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Zhang Y, Mo C, Ai P, He X, Xiao Q, Yang X. Pharmacomicrobiomics: a new field contributing to optimizing drug therapy in Parkinson's disease. Gut Microbes 2025; 17:2454937. [PMID: 39875349 PMCID: PMC11776486 DOI: 10.1080/19490976.2025.2454937] [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: 06/17/2024] [Revised: 11/19/2024] [Accepted: 01/13/2025] [Indexed: 01/30/2025] Open
Abstract
Gut microbiota, which act as a determinant of pharmacokinetics, have long been overlooked. In recent years, a growing body of evidence indicates that the gut microbiota influence drug metabolism and efficacy. Conversely, drugs also exert a substantial influence on the function and composition of the gut microbiota. Pharmacomicrobiomics, an emerging field focusing on the interplay of drugs and gut microbiota, provides a potential foundation for making certain advances in personalized medicine. Understanding the communication between gut microbiota and antiparkinsonian drugs is critical for precise treatment of Parkinson's disease. Here, we provide a historical overview of the interplay between gut microbiota and antiparkinsonian drugs. Moreover, we discuss potential mechanistic insights into the complex associations between gut microbiota and drug metabolism. In addition, we also draw attention to microbiota-based biomarkers for predicting antiparkinsonian drug efficacy and examine current state-of-the-art knowledge of microbiota-based strategies to optimize drug therapy in Parkinson's disease.
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Affiliation(s)
- Yi Zhang
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengjun Mo
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Penghui Ai
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoqin He
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qin Xiao
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaodong Yang
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Chakraborty S, Anand S, Numan M, Bhandari RK. Ancestral bisphenol A exposure led to non-alcoholic fatty liver disease and sex-specific alterations in proline and bile metabolism pathways in the liver. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY 2025; 44:958-972. [PMID: 39953842 PMCID: PMC11933882 DOI: 10.1093/etojnl/vgae081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 11/18/2024] [Accepted: 12/02/2024] [Indexed: 02/17/2025]
Abstract
Endocrine-disrupting chemicals can induce metabolic alterations, resulting in diseases such as obesity, diabetes, and fatty liver disease, which can be inherited by offspring inhabiting uncontaminated environments. Bisphenol A (BPA), a well-known endocrine disruptor, can induce endocrine disruption, leading to metabolic disorders in subsequent generations without further exposure to BPA via nongenetic transgenerational inheritance. Using medaka as an animal model, we reported that ancestral BPA exposure leads to transgenerational nonalcoholic fatty liver disease (NAFLD) in grandchildren four generations after the initial exposure. It is unclear if transgenerational NAFLD developed because ancestral BPA exposure differs from that developed due to direct and continuous BPA exposure because the transgenerational disease develops in the absence of the stressor. We induced transgenerational NAFLD in medaka with ancestral BPA exposure (10 µg/L) at the F0 generation and examined transcriptional and metabolomic alterations in the liver of the F4 generation fish that continued to develop NAFLD. To understand the etiology of NAFLD in unexposed generations, we performed nontargeted liquid chromatography-mass spectrometry-based metabolomic analysis in combination with bulk RNA sequencing and determined biomarkers, co-expressed gene networks, and sex-specific pathways triggered in the liver. An integrated analysis of metabolomic and transcriptional alterations revealed a positive association with the severity of the NAFLD disease phenotype. Females showed increased NAFLD severity and had metabolic disruption involving proline metabolism, tryptophan metabolism, and bile metabolism pathways. The present results provide the transcriptional and metabolomic underpinning of metabolic disruption caused by ancestral BPA exposure, providing avenues for further research to understand the development and progression of transgenerational NAFLD caused by ancestral bisphenol A exposure.
