inulin—a soluble fiber used as prebiotic—on the Pl content of the cortex in mice. No global modification in the Pl amounts was observed when evaluated by gas chromatographic analysis of dimethyl acetals (DMAs). However, the analysis of individual molecular species of Pls by liquid chromatography revealed a reduced abundance of major species of ethanolamine Pls (PlsEtn)―PE(P-18:0/22:6) and PE(P-34:1)―in the cortex of mice fed a diet supplemented with inulin. DMA and expression levels of genes (Far-1, Gnpat, Agps, Pla2g6 and Tmem86b) encoding key enzymes of Pl biosynthesis or degradation were not altered in the liver and in the cortex of mice exposed to inulin. In addition, the fatty acid profile and the amount of lyso forms derived from PlsEtn were not modified in the cortex by inulin consumption. To conclude, inulin affects the brain levels of major PlsEtn and further investigation is needed to determine the exact molecular mechanisms involved.
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22
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Khalyfa AA, Punatar S, Yarbrough A. Hepatocellular Carcinoma: Understanding the Inflammatory Implications of the Microbiome. Int J Mol Sci 2022; 23:ijms23158164. [PMID: 35897739 PMCID: PMC9332105 DOI: 10.3390/ijms23158164] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/17/2022] [Accepted: 07/20/2022] [Indexed: 01/25/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. It is well known that repeated inflammatory insults in the liver can cause hepatic cellular injury that lead to cirrhosis and, ultimately, hepatocellular carcinoma. Furthermore, the microbiome has been implicated in multiple inflammatory conditions which predispose patients to malignancy. With this in mind, we explore the inflammatory implications of the microbiome on pathways that lead to HCC. We also focus on how an understanding of these underlying inflammatory principles lead to a more wholistic understanding of this deadly disease, as well as potential therapeutic implications.
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Affiliation(s)
- Ahamed A. Khalyfa
- Department of Internal Medicine, Franciscan Health Olympia Fields, Olympia Fields, IL 60461, USA;
- Correspondence:
| | - Shil Punatar
- Department of Internal Medicine, Franciscan Health Olympia Fields, Olympia Fields, IL 60461, USA;
| | - Alex Yarbrough
- Department of Gastroenterology, Franciscan Health Olympia Fields, Olympia Fields, IL 60461, USA;
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23
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Koppe L, Soulage CO. The impact of dietary nutrient intake on gut microbiota in the progression and complications of chronic kidney disease. Kidney Int 2022; 102:728-739. [PMID: 35870642 DOI: 10.1016/j.kint.2022.06.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 06/02/2022] [Accepted: 06/10/2022] [Indexed: 11/29/2022]
Abstract
Chronic kidney disease (CKD) has been associated with changes in the function and composition of the gut microbiota. The ecosystem of the human gut consists of trillions of microorganisms forming an authentic metabolically active organ that is fueled by nutrients to produce bioactive compounds. These microbiota-derived metabolites may be protective for kidney function (e.g. short-chain fatty acids from fermentation of dietary fibers) or deleterious (e.g. gut-derived uremic toxins such as trimethylamine N-oxide, p-cresyl sulfate, and indoxyl sulfate from fermentation of amino acids). Although diet is the cornerstone of the management of the patient with CKD, it remains a relatively underused component of the clinician's armamentarium. In this review, we describe the latest advances in understanding diet-microbiota crosstalk in a uremic context, and how this communication might contribute to CKD progression and complications. We then discuss how this knowledge could be harnessed for personalized nutrition strategies to prevent patients with CKD progressing to end-stage kidney disease and its detrimental consequences.
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Affiliation(s)
- Laetitia Koppe
- Department of Nephrology, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, F-69495 Pierre-Bénite, France; Univ. Lyon, CarMeN lab, INSA-Lyon, INSERM U1060, INRA, Université Claude Bernard Lyon 1, F-69621 Villeurbanne, France.
| | - Christophe O Soulage
- Univ. Lyon, CarMeN lab, INSA-Lyon, INSERM U1060, INRA, Université Claude Bernard Lyon 1, F-69621 Villeurbanne, France
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24
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Yao N, Yang Y, Li X, Wang Y, Guo R, Wang X, Li J, Xie Z, Li B, Cui W. Effects of Dietary Nutrients on Fatty Liver Disease Associated With Metabolic Dysfunction (MAFLD): Based on the Intestinal-Hepatic Axis. Front Nutr 2022; 9:906511. [PMID: 35782947 PMCID: PMC9247350 DOI: 10.3389/fnut.2022.906511] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/26/2022] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has recently become the most common liver disease with a global prevalence of over 25% and is expected to increase. Recently, experts have reached a consensus that “fatty liver disease associated with metabolic dysfunction or MAFLD” may be a more appropriate and inclusive definition than NAFLD. Like the former name NAFLD, MAFLD, as a manifestation of multiple system metabolic disorders involving the liver, has certain heterogeneity in its pathogenesis, clinical manifestations, pathological changes and natural outcomes. We found that there is a delicate dynamic balance among intestinal microflora, metabolites and host immune system to maintain a healthy intestinal environment and host health. On the contrary, this imbalance is related to diseases such as MAFLD. However, there are no clear studies on how dietary nutrients affect the intestinal environment and participate in the pathogenesis of MAFLD. This review summarizes the interactions among dietary nutrients, intestinal microbiota and MAFLD in an attempt to provide evidence for the use of dietary supplements to regulate liver function in patients with MAFLD. These dietary nutrients influence the development and progression of MAFLD mainly through the hepatic-intestinal axis by altering dietary energy absorption, regulating bile acid metabolism, changing intestinal permeability and producing ethanol. Meanwhile, the nutrients have the ability to combat MAFLD in terms of enriching abundance of intestinal microbiota, reducing Firmicutes/Bacteroidetes ratio and promoting abundance of beneficial gut microbes. Therefore, family therapy with MAFLD using a reasonable diet could be considered.
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Affiliation(s)
- Nan Yao
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
| | - Yixue Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
| | - Xiaotong Li
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
| | - Yuxiang Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
| | - Ruirui Guo
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
| | - Xuhan Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
| | - Jing Li
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
| | - Zechun Xie
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
| | - Bo Li
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
- *Correspondence: Bo Li
| | - Weiwei Cui
- Department of Nutrition and Food Hygiene, School of Public Health, Jilin University, Changchun, China
- Weiwei Cui
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25
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Said I, Ahad H, Said A. Gut microbiome in non-alcoholic fatty liver disease associated hepatocellular carcinoma: Current knowledge and potential for therapeutics. World J Gastrointest Oncol 2022; 14:947-958. [PMID: 35646285 PMCID: PMC9124992 DOI: 10.4251/wjgo.v14.i5.947] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/14/2021] [Accepted: 04/16/2022] [Indexed: 02/06/2023] Open
Abstract
Metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) are rising in incidence and are an increasingly common cause of cirrhosis and hepatocellular carcinoma (HCC). The gut microbiome is closely connected to the liver via the portal vein, and has recently been identified as a predictor of liver disease state. Studies in NAFLD, cirrhosis and HCC have identified certain microbial signatures associated with these diseases, with the disease-associated microbiome changes collectively referred to as dysbiosis. The pathophysiologic underpinnings of these observations are an area of ongoing investigation, with current evidence demonstrating that the gut microbiome can influence liver disease and carcinogenesis via effects on intestinal permeability (leaky gut) and activation of the innate immune system. In the innate immune system, pathogen recognition receptors (Toll like receptors) on resident liver cells and macrophages cause liver inflammation, fibrosis, hepatocyte proliferation and reduced antitumor immunity, leading to chronic liver disease and carcinogenesis. Dysbiosis-associated changes include increase in secondary bile acids and reduced expression of FXR (nuclear receptor), which have also been associated with deleterious effects on lipid and carbohydrate metabolism associated with progressive liver disease. Longitudinal experimental and clinical studies are needed in different populations to examine these questions further. The role of therapeutics that modulate the microbiome is an emerging field with experimental studies showing the potential of diet, probiotics, fecal microbiota transplantation and prebiotics in improving liver disease in experimental models. Clinical studies are ongoing with preliminary evidence showing improvement in liver enzymes and steatosis. The microbial profile is different in responders to cancer immunotherapy including liver cancer, but whether or not manipulation of the microbiome can be utilized to affect response is being investigated.