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Affiliation(s)
- Sourav Chakraborty
- Division of Biological Sciences, University of Missouri, Columbia, MO 65211, United States
| | - Santosh Anand
- Division of Biological Sciences, University of Missouri, Columbia, MO 65211, United States
| | - Muhammad Numan
- Department of Biology, University of North Carolina Greensboro, Greensboro, NC 27412, United States
| | - Ramji Kumar Bhandari
- Division of Biological Sciences, University of Missouri, Columbia, MO 65211, United States
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Huang Y, Liu W, Song G, Wu S, Li X, Shen G, Feng J. Metabolomic analyses of multiple biologic matrices reveal metabolic heterogeneity in diabetic complications. Acta Diabetol 2025:10.1007/s00592-025-02481-8. [PMID: 40080196 DOI: 10.1007/s00592-025-02481-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Accepted: 02/27/2025] [Indexed: 03/15/2025]
Abstract
AIMS Type 2 diabetes mellitus (T2DM) arises from a complex interplay of genetic and environmental factors. Patients with T2DM are susceptible to hyperglycemia-related complications that can impair organ function, underscoring the need to explore the metabolic profiles of affected organs. METHODS In this study, a comprehensive metabolomic analysis was conducted on the serum, kidney, and heart tissues from a rat model of diabetic complications (DC). Pattern recognition and multivariate statistical analyses were applied to identify the potential biomarkers of DC, and metabolic network analysis served to understand the specific metabolic pathways associated with DC. RESULTS Fourteen significantly altered metabolites were identified in serum, 20 in the kidney, and 14 in the heart. The corresponding metabolic pathways included mineral absorption, mTOR signaling pathway, taurine and hypotaurine metabolism, glycine, serine and threonine metabolism, ABC transporters, glucagon signaling pathway, protein degradation and uptake, galactose metabolism, purine metabolism, nicotinic acid and nicotinamide metabolism, and glycolysis and gluconeogenesis. Differential metabolite network analysis revealed instinct metabolic patterns among the serum, kidney, and heart. Notably, the serum's metabolic correlation patterns were found to be somewhat similar to those observed in the kidney, whereas the heart exhibited less pronounced metabolite correlations compared to the other two biological matrices. CONCLUSIONS These findings provide insights into the mechanism underlying the development of diabetic complications. The integration of metabolomics and biological network analyses into diabetes research can potentially revolutionize the field by revealing novel biomarkers for early detection and personalized treatment of diabetes and its associated complications.
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Affiliation(s)
- Yao Huang
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, 422 Siming South Road, Siming District, Xiamen, 361005, Fujian, China
| | - Wuping Liu
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, 422 Siming South Road, Siming District, Xiamen, 361005, Fujian, China
| | - Ge Song
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, 422 Siming South Road, Siming District, Xiamen, 361005, Fujian, China
| | - Sheng Wu
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, 422 Siming South Road, Siming District, Xiamen, 361005, Fujian, China
| | - Xuejun Li
- The Xiamen Diabetes Institute and Department of Endocrinology and Diabetes, the First Affiliated Hospital of Xiamen University, Xiamen, 361003, China
| | - Guiping Shen
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, 422 Siming South Road, Siming District, Xiamen, 361005, Fujian, China
| | - Jianghua Feng
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, 422 Siming South Road, Siming District, Xiamen, 361005, Fujian, China.
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Wang X, Duan H, Lu F, Yu X, Xie M, Chen P, Zou J, Gao L, Cai Y, Chen R, Guo Y. Anatomizing causal relationships between gut microbiota, plasma metabolites, and epilepsy: A mendelian randomization study. Neurochem Int 2025; 183:105924. [PMID: 39743181 DOI: 10.1016/j.neuint.2024.105924] [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: 10/21/2024] [Revised: 12/07/2024] [Accepted: 12/23/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND Epilepsy causes a heavy disease burden, and the gut microbiota (GM) influences the progression of epilepsy, while plasma metabolites directly or indirectly associated with GM may play a mediating role. However, the causal relationships between epilepsy, GM, and potential metabolite mediators are lack of investigation. METHODS Mendelian randomization (MR) analysis was applied to estimate the effects of GM and plasma metabolites on epilepsy. Genetic instruments were obtained from large-scale genome-wide meta-analysis of GM (n = 5959), plasma metabolites (n = 136,016), and epilepsy (Cases/controls = 12891/312803) of European ancestry. Epilepsy phenotypes included all epilepsy, generalized epilepsy and focal epilepsy from the Finn Gen R10 database. And two-step MR (TSMR) to discover the potential mediating metabolites. RESULTS In total, we found 19 gut microbial taxa to be causally associated with the risk of epilepsy, among which Omnitrophota phylum had the strongest association (OR, 2.3; P = 0.009) with promoting effect. We also identified 21 plasma metabolites associated with epilepsy, the strongest ones of which are eastotal fatty acids (OR, 1.12; P = 0.001) that exhibited a facilitating effect. We observed indirect effects of free cholesterol to total lipids ratio in large LDL in associations between Fournierella massiliensis species and epilepsy, with a mediated proportion of -3.64% (95%CI, -7.22%∼-0.06%; P = 0.046). CONCLUSION This study supports a causal link between Fournierella massiliensis species, free cholesterol to total lipids ratio in large LDL and epilepsy, as well as a mediating effect of free cholesterol to total lipids ratio in large LDL in epilepsy.
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Affiliation(s)
- Xi Wang
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Haowen Duan
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Fengfei Lu
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Xinyue Yu
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Minghan Xie
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Peiyi Chen
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Junjie Zou
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Lijie Gao
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Yingqian Cai
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
| | - Rongqing Chen
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
| | - Yanwu Guo
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
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Wu Z, Li L, Chen S, Gong Y, Liu Y, Jin T, Wang Y, Tang J, Dong Q, Yang B, Yang F, Dong W. Microbiota contribute to regulation of the gut-testis axis in seasonal spermatogenesis. THE ISME JOURNAL 2025; 19:wraf036. [PMID: 39999373 PMCID: PMC11964897 DOI: 10.1093/ismejo/wraf036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 01/07/2025] [Accepted: 02/21/2025] [Indexed: 02/27/2025]
Abstract
Seasonal breeding is an important adaptive strategy for animals. Recent studies have highlighted the potential role of the gut microbiota in reproductive health. However, the relationship between the gut microbiota and reproduction in seasonal breeders remains unclear. In this study, we selected a unique single food source animal, the flying squirrel (Trogopterus xanthipes), as a model organism for studying seasonal breeding. By integrating transcriptomic, metabolomic, and microbiome data, we comprehensively investigated the regulation of the gut-metabolism-testis axis in seasonal breeding. Here, we demonstrated a significant spermatogenic phenotype and highly active spermatogenic transcriptional characteristics in the testes of flying squirrels during the breeding season, which were associated with increased polyamine metabolism, primarily involving spermine and γ-amino butyric acid. Moreover, an enrichment of Ruminococcus was observed in the large intestine during the breeding season and may contribute to enhanced methionine biosynthesis in the gut. Similar changes in Ruminococcus abundance were also observed in several other seasonal breeders. These findings innovatively revealed that reshaping the gut microbiota regulates spermatogenesis in seasonal breeders through polyamine metabolism, highlighting the great potential of the gut-testis axis in livestock animal breeding and human health management.
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Affiliation(s)
- Zifang Wu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Long Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Shaoxian Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Ye Gong
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yuyan Liu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Tianqi Jin
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yang Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Jie Tang
- Shaanxi Institute of Zoology, Xi'an, Shaanxi 710032, China
| | - Qian Dong
- Department of Thyroid and Breast Surgery, Shenzhen Luohu Hospital Group Luohu People’s Hospital (Third Affiliated Hospital of Shenzhen University), Shenzhen, Guangdong 518000, China
| | - Bangzhu Yang
- Luonan Science and Technology Bureau, Shangluo, Shaanxi 726000, China
| | - Fangxia Yang
- College of Forestry, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Wuzi Dong
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
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Chen L, Xu S, Wang S, Chen H, Han Y. Xiaohuafuning tang intervenes liver-depression-and-spleen-deficiency syndrome chronic-atrophic-gastritis by reshaping amino acid metabolism through gut Microbiota. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 136:156346. [PMID: 39740378 DOI: 10.1016/j.phymed.2024.156346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 11/22/2024] [Accepted: 12/23/2024] [Indexed: 01/02/2025]
Abstract