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Affiliation(s)
- Imaad Said
- Brown University, Providence, RI 02912, United States
| | - Hassan Ahad
- Kansas University, Lawrence, KS 66045, United States
| | - Adnan Said
- Division of Gastroenterology and Hepatology, Department of Medicine, William S. Middleton VAMC, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
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26
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Wu J, Zhang D, Zhu B, Wang S, Xu Y, Zhang C, Yang H, Wang S, Liu P, Qin L, Liu W. Rubus chingii Hu. unripe fruits extract ameliorates carbon tetrachloride-induced liver fibrosis and improves the associated gut microbiota imbalance. Chin Med 2022; 17:56. [PMID: 35549741 PMCID: PMC9097331 DOI: 10.1186/s13020-022-00607-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/10/2022] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND The unripe fruits of Rubus chingii Hu. ("Fu-peng-zi" in Chinese) is a well-known herbal tonic in traditional Chinese medicine (TCM) for tonifying liver and kidney. However, little is known regarding its therapeutic efficacy against liver fibrosis and the underlying mechanism. METHODS The current research aims to explore the potential of Rubus chingii Hu. unripe fruits extract (RF) in the treatment of liver fibrosis and explore the underlying mechanism. RF was administered (450 and 900 mg·kg- 1 of body weight per day) orally to male C57BL/6 mice with CCl4-induced liver fibrosis for 3 weeks. The histopathological changes and fibrosis stage in liver tissue were assessed using hematoxylin and eosin (H&E) and Sirius red staining. The distribution of α-SMA and Col1A1 in the liver was analyzed to determine the hepatic stellate cells (HSCs) activation using immunohistochemistry and immunofluorescent analysis. Various biochemical markers in serum (ALT, AST) and liver (Hyp, IL1-β, IL6, TNF-α and MCP-1) were observed to assess the liver's injury, fibrosis, and inflammation. In liver tissue, fibrosis-associated proteins including α-SMA, TGF-β1, Smad2/3, p-Smad2/3, and Smad4 were detected through a Western blot assay. Pyrosequencing-based analysis of bacterial 16 S ribosomal RNA from variable regions V3-V4 of fecal samples characterized the gut microbiota. Spearman's rank correlation analysis was performed for the association between altered bacterial genera by RF and pharmacodynamics parameters. RESULTS Three weeks of RF treatment can significantly lower liver inflammatory levels, pathological abnormalities, and collagen fibrous deposition in mice with CCl4-induced liver fibrosis. The expressions of α-SMA and Col1A1 were lowered by RF, while the expression levels of TGF-β/Smads signaling pathway-related proteins, including TGF-β1, p-Smad2/3, and Smad4, were dramatically decreased by RF. The RF treatment significantly increased or reduced 18 different bacterial species, restoring the CCl4-induced gut microbiota imbalance to the normal group's levels. According to correlation analysis, the bacterial genera Bifidobacterium and Turicibacter were the most significant in restoring CCl4-induced liver fibrosis. CONCLUSIONS RF can reduce liver damage and delay the onset of liver fibrosis through modulating TGF-β/Smads signaling pathway. Furthermore, RF's anti-liver fibrosis effect was related to balancing the gut microbial community, partly attained by increasing Bifidobacterium and Turicibacter in liver fibrosis.
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Affiliation(s)
- Jianjun Wu
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Dingqi Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Bo Zhu
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Siqi Wang
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Yongbin Xu
- The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Rood, Shanghai, 201203, China
| | - Congcong Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Rood, Shanghai, 201203, China
| | - Hailing Yang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Shunchun Wang
- The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Rood, Shanghai, 201203, China
| | - Ping Liu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Luping Qin
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.
| | - Wei Liu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China.
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27
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Smati S, Polizzi A, Fougerat A, Ellero-Simatos S, Blum Y, Lippi Y, Régnier M, Laroyenne A, Huillet M, Arif M, Zhang C, Lasserre F, Marrot A, Al Saati T, Wan J, Sommer C, Naylies C, Batut A, Lukowicz C, Fougeray T, Tramunt B, Dubot P, Smith L, Bertrand-Michel J, Hennuyer N, Pradere JP, Staels B, Burcelin R, Lenfant F, Arnal JF, Levade T, Gamet-Payrastre L, Lagarrigue S, Loiseau N, Lotersztajn S, Postic C, Wahli W, Bureau C, Guillaume M, Mardinoglu A, Montagner A, Gourdy P, Guillou H. Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target. Gut 2022; 71:807-821. [PMID: 33903148 DOI: 10.1136/gutjnl-2020-323323] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 03/28/2021] [Accepted: 04/09/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVE We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans. DESIGN Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver. RESULTS The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα. CONCLUSIONS These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target. TRIAL REGISTRATION NUMBER NCT02390232.
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Affiliation(s)
- Sarra Smati
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France.,Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Arnaud Polizzi
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Anne Fougerat
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Sandrine Ellero-Simatos
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Yuna Blum
- CIT, Ligue Nationale Contre Le Cancer, Paris, France.,IGDR UMR 6290, CNRS, Université de Rennes 1, Rennes, France
| | - Yannick Lippi
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Marion Régnier
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Alexia Laroyenne
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Marine Huillet
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Muhammad Arif
- Science for Life Laboratory, KTH-Royal Institute of Technology, Solna, Sweden
| | - Cheng Zhang
- Science for Life Laboratory, KTH-Royal Institute of Technology, Solna, Sweden
| | - Frederic Lasserre
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Alain Marrot
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Talal Al Saati
- Experimental Histopathology Department, INSERM US006-CREFRE, University Hospital of Toulouse, Toulouse, France
| | - JingHong Wan
- INSERM-UMR1149, Centre de Recherche sur l'Inflammation, Paris, France.,Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Université Paris Diderot, Paris, France
| | - Caroline Sommer
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Claire Naylies
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Aurelie Batut
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Celine Lukowicz
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Tiffany Fougeray
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Blandine Tramunt
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Patricia Dubot
- Laboratoire de Biochimie Métabolique, CHU Toulouse, Toulouse, France.,INSERM U1037, CRCT, Université Paul Sabatier, Toulouse, France
| | - Lorraine Smith
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Justine Bertrand-Michel
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Nathalie Hennuyer
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000, Lille, France
| | - Jean-Philippe Pradere
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Bart Staels
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000, Lille, France
| | - Remy Burcelin
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Françoise Lenfant
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Jean-François Arnal
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Thierry Levade
- Laboratoire de Biochimie Métabolique, CHU Toulouse, Toulouse, France.,INSERM U1037, CRCT, Université Paul Sabatier, Toulouse, France
| | - Laurence Gamet-Payrastre
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | | | - Nicolas Loiseau
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Sophie Lotersztajn
- INSERM-UMR1149, Centre de Recherche sur l'Inflammation, Paris, France.,Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Université Paris Diderot, Paris, France
| | - Catherine Postic
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Walter Wahli
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France.,Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.,Center for Integrative Genomics, University of Lausanne, Le Génopode, Lausanne, Switzerland
| | - Christophe Bureau
- Hepatology Unit, Rangueil Hospital Toulouse, Paul Sabatier University Toulouse 3, Toulouse, France
| | - Maeva Guillaume
- Hepatology Unit, Rangueil Hospital Toulouse, Paul Sabatier University Toulouse 3, Toulouse, France
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH-Royal Institute of Technology, Solna, Sweden.,Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Alexandra Montagner
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Pierre Gourdy
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France .,Endocrinology-Diabetology-Nutrition Department, Toulouse University Hospital, Toulouse, France
| | - Hervé Guillou
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
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28
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Song Q, Zhang X. The Role of Gut–Liver Axis in Gut Microbiome Dysbiosis Associated NAFLD and NAFLD-HCC. Biomedicines 2022; 10:biomedicines10030524. [PMID: 35327326 PMCID: PMC8945287 DOI: 10.3390/biomedicines10030524] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 02/18/2022] [Accepted: 02/21/2022] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered as one of the most prevalent chronic liver diseases worldwide due to the rapidly rising prevalence of obesity and metabolic syndrome. As a hepatic manifestation of metabolic disease, NAFLD begins with hepatic fat accumulation and progresses to hepatic inflammation, termed as non-alcoholic steatohepatitis (NASH), hepatic fibrosis/cirrhosis, and finally leading to NAFLD-related hepatocellular carcinoma (NAFLD-HCC). Accumulating evidence showed that the gut microbiome plays a vital role in the initiation and progression of NAFLD through the gut–liver axis. The gut–liver axis is the mutual communication between gut and liver comprising the portal circulation, bile duct, and systematic circulation. The gut microbiome dysbiosis contributes to NAFLD development by dysregulating the gut–liver axis, leading to increased intestinal permeability and unrestrained transfer of microbial metabolites into the liver. In this review, we systematically summarized the up-to-date information of gut microbiome dysbiosis and metabolomic changes along the stages of steatosis, NASH, fibrosis, and NAFLD-HCC. The components and functions of the gut–liver axis and its association with NAFLD were then discussed. In addition, we highlighted current knowledge of gut microbiome-based treatment strategies targeting the gut–liver axis for preventing NAFLD and its associated HCC.