BACKGROUND Xiaohua Funing Tang (XHFND) is a decoction formula of traditional Chinese medicine (TCM) and possesses the potential to manage chronic atrophic gastritis (CAG) with liver depression and spleen deficiency (LDSD), but the mechanisms were still unclear. PURPOSE Our aim is to reveal the overall synergistic mechanisms of XHFND against CAG with LDSD. METHODS Based on a CAG rat model with LDSD, this study combined metabolomics, gut microbiota, and network pharmacology techniques to demonstrate the XHFND mechanisms with multiple components and targets. RESULTS Through the integration analysis of gut microbiome and metabolome using metorigin, we found that XHFND regulates arginine metabolism levels in the urea cycle by regulating the gut ecological environment and the host. The XHFND mainly promotes aspartate 1 metabolism by regulating the abundance of odoribacter, bacteroides, phocaeicola, lachnospire, and intestinimonas, intervened in the imbalance of arginine metabolism in CAG rats with LDSD, suppresses the pathogenic Th17 cell differentiation, and inhibits the gastric mucosa damage in rats. Through Cytoscape analysis of network pharmacology and metabolomics integration, we found that XHFND might regulate host phospholipid metabolism through PTEN and PIK3CA to inhibit the PI3K-AKT-TSC axis and then inhibit mTORC1 to control arginine metabolism in the urea cycle and produce polyamines, thereby inhibiting the pathogenic Th17 cell differentiation and preventing rat gastric mucosa damage. Intervention in arginine metabolism in the urea cycle is the primary pathway in which XHFND exerts its therapeutic effects. XHFND may mainly control the pathogenic Th17 cell differentiation in the gastric mucosa of model rats through the pathway. CONCLUSION This study indicated that XHFND might intervene in treating CAG with LDSD from multiple levels and perspectives to suppress the pathogenic Th17 cell differentiation, which aligns with the characteristics of TCM treatment. This study presents experimental evidence for the clinical use of XHFND and promotes the development of drugs for the therapy of CAG with LDSD.
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Affiliation(s)
- Li Chen
- Institue of Pharmaceutical Department, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, No 117, Meishan Road, Hefei 230031, Anhui, PR China
| | - ShaoYu Xu
- Institue of School of Pharmacy, Anhui University of Chinese Medicine, No 350, Longzihu Road, Hefei 230012, Anhui, PR China
| | - Sheng Wang
- Institue of Pharmaceutical Department, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, No 117, Meishan Road, Hefei 230031, Anhui, PR China
| | - Hao Chen
- Institue of Pharmaceutical Department, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, No 117, Meishan Road, Hefei 230031, Anhui, PR China.
| | - Yanquan Han
- Institue of Pharmaceutical Department, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, No 117, Meishan Road, Hefei 230031, Anhui, PR China.
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Si ZL, Wang HY, Wang T, Cao YZ, Li QZ, Liu K, Huang Z, Liu HL, Tan YJ, Wang YY, Huang FQ, Ma GX, Alolga RN, Yan M, Chen C, Li JH, Li J, Liu HW, Zhang ZH. Gut Bacteroides ovatus ameliorates renal fibrosis by promoting the production of HDCA through upregulation of Clostridium scindens. Cell Rep 2024; 43:114830. [PMID: 39392759 DOI: 10.1016/j.celrep.2024.114830] [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: 01/10/2024] [Revised: 07/14/2024] [Accepted: 09/19/2024] [Indexed: 10/13/2024] Open
Abstract
Renal fibrosis, inflammation, and gut dysbiosis are all linked to chronic kidney disease (CKD). Here we show that Bacteroides ovatus protects against renal fibrosis. Mechanistically, B. ovatus enhances intestinal hyodeoxycholic acid (HDCA) levels by upregulating a strain of intestinal bacteria, Clostridium scindens, that has the capacity for direct HDCA production in mice. HDCA significantly promoted GLP-1 secretion by upregulating the expression of TGR5 and downregulating the expression of farnesoid X receptor (FXR) in the gut. Activation of renal GLP-1R attenuates renal fibrosis while delaying the subsequent development of CKD. In addition, HDCA can also protect against renal fibrosis by directly upregulating renal TGR5. The natural product neohesperidin (NHP) was found to exert its anti-renal fibrotic effects by promoting the growth of B. ovatus. Our findings provide mechanistic insights into the therapeutic potential of B. ovatus, C. scindens, and HDCA in treating CKD.