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Affiliation(s)
- Qian Song
- Department of Medicine and Therapeutics, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong 999077, China;
- State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong 999077, China
| | - Xiang Zhang
- Department of Medicine and Therapeutics, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong 999077, China;
- State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong 999077, China
- Correspondence: ; Tel.: +852-3763-6102
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29
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Zhang Y, Feng H, Liang XF, He S, Lan J, Li L. Dietary bile acids reduce liver lipid deposition via activating farnesoid X receptor, and improve gut health by regulating gut microbiota in Chinese perch (Siniperca chuatsi). FISH & SHELLFISH IMMUNOLOGY 2022; 121:265-275. [PMID: 35026410 DOI: 10.1016/j.fsi.2022.01.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 12/17/2021] [Accepted: 01/08/2022] [Indexed: 06/14/2023]
Abstract
The aim of this study is to explore the effects of dietary bile acids (BAs) supplementation on lipid metabolism and gut health of Chinese perch (Siniperca chuatsi), and its possible mechanisms. Two isonitrogenous and isolipidic diets were formulated to supplement different levels of BAs (0 and 900 mg BAs kg-1 diet, respectively). All fish (Initial mean body weight: 171.29 ± 0.77g) were randomly divided into 2 groups (triplicate, 54 fish/group) and were fed with different experimental diets for 56 days, respectively. Dietary exogenous BAs supplementation at the concentration of 900 mg kg-1 significantly increased weight gain and survival rate, and decreased feed conversion ratio. BAs could inhibit lipid synthesis and promote lipid oxidation to reduce lipid deposition by activating farnesoid X receptor (FXR). Dietary BAs supplementation increased the abundance of Lactobacilli in Firmicutes, and the increase of Lactobacillus caused the increase of lactic acid level and the decrease of pH, which might be the reason for the gut villus length and gut wall high in this study. Dietary BAs supplementation increased the levels of catalase and superoxide dismutase and decreased the level of malondialdehyde in the gut and plasma, which might be contributed to the regulating the antioxidant stress phenotype of gut microbiota by the increased abundance of Firmicutes. Then it caused the increase of the globulin level in the plasma, meaning the enhancement of immune state. The increased immunity might also be thought to be responsible for increased survival rate. These results suggest dietary BAs reduce liver lipid deposition via activating FXR, and improve gut health by regulating gut microbiota in Chinese perch.
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Affiliation(s)
- Yanpeng Zhang
- College of Fisheries, Chinese Perch Research Center, Huazhong Agricultural University, Wuhan, 430070, China; Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, 430070, China
| | - Hexiong Feng
- College of Fisheries, Chinese Perch Research Center, Huazhong Agricultural University, Wuhan, 430070, China; Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, 430070, China
| | - Xu-Fang Liang
- College of Fisheries, Chinese Perch Research Center, Huazhong Agricultural University, Wuhan, 430070, China; Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, 430070, China.
| | - Shan He
- College of Fisheries, Chinese Perch Research Center, Huazhong Agricultural University, Wuhan, 430070, China; Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, 430070, China
| | - Jie Lan
- College of Fisheries, Chinese Perch Research Center, Huazhong Agricultural University, Wuhan, 430070, China; Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, 430070, China
| | - Ling Li
- College of Fisheries, Chinese Perch Research Center, Huazhong Agricultural University, Wuhan, 430070, China; Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, 430070, China
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30
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Guo K, Xu S, Zeng Z. "Liver-gut" axis: A target of traditional Chinese medicine for the treatment of non-alcoholic fatty liver disease. Front Endocrinol (Lausanne) 2022; 13:1050709. [PMID: 36531498 PMCID: PMC9747758 DOI: 10.3389/fendo.2022.1050709] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 10/28/2022] [Indexed: 12/05/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) occurs when fat accumulates in the liver even without excessive alcohol intake. Among the current therapeutic approaches for NAFLD, lifestyle modification with dietary changes and regular exercise is the mainstay treatment. With the rise of intestinal microecology, regulation of the "liver-gut" axis can be an effective treatment for NAFLD. This review aimed to assess the modulation of the liver-gut microbiota axis with traditional Chinese medicine (TCM) as a therapeutic approach to NAFLD and further explored its application in the newly discovered therapeutic avenues beyond NAFLD treatment.
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31
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Portincasa P, Bonfrate L, Khalil M, Angelis MD, Calabrese FM, D’Amato M, Wang DQH, Di Ciaula A. Intestinal Barrier and Permeability in Health, Obesity and NAFLD. Biomedicines 2021; 10:83. [PMID: 35052763 PMCID: PMC8773010 DOI: 10.3390/biomedicines10010083] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/20/2021] [Accepted: 12/28/2021] [Indexed: 02/07/2023] Open
Abstract
The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal barrier is characterized by the selective permeability of nutrients, metabolites, water, and bacterial products, and processes are governed by cellular, neural, immune, and hormonal factors. Disrupted gut permeability (leaky gut syndrome) can represent a predisposing or aggravating condition in obesity and the metabolically associated liver steatosis (nonalcoholic fatty liver disease, NAFLD). In what follows, we describe the morphological-functional features of the intestinal barrier, the role of major modifiers of the intestinal barrier, and discuss the recent evidence pointing to the key role of intestinal permeability in obesity/NAFLD.
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Affiliation(s)
- Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
| | - Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Maria De Angelis
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Francesco Maria Calabrese
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Mauro D’Amato
- Gastrointestinal Genetics Lab, CIC bioGUNE-BRTA, 48160 Derio, Spain;
- Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York, NY 10461, USA;
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
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32
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Yu JS, Youn GS, Choi J, Kim C, Kim BY, Yang S, Lee JH, Park T, Kim BK, Kim YB, Roh SW, Min BH, Park HJ, Yoon SJ, Lee NY, Choi YR, Kim HS, Gupta H, Sung H, Han SH, Suk KT, Lee DY. Lactobacillus lactis and Pediococcus pentosaceus-driven reprogramming of gut microbiome and metabolome ameliorates the progression of non-alcoholic fatty liver disease. Clin Transl Med 2021; 11:e634. [PMID: 34965016 PMCID: PMC8715831 DOI: 10.1002/ctm2.634] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 10/11/2021] [Accepted: 10/17/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Although microbioa-based therapies have shown putative effects on the treatment of non-alcoholic fatty liver disease (NAFLD), it is not clear how microbiota-derived metabolites contribute to the prevention of NAFLD. We explored the metabolomic signature of Lactobacillus lactis and Pediococcus pentosaceus in NAFLD mice and its association in NAFLD patients. METHODS We used Western diet-induced NAFLD mice, and L. lactis and P. pentosaceus were administered to animals in the drinking water at a concentration of 109 CFU/g for 8 weeks. NAFLD severity was determined based on liver/body weight, pathology and biochemistry markers. Caecal samples were collected for the metagenomics by 16S rRNA sequencing. Metabolite profiles were obtained from caecum, liver and serum. Human stool samples (healthy control [n = 22] and NAFLD patients [n = 23]) were collected to investigate clinical reproducibility for microbiota-derived metabolites signature and metabolomics biomarker. RESULTS L. lactis and P. pentosaceus supplementation effectively normalized weight ratio, NAFLD activity score, biochemical markers, cytokines and gut-tight junction. While faecal microbiota varied according to the different treatments, key metabolic features including short chain fatty acids (SCFAs), bile acids (BAs) and tryptophan metabolites were analogously restored by both probiotic supplementations. The protective effects of indole compounds were validated with in vitro and in vivo models, including anti-inflammatory effects. The metabolomic signatures were replicated in NAFLD patients, accompanied by the comparable levels of Firmicutes/Bacteroidetes ratio, which was significantly higher (4.3) compared with control (0.6). Besides, the consequent biomarker panel with six stool metabolites (indole, BAs, and SCFAs) showed 0.922 (area under the curve) in the diagnosis of NAFLD. CONCLUSIONS NAFLD progression was robustly associated with metabolic dys-regulations in the SCFAs, bile acid and indole compounds, and NAFLD can be accurately diagnosed using the metabolites. L. lactis and P. pentosaceus ameliorate NAFLD progression by modulating gut metagenomic and metabolic environment, particularly tryptophan pathway, of the gut-liver axis.
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Affiliation(s)
- Jeong Seok Yu
- Department of Agricultural BiotechnologyCenter for Food and BioconvergenceResearch Institute for Agricultural and Life SciencesSeoul National UniversitySeoulRepublic of Korea
| | - Gi Soo Youn
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Jieun Choi
- Department of Agricultural BiotechnologyCenter for Food and BioconvergenceResearch Institute for Agricultural and Life SciencesSeoul National UniversitySeoulRepublic of Korea
| | - Chang‐Ho Kim
- Department of Agricultural BiotechnologyCenter for Food and BioconvergenceResearch Institute for Agricultural and Life SciencesSeoul National UniversitySeoulRepublic of Korea
| | | | | | | | - Tae‐Sik Park
- Department of Life ScienceGachon UniversitySungnamRepublic of Korea
| | - Byoung Kook Kim
- Chong Kun Dang Bio Research InstituteGyeonggi‐doRepublic of Korea
| | - Yeon Bee Kim
- Department of Agricultural BiotechnologyCenter for Food and BioconvergenceResearch Institute for Agricultural and Life SciencesSeoul National UniversitySeoulRepublic of Korea
- Microbiology and Functionality Research GroupWorld Institute of KimchiGwangjuRepublic of Korea
| | - Seong Woon Roh
- Microbiology and Functionality Research GroupWorld Institute of KimchiGwangjuRepublic of Korea
| | - Byeong Hyun Min
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Hee Jin Park
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Sang Jun Yoon
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Na Young Lee
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Ye Rin Choi
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Hyeong Seob Kim
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Haripriya Gupta
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Hotaik Sung
- School of MedicineKyungpook National UniversityDaeguRepublic of Korea
| | - Sang Hak Han
- Department of PathologyHallym University College of MedicineChuncheonRepublic of Korea
| | - Ki Tae Suk
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Do Yup Lee
- Department of Agricultural BiotechnologyCenter for Food and BioconvergenceResearch Institute for Agricultural and Life SciencesSeoul National UniversitySeoulRepublic of Korea
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33
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Gao X, Ruan Y, Zhu X, Lin X, Xin Y, Li X, Mai M, Guo H. Deoxycholic Acid Promotes Pyroptosis in Free Fatty Acid-Induced Steatotic Hepatocytes by Inhibiting PINK1-Mediated Mitophagy. Inflammation 2021; 45:639-650. [PMID: 34674097 DOI: 10.1007/s10753-021-01573-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 09/28/2021] [Accepted: 09/29/2021] [Indexed: 02/06/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) is the inflammatory subtype of nonalcoholic fatty liver disease (NAFLD), which can lead to liver fibrosis and cirrhosis. Bile acid levels are correlated with markers of hepatic injury in NASH, suggesting a possible role for bile acids in the progression of NAFLD. Here, we examined the role of deoxycholic acid (DCA) in driving steatotic hepatocytes to pyroptosis, a pro-inflammatory form of programmed cell death. HepG2 cells were stimulated with odium oleate and sodium palmitate for modeling steatotic hepatocytes and then treated with DCA alone or in combination with a specific mitophagy agonist, carbonyl cyanide 3-chlorophenylhydrazone (CCCP). Our results showed that DCA dose-dependently induced a pro-inflammatory response in steatotic hepatocytes but had no significant effect on lipid accumulation. Moreover, activation of the NLRP3 inflammasome and pyroptosis were triggered by DCA. Expression levels of the mitophagy markers PTEN-induced kinase 1 (PINK1) and E3 ubiquitin ligase Parkin were significantly diminished by DCA, whereas induction of mitophagy by CCCP prevented DCA-induced inflammatory response and restored the pyroptosis. Collectively, our data showed that DCA-induced pyroptosis involves the inhibition of PINK1-mediated mitophagy and the activation of the NLRP3 inflammasome. These findings provide insight into the association of DCA with mitophagy, pyroptosis, and inflammation in NASH.
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Affiliation(s)
- Xuebin Gao
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, 523808, China
| | - Yongdui Ruan
- Department of Traditional Chinese Medicine, the First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, China
| | - Xuan Zhu
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, 523808, China
| | - Xiaozhuan Lin
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, 523808, China
| | - Yan Xin
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, 523808, China
| | - Xiang Li
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, 523808, China
| | - Meiqing Mai
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, 523808, China
| | - Honghui Guo
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, 523808, China. .,Dongguan Key Laboratory of Environmental Medicine, Guangdong Medical University, Dongguan, 523808, China.
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34
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Jacob JS, Ahmed A, Cholankeril G. The impact of alteration in gut microbiome in the pathogenesis of nonalcoholic fatty liver disease. Curr Opin Infect Dis 2021; 34:477-482. [PMID: 34267042 DOI: 10.1097/qco.0000000000000759] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW We have increasing evidence that alterations of the intestinal microbiome have a strong influence on human health. Previous work has demonstrated the association between changes in the microbiome and metabolic risk factors. One related area of interest is the relationship between dysbiosis and nonalcoholic fatty liver disease (NAFLD), as the global prevalence of NAFLD, and its resultant complications, increases. RECENT FINDINGS In this review, we summarize the hypothesized pathophysiology of dysbiosis-mediated progression of NAFLD, including promotion of an inflammatory intestinal environment, increased intestinal permeability, endogenous ethanol production, short-chain fatty acid production, secondary bile acid metabolism, and choline depletion. We also review potential therapeutic interventions of the microbiome to slow or prevent NAFLD progression, including antibiotics, probiotics, prebiotics, fecal microbiota transplant, and farnesoid × receptor agonism. SUMMARY Much of the evidence supporting dysbiosis-mediated NAFLD progression has been gathered in high-quality animal trials. There remains a need for additional observational and randomized controlled trials in humans to establish causality between the suspected factors and pathogenesis of NAFLD.
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Affiliation(s)
- Jake S Jacob
- Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford, California
| | - George Cholankeril
- Liver Center, Division of Abdominal Transplantation, Michael E DeBakey Department of General Surgery, Baylor College of Medicine
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
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35
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Bozward AG, Ronca V, Osei-Bordom D, Oo YH. Gut-Liver Immune Traffic: Deciphering Immune-Pathogenesis to Underpin Translational Therapy. Front Immunol 2021; 12:711217. [PMID: 34512631 PMCID: PMC8425300 DOI: 10.3389/fimmu.2021.711217] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022] Open
Abstract
The tight relationship between the gut and liver on embryological, anatomical and physiological levels inspired the concept of a gut-liver axis as a central element in the pathogenesis of gut-liver axis diseases. This axis refers to the reciprocal regulation between these two organs causing an integrated system of immune homeostasis or tolerance breakdown guided by the microbiota, the diet, genetic background, and environmental factors. Continuous exposure of gut microbiome, various hormones, drugs and toxins, or metabolites from the diet through the portal vein adapt the liver to maintain its tolerogenic state. This is orchestrated by the combined effort of immune cells network: behaving as a sinusoidal and biliary firewall, along with a regulatory network of immune cells including, regulatory T cells and tolerogenic dendritic cells (DC). In addition, downregulation of costimulatory molecules on hepatic sinusoids, hepatocytes and biliary epithelial cells as well as regulating the bile acids chain also play a part in hepatic immune homeostasis. Recent evidence also demonstrated the link between changes in the gut microbiome and liver resident immune cells in the progression of cirrhosis and the tight correlation among primary sclerosing cholangitis (PSC) and also checkpoint induced liver and gut injury. In this review, we will summarize the most recent evidence of the bidirectional relationship among the gut and the liver and how it contributes to liver disease, focusing mainly on PSC and checkpoint induced hepatitis and colitis. We will also focus on completed therapeutic options and on potential targets for future treatment linking with immunology and describe the future direction of this research, taking advantage of modern technologies.
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Affiliation(s)
- Amber G. Bozward
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network - Rare Liver Centre, Birmingham, United Kingdom
- Birmingham Advanced Cellular Therapy Facility, University of Birmingham, Birmingham, United Kingdom
| | - Vincenzo Ronca
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network - Rare Liver Centre, Birmingham, United Kingdom
| | - Daniel Osei-Bordom
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Queen Elizabeth Hospital, University Hospital of Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
| | - Ye Htun Oo
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network - Rare Liver Centre, Birmingham, United Kingdom
- Birmingham Advanced Cellular Therapy Facility, University of Birmingham, Birmingham, United Kingdom
- Queen Elizabeth Hospital, University Hospital of Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
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Visekruna A, Luu M. The Role of Short-Chain Fatty Acids and Bile Acids in Intestinal and Liver Function, Inflammation, and Carcinogenesis. Front Cell Dev Biol 2021; 9:703218. [PMID: 34381785 PMCID: PMC8352571 DOI: 10.3389/fcell.2021.703218] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/06/2021] [Indexed: 12/12/2022] Open
Abstract
During the past decade, researchers have investigated the role of microbiota in health and disease. Recent findings support the hypothesis that commensal bacteria and in particular microbiota-derived metabolites have an impact on development of inflammation and carcinogenesis. Major classes of microbial-derived molecules such as short-chain fatty acids (SCFA) and secondary bile acids (BAs) were shown to have immunomodulatory potential in various autoimmune, inflammatory as well as cancerous disease models and are dependent on diet-derived substrates. The versatile mechanisms underlying both beneficial and detrimental effects of bacterial metabolites comprise diverse regulatory pathways in lymphocytes and non-immune cells including changes in the signaling, metabolic and epigenetic status of these. Consequently, SCFAs as strong modulators of immunometabolism and histone deacetylase (HDAC) inhibitors have been investigated as therapeutic agents attenuating inflammatory and autoimmune disorders. Moreover, BAs were shown to modulate the microbial composition, adaptive and innate immune response. In this review, we will discuss the recent findings in the field of microbiota-derived metabolites, especially with respect to the molecular and cellular mechanisms of SCFA and BA biology in the context of intestinal and liver diseases.
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Affiliation(s)
- Alexander Visekruna
- Institute for Medical Microbiology and Hygiene, Philipps-University Marburg, Marburg, Germany
| | - Maik Luu
- Institute for Medical Microbiology and Hygiene, Philipps-University Marburg, Marburg, Germany.,Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
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Activation of a Specific Gut Bacteroides-Folate-Liver Axis Benefits for the Alleviation of Nonalcoholic Hepatic Steatosis. Cell Rep 2021; 32:108005. [PMID: 32783933 DOI: 10.1016/j.celrep.2020.108005] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 06/24/2020] [Accepted: 07/16/2020] [Indexed: 02/08/2023] Open
Abstract
A beneficial gut Bacteroides-folate-liver pathway regulating lipid metabolism is demonstrated. Oral administration of a Ganoderma meroterpene derivative (GMD) ameliorates nonalcoholic hepatic steatosis in the liver of fa/fa rats by reducing endotoxemia, enhancing lipid oxidation, decreasing de novo lipogenesis, and suppressing lipid export from the liver. An altered gut microbiota with an increase of butyrate and folate plays a causative role in the effects of GMD. The commensal bacteria Bacteroides xylanisolvens, Bacteroides thetaiotaomicron, Bacteroides dorei, and Bacteroides uniformis, which are enriched by GMD, are major contributors to the increased gut folate. Administration of live B. xylanisolvens reduces hepatic steatosis and enhances the folate-mediated signaling pathways in mice. Knockout of the folate biosynthetic folp gene in B. xylanisolvens blocks its folate production and beneficial effects. This work confirms the therapeutic potential of GMD and B. xylanisolvens in alleviating nonalcoholic hepatic steatosis and provides evidence for benefits of the gut Bacteroides-folate-liver pathway.
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Mirzaei R, Afaghi A, Babakhani S, Sohrabi MR, Hosseini-Fard SR, Babolhavaeji K, Khani Ali Akbari S, Yousefimashouf R, Karampoor S. Role of microbiota-derived short-chain fatty acids in cancer development and prevention. Biomed Pharmacother 2021; 139:111619. [PMID: 33906079 DOI: 10.1016/j.biopha.2021.111619] [Citation(s) in RCA: 177] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 04/01/2021] [Accepted: 04/12/2021] [Indexed: 02/07/2023] Open
Abstract
Following cancer, cells in a particular tissue can no longer respond to the factors involved in controlling cell survival, differentiation, proliferation, and death. In recent years, it has been indicated that alterations in the gut microbiota components, intestinal epithelium, and host immune system are associated with cancer incidence. Also, it has been demonstrated that the short-chain fatty acids (SCFAs) generated by gut microbiota are vitally crucial in cell homeostasis as they contribute to the modulation of histone deacetylases (HDACs), resulting effected cell attachment, immune cell immigration, cytokine production, chemotaxis, and the programmed cell death. Therefore, the manipulation of SCFA levels in the intestinal tract by alterations in the microbiota structure can be potentially taken into consideration for cancer treatment/prevention. In the current study, we will explain the most recent findings on the detrimental or protective roles of SFCA (particularly butyrate, propionate, and acetate) in several cancers, including bladder, colon, breast, stomach, liver, lung, pancreas, and prostate cancers.
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Affiliation(s)
- Rasoul Mirzaei
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
| | - Azam Afaghi
- Department of Biology, Sofian Branch, Islamic Azad University, Sofian, Iran
| | - Sajad Babakhani
- Department of Microbiology, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Masoud Reza Sohrabi
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Reza Hosseini-Fard
- Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kiandokht Babolhavaeji
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Shabnam Khani Ali Akbari
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Rasoul Yousefimashouf
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Zhang C, Cui X, Feng L, Han Z, Peng D, Fu W, Xing Y. The deficiency of FKBP-5 inhibited hepatocellular progression by increasing the infiltration of distinct immune cells and inhibiting obesity-associated gut microbial metabolite. J Gastrointest Oncol 2021; 12:711-721. [PMID: 34012660 DOI: 10.21037/jgo-21-71] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Gut microbiota has a number of essential roles in nutrition metabolism and immune homeostasis, and is closely related to hepatocellular progression. In recent years, studies have also shown that FK506 binding protein 5 (FKBP-5) plays a crucial role in immune regulation. However, it is not yet clear whether FKBP-5 promotes the development of hepatocellular carcinoma (HCC) by affecting immune function and gut microbiota. Methods FKBP-5 expression was verified by immunochemistry and western blot and reverse transcription polymerase chain reaction (RT-qPCR) assays. After treatment in WT and FKBP-5-/- mice, the histological characteristic of mice liver tissue was assessed by H&E staining, and hepatic leukocytes and hepatic NKT cells were identified by flow cytometer. Meanwhile, primary bile acids (BAs), secondary BAs, serum total cholesterol, and the weight of abdomen adipose tissues were examined, and the gut microbiota was evaluated by 16S ribosomal ribonucleic acid (rRNA) sequencing. Results We discovered that FKBP-5 was highly expressed in HCC tissues. Meanwhile, FKBP-5 deletion inhibited tumor progression by increasing CD8+ T, CD4+ T, NKT and CD4+NKT cells in mice after diethylnitrosamine (DEN) injection. Besides, we proved that FKBP-5 deletion generated rapid and significant reductions in the intestinal BAs, the weight of abdomen adipose tissues and the serum total cholesterol. FKBP-5 deletion also led to a change in the composition of gut microbiota, suggesting that BAs are the main dietary factor regulating gut microbiota, which could be affected by FKBP-5 deletion. Further, we uncovered that anti-CD4 and anti-CD8 treatments facilitated hepatocellular progression by modulating gut microbiota composition in FKBP-5-/- mice. Conclusions Therefore, we demonstrated that FKBP-5 deletion inhibited hepatocellular progression by modulating immune response and gut microbiome-mediated BAs metabolism.
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Affiliation(s)
- Chuantao Zhang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiang Cui
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
| | - Lian Feng
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Zhiyi Han
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
| | - Deti Peng
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
| | - Wenjun Fu
- South China Research Center for Acupuncture and Moxibustion, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yufeng Xing
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
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An update on the role of the microbiome in non-alcoholic fatty liver disease pathogenesis, diagnosis, and treatment. ACTA ACUST UNITED AC 2021; 18:270-280. [PMID: 33716495 DOI: 10.1007/s11938-020-00290-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The microbiome was originally postulated to contribute to the pathogenesis of NAFLD when the first studies of dysbiosis in NAFLD were reported. Since then, a number of studies have investigated this finding further, in order to discern whether the dysbiosis is the result of the metabolic dysregulation seen with NAFLD or a contributor to the pathogenesis of this condition.
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Yang X, Mo W, Zheng C, Li W, Tang J, Wu X. Alleviating effects of noni fruit polysaccharide on hepatic oxidative stress and inflammation in rats under a high-fat diet and its possible mechanisms. Food Funct 2021; 11:2953-2968. [PMID: 32315005 DOI: 10.1039/d0fo00178c] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease is associated with gut microbiota, oxidative stress, and inflammation. We aimed to investigate the possible mechanism by which noni fruit polysaccharide (NFP) improved hepatic oxidative stress and inflammation in rats under a high-fat diet (HFD) by modulating short-chain fatty acids (SCFAs), the intestinal barrier, and gut microbiota. Hepatic oxidative stress, inflammation, and gut dysbiosis in rats were induced through HFD feeding for 4 weeks, followed by intervention with NFP treatment (100 mg per kg bw) for 5 weeks. The results showed that NFP reduced body weight gain and improved lipid metabolism, hepatic oxidative stress, and inflammation in rats under a HFD. Aside from these beneficial effects, NFP positively affected the SCFA production and reversed the HFD-induced gut dysbiosis as indicated by improved microbiota diversity and composition. The levels of Lactobacillus, Ruminococcaceae_UCG_014, Parasutterella, [Eubacterium]_coprostanoligenes_group, and Ruminococcus_1 improved, whereas the levels of Prevotella_9, Collinsella, Bacteroides, and Turicibacter decreased. Furthermore, NFP maintained the colonic barrier integrity (increased the mRNA relative expression of CCL5, ZO-1, and occludin in the colon, and decreased the serum CCL5 level), and decreased the serum lipopolysaccharide level. Thus, NFP may modulate the gut microflora and SCFA production and reduce the permeability of the colonic barrier and metabolic endotoxemia, thereby alleviating hepatic oxidative stress and inflammation in rats under a HFD.
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Affiliation(s)
- Xiaobing Yang
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Wenjing Mo
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Chuanjin Zheng
- School of Food Science, Guangdong Pharmaceutical University, Zhongshan 528453, China.
| | - Wenzhi Li
- Infinitus (China) Co. Ltd, Xinhui 529156, China
| | - Jian Tang
- Infinitus (China) Co. Ltd, Xinhui 529156, China
| | - Xiaoyong Wu
- School of Food Science, Guangdong Pharmaceutical University, Zhongshan 528453, China.
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Yang M, Zhang CY. G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment. World J Gastroenterol 2021; 27:677-691. [PMID: 33716447 PMCID: PMC7934005 DOI: 10.3748/wjg.v27.i8.677] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/24/2020] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a broad-spectrum disease, ranging from simple hepatic steatosis to nonalcoholic steatohepatitis, which can progress to cirrhosis and liver cancer. Abnormal hepatic lipid accumulation is the major manifestation of this disease, and lipotoxicity promotes NAFLD progression. In addition, intermediate metabolites such as succinate can stimulate the activation of hepatic stellate cells to produce extracellular matrix proteins, resulting in progression of NAFLD to fibrosis and even cirrhosis. G protein-coupled receptors (GPCRs) have been shown to play essential roles in metabolic disorders, such as NAFLD and obesity, through their function as receptors for bile acids and free fatty acids. In addition, GPCRs link gut microbiota-mediated connections in a variety of diseases, such as intestinal diseases, hepatic steatosis, diabetes, and cardiovascular diseases. The latest findings show that gut microbiota-derived acetate contributes to liver lipogenesis by converting dietary fructose into hepatic acetyl-CoA and fatty acids. GPCR agonists, including peptides and natural products like docosahexaenoic acid, have been applied to investigate their role in liver diseases. Therapies such as probiotics and GPCR agonists may be applied to modulate GPCR function to ameliorate liver metabolism syndrome. This review summarizes the current findings regarding the role of GPCRs in the development and progression of NAFLD and describes some preclinical and clinical studies of GPCR-mediated treatment. Overall, understanding GPCR-mediated signaling in liver disease may provide new therapeutic options for NAFLD.
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Affiliation(s)
- Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
| | - Chun-Ye Zhang
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65212, United States
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Zhou H, Ma C, Wang C, Gong L, Zhang Y, Li Y. Research progress in use of traditional Chinese medicine monomer for treatment of non-alcoholic fatty liver disease. Eur J Pharmacol 2021; 898:173976. [PMID: 33639194 DOI: 10.1016/j.ejphar.2021.173976] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 02/09/2021] [Accepted: 02/19/2021] [Indexed: 02/06/2023]
Abstract
With the improvement of people's living standards and the change of eating habits, non-alcoholic fatty liver disease (NAFLD) has gradually become one of the most common chronic liver diseases in the world. However, there are no effective drugs for the treatment of NAFLD. Therefore, it is urgent to find safe, efficient, and economical anti-NAFLD drugs. Compared with western medicines that possess fast lipid-lowering effect, traditional Chinese medicines (TCM) have attracted increasing attention for the treatment of NAFLD due to their unique advantages such as multi-targets and multi-channel mechanisms of action. TCM monomers have been proved to treat NAFLD through regulating various pathways, including inflammation, lipid production, insulin sensitivity, mitochondrial dysfunction, autophagy, and intestinal microbiota. In particular, peroxisome proliferator-activated receptor α (PPAR-α), sterol regulatory element-binding protein 1c (SREBP-1c), nuclear transcription factor kappa (NF-κB), phosphoinositide 3-kinase (PI3K), sirtuin1 (SIRT1), AMP-activated protein kinase (AMPK), p53 and nuclear factor erythroid 2-related factor 2 (Nrf2) are considered as important molecular targets for ameliorating NAFLD by TCM monomers. Therefore, by searching PubMed, Web of Science and SciFinder databases, this paper updates and summarizes the experimental and clinical evidence of TCM monomers for the treatment of NAFLD in the past six years (2015-2020), thus providing thoughts and prospects for further exploring the pathogenesis of NAFLD and TCM monomer therapies.
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Affiliation(s)
- Honglin Zhou
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Cheng Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Cheng Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Lihong Gong
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yafang Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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Zhao M, Chen S, Ji X, Shen X, You J, Liang X, Yin H, Zhao L. Current innovations in nutraceuticals and functional foods for intervention of non-alcoholic fatty liver disease. Pharmacol Res 2021; 166:105517. [PMID: 33636349 DOI: 10.1016/j.phrs.2021.105517] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/27/2021] [Accepted: 02/21/2021] [Indexed: 02/07/2023]
Abstract
As innovations in global agricultural production and food trading systems lead to major dietary shifts, high morbidity rates from non-alcoholic fatty liver disease (NAFLD), accompanied by elevated risk of lipid metabolism-related complications, has emerged as a growing problem worldwide. Treatment and prevention of NAFLD and chronic liver disease depends on the availability of safe, effective, and diverse therapeutic agents, the development of which is urgently needed. Supported by a growing body of evidence, considerable attention is now focused on interventional approaches that combines nutraceuticals and functional foods. In this review, we summarize the pathological progression of NAFLD and discuss the beneficial effects of nutraceuticals and the active ingredients in functional foods. We also describe the underlying mechanisms of these compounds in the intervention of NAFLD, including their effects on regulation of lipid homeostasis, activation of signaling pathways, and their role in gut microbial community dynamics and the gut-liver axis. In order to identify novel targets for treatment of lipid metabolism-related diseases, this work broadly explores the molecular mechanism linking nutraceuticals and functional foods, host physiology, and gut microbiota. Additionally, the limitations in existing knowledge and promising research areas for development of active interventions and treatments against NAFLD are discussed.
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Affiliation(s)
- Mengyao Zhao
- School of Biotechnology, State Key Laboratory of Bioreactor Engineering, R&D Center of Separation and Extraction Technology in Fermentation Industry, East China University of Science and Technology, Shanghai 200237, China; Shanghai Collaborative Innovation Center for Biomanufacturing Technology (SCICBT), Shanghai 200237, China
| | - Shumin Chen
- School of Biotechnology, State Key Laboratory of Bioreactor Engineering, R&D Center of Separation and Extraction Technology in Fermentation Industry, East China University of Science and Technology, Shanghai 200237, China
| | - Xiaoguo Ji
- School of Biotechnology, State Key Laboratory of Bioreactor Engineering, R&D Center of Separation and Extraction Technology in Fermentation Industry, East China University of Science and Technology, Shanghai 200237, China
| | - Xin Shen
- School of Biotechnology, State Key Laboratory of Bioreactor Engineering, R&D Center of Separation and Extraction Technology in Fermentation Industry, East China University of Science and Technology, Shanghai 200237, China
| | - Jiangshan You
- School of Biotechnology, State Key Laboratory of Bioreactor Engineering, R&D Center of Separation and Extraction Technology in Fermentation Industry, East China University of Science and Technology, Shanghai 200237, China
| | - Xinyi Liang
- School of Biotechnology, State Key Laboratory of Bioreactor Engineering, R&D Center of Separation and Extraction Technology in Fermentation Industry, East China University of Science and Technology, Shanghai 200237, China
| | - Hao Yin
- Organ Transplant Center, Shanghai Changzheng Hospital, Shanghai 200003, China.
| | - Liming Zhao
- School of Biotechnology, State Key Laboratory of Bioreactor Engineering, R&D Center of Separation and Extraction Technology in Fermentation Industry, East China University of Science and Technology, Shanghai 200237, China; School of Life Science, Shandong University of Technology, Zibo, Shandong 255000, China; Shanghai Collaborative Innovation Center for Biomanufacturing Technology (SCICBT), Shanghai 200237, China.
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Effects of chitooligosaccharides on the rebalance of gut microorganisms and their metabolites in patients with nonalcoholic fatty liver disease. J Funct Foods 2021. [DOI: 10.1016/j.jff.2020.104333] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Tan H, Nie S. Functional hydrocolloids, gut microbiota and health: picking food additives for personalized nutrition. FEMS Microbiol Rev 2021; 45:6123724. [PMID: 33512498 DOI: 10.1093/femsre/fuaa065] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 12/02/2020] [Indexed: 12/15/2022] Open
Abstract
The human gut microbiota respond to particular food components, interact with intestinal mucosa and thereby contribute to health and diseases. Key microbiome features are under comprehensive investigation and are likely to be developed as reliable evidences for clinical diagnosis. And the underlying mechanisms lay the foundation of assembling bespoke nutritional ingredients including functional food additives that may lead to favorable outcomes in facilitating amelioration of host dysfunctions. Functional hydrocolloids serve as multiple food additives with promising application prospects and outstanding adjunctive beneficial characteristics. Therefore, in this review, we introduce the latest advances in food additives-gut microbiota-host axis by summarizing the physiochemical and physiological properties of a collection of functional hydrocolloids from various sources, describing the functional hydrocolloids-related intestinal commensal markers, and deciphering the underlying mechanisms of their beneficial effects, and propose the feasibilities and guidelines for further developments of gut microbiota-oriented personalized nutrition.
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Affiliation(s)
- Huizi Tan
- State Key Laboratory of Food Science and Technology, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Nanchang University, China
| | - Shaoping Nie
- State Key Laboratory of Food Science and Technology, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Nanchang University, China
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Hullar MAJ, Jenkins IC, Randolph TW, Curtis KR, Monroe KR, Ernst T, Shepherd JA, Stram DO, Cheng I, Kristal BS, Wilkens LR, Franke A, Le Marchand L, Lim U, Lampe JW. Associations of the gut microbiome with hepatic adiposity in the Multiethnic Cohort Adiposity Phenotype Study. Gut Microbes 2021; 13:1965463. [PMID: 34491886 PMCID: PMC8425768 DOI: 10.1080/19490976.2021.1965463] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 07/09/2021] [Accepted: 07/27/2021] [Indexed: 02/04/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a risk factor for liver cancer and prevalence varies by ethnicity. Along with genetic and lifestyle factors, the gut microbiome (GM) may contribute to NAFLD and its progression to advanced liver disease. Our cross-sectional analysis assessed the association of the GM with hepatic adiposity among African American, Japanese American, White, Latino, and Native Hawaiian participants in the Multiethnic Cohort. We used MRI to measure liver fat and determine nonalcoholic fatty liver disease (NAFLD) status (n = 511 cases) in 1,544 participants, aged 60-77 years, with 12-53% overall adiposity (BMI of 17.8-46.2 kg/m2). The GM was measured by 16S rRNA gene sequencing and, on a subset, by metagenomic sequencing. Alpha diversity was lower overall with NAFLD and in certain ethnicities (African Americans, Whites, and Latinos). In models regressing genus on NAFLD status, 62 of 149 genera (40%) exhibited a significant interaction between NAFLD and ethnicity stratified analysis found 69 genera significantly associated with NAFLD in at least one ethnic group. No single genus was significantly associated with NAFLD across all ethnicities. In contrast, the same bacterial metabolic pathways were over-represented in participants with NAFLD regardless of ethnicity. Imputed secondary bile acid and carbohydrate pathways were associated with NAFLD, the latter of which was corroborated by metagenomics, although different genera in different ethnicities were associated with these pathways. Overall, we found that NAFLD was associated with altered bacterial composition and metabolism, and that bacterial endotoxin, assessed by plasma lipopolysaccharide binding protein (LBP), may mediate liver fat-associated systemic inflammation in a manner that seems to vary by ethnicity.
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Affiliation(s)
- Meredith A. J. Hullar
- Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, U.S.A
| | - Isaac C. Jenkins
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, U.S.A
| | - Timothy W. Randolph
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, U.S.A
| | - Keith R. Curtis
- Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, U.S.A
| | - Kristine R. Monroe
- Preventive Medicine, Keck School Of Medicine, University Of Southern California, Los Angeles, California, U.S.A
| | - Thomas Ernst
- John A. Burns School Of Medicine, University Of Hawaii, Honolulu, Hawaii, U.S.A
| | - John A. Shepherd
- University Of Hawaii Cancer Center, University Of Hawaii, Honolulu, Hawaii, U.S.A
| | - Daniel O. Stram
- Keck School Of Medicine, University Of Southern California, Los Angeles, California, U.S.A
| | - Iona Cheng
- School Of Medicine, University Of California San Francisco, San Francisco, California, U.S.A
| | - Bruce S. Kristal
- Department Of Medicine, Brigham And Women’s Hospital And Harvard Medical School, Boston, Massachusetts, U.S.A
| | - Lynne R. Wilkens
- University Of Hawaii Cancer Center, University Of Hawaii, Honolulu, Hawaii, U.S.A
| | - Adrian Franke
- University Of Hawaii Cancer Center, University Of Hawaii, Honolulu, Hawaii, U.S.A
| | - Loic Le Marchand
- University Of Hawaii Cancer Center, University Of Hawaii, Honolulu, Hawaii, U.S.A
| | - Unhee Lim
- University Of Hawaii Cancer Center, University Of Hawaii, Honolulu, Hawaii, U.S.A
| | - Johanna W. Lampe
- Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, U.S.A
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48
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Moore R, Anturaniemi J, Velagapudi V, Nandania J, Barrouin-Melo SM, Hielm-Björkman A. Targeted Metabolomics With Ultraperformance Liquid Chromatography-Mass Spectrometry (UPLC-MS) Highlights Metabolic Differences in Healthy and Atopic Staffordshire Bull Terriers Fed Two Different Diets, A Pilot Study. Front Vet Sci 2020; 7:554296. [PMID: 33195525 PMCID: PMC7653775 DOI: 10.3389/fvets.2020.554296] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 09/22/2020] [Indexed: 01/09/2023] Open
Abstract
Background: While anecdotal evidence has long claimed that a raw meat-based diet (RMBD) improves the metabolic health of canines, no rigorous scientific study has clarified this issue. Canine atopic dermatitis (CAD) has also been linked to metabolic health, but its relation to diet remains poorly understood. This study investigates whether dietary choice is linked to metabolic health in healthy and CAD-diagnosed canines via targeted serum and urine metabolomic analysis of polar, non-ionic metabolites, as well as whether the underlying CAD condition modulates the response to nutritional intake. Materials and Methods: Serum metabolites of client-owned Staffordshire bull terriers, divided into CAD-diagnosed (n = 14) and healthy (n = 6) cohorts, were studied. Urine metabolites of a subset of the CAD-diagnosed canines (n = 8) were also studied. The canines were split into two cohorts based on diet. The first cohort were fed a commercially available high-fat, moderate-protein, low-carbohydrate RMBD (n = 11, CAD diagnosed n = 8, healthy n = 3). Those in the second cohort were fed a commercially available moderate-fat, moderate-protein, high-carbohydrate kibble diet (KD) (n = 9: CAD diagnosed n = 6, healthy n = 3). The diet intervention period lasted approximately 4.5 months (median 135 days). Statistical analyses of the serum profiles across all dogs (n = 20) and the urine profiles of the CAD-diagnosed subset (n = 8) were performed. Results and Discussion: The KD cohort was found to have higher concentrations of methionine than the RMBD cohort, both in serum (all dogs, p < 0.0001) and in urine (CAD-only cohort, p < 0.0002), as well as cystathionine and 4-pyridoxic acid. Methionine plays important roles in homocysteine metabolism, and elevated levels have been implicated in various pathologies. The CAD (n = 14) cohort dogs showed starker metabolic changes in response to diet regarding these pathways compared to the healthy (n = 6) cohort. However, there was no significant change in CAD severity as a result of either diet. Likely due to the higher meat content of the RMBD, higher concentrations of several carnitines and creatine were found in the RMBD cohort. Citrulline was found in higher concentrations in the KD cohort. Our findings provide insight into the relationship between diet and the serum and urine metabolite profiles of canines. They also suggest that neither diet significantly affected CAD severity.
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Affiliation(s)
- Robin Moore
- Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland
| | - Johanna Anturaniemi
- Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland
| | - Vidya Velagapudi
- Metabolomics Unit, Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | - Jatin Nandania
- Metabolomics Unit, Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | - Stella Maria Barrouin-Melo
- Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland
- Department of Veterinary Anatomy, Pathology and Clinics, School of Veterinary Medicine and Zootechny, Federal University of Bahia, Salvador, Brazil
| | - Anna Hielm-Björkman
- Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland
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49
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Pauly MJ, Rohde JK, John C, Evangelakos I, Koop AC, Pertzborn P, Tödter K, Scheja L, Heeren J, Worthmann A. Inulin Supplementation Disturbs Hepatic Cholesterol and Bile Acid Metabolism Independent from Housing Temperature. Nutrients 2020; 12:nu12103200. [PMID: 33092056 PMCID: PMC7589137 DOI: 10.3390/nu12103200] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/16/2020] [Accepted: 10/17/2020] [Indexed: 01/04/2023] Open
Abstract
Dietary fibers are fermented by gut bacteria into the major short chain fatty acids (SCFAs) acetate, propionate, and butyrate. Generally, fiber-rich diets are believed to improve metabolic health. However, recent studies suggest that long-term supplementation with fibers causes changes in hepatic bile acid metabolism, hepatocyte damage, and hepatocellular cancer in dysbiotic mice. Alterations in hepatic bile acid metabolism have also been reported after cold-induced activation of brown adipose tissue. Here, we aim to investigate the effects of short-term dietary inulin supplementation on liver cholesterol and bile acid metabolism in control and cold housed specific pathogen free wild type (WT) mice. We found that short-term inulin feeding lowered plasma cholesterol levels and provoked cholestasis and mild liver damage in WT mice. Of note, inulin feeding caused marked perturbations in bile acid metabolism, which were aggravated by cold treatment. Our studies indicate that even relatively short periods of inulin consumption in mice with an intact gut microbiome have detrimental effects on liver metabolism and function.
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Affiliation(s)
- Mira J. Pauly
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (M.J.P.); (J.K.R.); (C.J.); (I.E.); (P.P.); (K.T.); (L.S.); (J.H.)
| | - Julia K. Rohde
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (M.J.P.); (J.K.R.); (C.J.); (I.E.); (P.P.); (K.T.); (L.S.); (J.H.)
| | - Clara John
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (M.J.P.); (J.K.R.); (C.J.); (I.E.); (P.P.); (K.T.); (L.S.); (J.H.)
| | - Ioannis Evangelakos
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (M.J.P.); (J.K.R.); (C.J.); (I.E.); (P.P.); (K.T.); (L.S.); (J.H.)
| | - Anja Christina Koop
- Department of Internal Medicine I, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
| | - Paul Pertzborn
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (M.J.P.); (J.K.R.); (C.J.); (I.E.); (P.P.); (K.T.); (L.S.); (J.H.)
| | - Klaus Tödter
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (M.J.P.); (J.K.R.); (C.J.); (I.E.); (P.P.); (K.T.); (L.S.); (J.H.)
| | - Ludger Scheja
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (M.J.P.); (J.K.R.); (C.J.); (I.E.); (P.P.); (K.T.); (L.S.); (J.H.)
| | - Joerg Heeren
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (M.J.P.); (J.K.R.); (C.J.); (I.E.); (P.P.); (K.T.); (L.S.); (J.H.)
| | - Anna Worthmann
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (M.J.P.); (J.K.R.); (C.J.); (I.E.); (P.P.); (K.T.); (L.S.); (J.H.)
- Correspondence:
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50
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Nogacka AM, de Los Reyes-Gavilán CG, Martínez-Faedo C, Ruas-Madiedo P, Suarez A, Mancabelli L, Ventura M, Cifuentes A, León C, Gueimonde M, Salazar N. Impact of Extreme Obesity and Diet-Induced Weight Loss on the Fecal Metabolome and Gut Microbiota. Mol Nutr Food Res 2020; 65:e2000030. [PMID: 32966685 DOI: 10.1002/mnfr.202000030] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
SCOPE A limited number of human studies have characterized fecal microbiota and metabolome in extreme obesity and after diet-induced weight loss. METHODS AND RESULTS Fecal samples from normal-weight and extremely obese adults and from obese participants before and after moderate diet-induced weight loss are evaluated for their interaction with the intestinal adenocarcinoma cell line HT29 using an impedance-based in vitro model, which reveals variations in the interaction between the gut microbiota and host linked to obesity status. Microbiota composition, short chain fatty acids, and other intestinal metabolites are further analyzed to assess the interplay among diet, gut microbiota, and host in extreme obesity. Microbiota profiles are distinct between normal-weight and obese participants and are accompanied by fecal signatures in the metabolism of biliary compounds and catecholamines. Moderate diet-induced weight loss promotes shifts in the gut microbiota, and the primary fecal metabolomics features are associated with diet and the gut-liver and gut-brain axes. CONCLUSIONS Analyses of the fecal microbiota and metabolome enable assessment of the impact of diet on gut microbiota composition and activity, supporting the potential use of certain fecal metabolites or members of the gut microbiota as biomarkers for the efficacy of weight loss in extreme obesity.
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Affiliation(s)
- Alicja M Nogacka
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (IPLA-CSIC), Villaviciosa, Asturias, 33300, Spain.,Diet, Human Microbiota and Health Group, Institute of Health Research of the Principality of Asturias (ISPA), Oviedo, 33011, Spain
| | - Clara G de Los Reyes-Gavilán
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (IPLA-CSIC), Villaviciosa, Asturias, 33300, Spain.,Diet, Human Microbiota and Health Group, Institute of Health Research of the Principality of Asturias (ISPA), Oviedo, 33011, Spain
| | - Ceferino Martínez-Faedo
- Endocrinology and Nutrition Service, Central University Hospital of Asturias (HUCA), Oviedo, Asturias, 33011, Spain.,Endocrinology, Nutrition, Diabetes and Obesity Group, Institute of Health Research of the Principality of Asturias (ISPA), Oviedo, 33011, Spain
| | - Patricia Ruas-Madiedo
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (IPLA-CSIC), Villaviciosa, Asturias, 33300, Spain.,Functionality and Ecology of Beneficial Microorganisms, Institute of Health Research of the Principality of Asturias (ISPA), Oviedo, 33011, Spain
| | - Adolfo Suarez
- Diet, Human Microbiota and Health Group, Institute of Health Research of the Principality of Asturias (ISPA), Oviedo, 33011, Spain.,Digestive Service, Central University Hospital of Asturias (HUCA), Oviedo, Asturias, 33011, Spain
| | - Leonardo Mancabelli
- Laboratory of Probiogenomics, Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, 43121, Italy
| | - Marco Ventura
- Laboratory of Probiogenomics, Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, 43121, Italy
| | - Alejandro Cifuentes
- Laboratory of Foodomics, Institute of Food Science Research, CIAL, CSIC, Nicolás Cabrera 9, Madrid, 28049, Spain
| | - Carlos León
- Department of Bioengineering, Universidad Carlos III de Madrid, Leganés, Madrid, Spain
| | - Miguel Gueimonde
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (IPLA-CSIC), Villaviciosa, Asturias, 33300, Spain.,Diet, Human Microbiota and Health Group, Institute of Health Research of the Principality of Asturias (ISPA), Oviedo, 33011, Spain
| | - Nuria Salazar
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (IPLA-CSIC), Villaviciosa, Asturias, 33300, Spain.,Diet, Human Microbiota and Health Group, Institute of Health Research of the Principality of Asturias (ISPA), Oviedo, 33011, Spain
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