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Affiliation(s)
- Zi-Lin Si
- Key Laboratory of Tropical Biological Resources of the Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Han-Yu Wang
- Key Laboratory of Tropical Biological Resources of the Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Tao Wang
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, No. 1 Beichenxi Road, Chaoyang District, Beijing 100101, P.R. China
| | - Yi-Zhi Cao
- Key Laboratory of Tropical Biological Resources of the Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Qing-Zhen Li
- Key Laboratory of Tropical Biological Resources of the Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Kang Liu
- Department of Nephrology, Jiangsu Province Hospital (The First Affiliated Hospital of Nanjing Medical University), Nanjing 210029, China
| | - Zhou Huang
- Key Laboratory of Tropical Biological Resources of the Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Hui-Ling Liu
- Key Laboratory of Tropical Biological Resources of the Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
| | - Ya-Jie Tan
- State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Yin-Yin Wang
- State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Feng-Qing Huang
- State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Gao-Xiang Ma
- State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Raphael N Alolga
- State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Miao Yan
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Cheng Chen
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Jun-Hui Li
- Putuo People's Hospital, Tongji University, Shanghai 200060, China
| | - Jing Li
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Hong-Wei Liu
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, No. 1 Beichenxi Road, Chaoyang District, Beijing 100101, P.R. China
| | - Zhi-Hao Zhang
- Key Laboratory of Tropical Biological Resources of the Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
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Datta S, Pasham S, Inavolu S, Boini KM, Koka S. Role of Gut Microbial Metabolites in Cardiovascular Diseases-Current Insights and the Road Ahead. Int J Mol Sci 2024; 25:10208. [PMID: 39337693 PMCID: PMC11432476 DOI: 10.3390/ijms251810208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of premature morbidity and mortality globally. The identification of novel risk factors contributing to CVD onset and progression has enabled an improved understanding of CVD pathophysiology. In addition to the conventional risk factors like high blood pressure, diabetes, obesity and smoking, the role of gut microbiome and intestinal microbe-derived metabolites in maintaining cardiovascular health has gained recent attention in the field of CVD pathophysiology. The human gastrointestinal tract caters to a highly diverse spectrum of microbes recognized as the gut microbiota, which are central to several physiologically significant cascades such as metabolism, nutrient absorption, and energy balance. The manipulation of the gut microbial subtleties potentially contributes to CVD, inflammation, neurodegeneration, obesity, and diabetic onset. The existing paradigm of studies suggests that the disruption of the gut microbial dynamics contributes towards CVD incidence. However, the exact mechanistic understanding of such a correlation from a signaling perspective remains elusive. This review has focused upon an in-depth characterization of gut microbial metabolites and their role in varied pathophysiological conditions, and highlights the potential molecular and signaling mechanisms governing the gut microbial metabolites in CVDs. In addition, it summarizes the existing courses of therapy in modulating the gut microbiome and its metabolites, limitations and scientific gaps in our current understanding, as well as future directions of studies involving the modulation of the gut microbiome and its metabolites, which can be undertaken to develop CVD-associated treatment options. Clarity in the understanding of the molecular interaction(s) and associations governing the gut microbiome and CVD shall potentially enable the development of novel druggable targets to ameliorate CVD in the years to come.
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Affiliation(s)
- Sayantap Datta
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Sindhura Pasham
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA
| | - Sriram Inavolu
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA
| | - Krishna M Boini
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Saisudha Koka
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA
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Stagaman K, Alexiev A, Sieler MJ, Hammer A, Kasschau KD, Truong L, Tanguay RL, Sharpton TJ. The zebrafish gut microbiome influences benzo[a]pyrene developmental neurobehavioral toxicity. Sci Rep 2024; 14:14618. [PMID: 38918492 PMCID: PMC11199668 DOI: 10.1038/s41598-024-65610-3] [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: 02/09/2024] [Accepted: 06/21/2024] [Indexed: 06/27/2024] Open
Abstract
Early-life exposure to environmental toxicants like Benzo[a]pyrene (BaP) is associated with several health consequences in vertebrates (i.e., impaired or altered neurophysiological and behavioral development). Although toxicant impacts were initially studied relative to host physiology, recent studies suggest that the gut microbiome is a possible target and/or mediator of behavioral responses to chemical exposure in organisms, via the gut-brain axis. However, the connection between BaP exposure, gut microbiota, and developmental neurotoxicity remains understudied. Using a zebrafish model, we determined whether the gut microbiome influences BaP impacts on behavior development. Embryonic zebrafish were treated with increasing concentrations of BaP and allowed to grow to the larval life stage, during which they underwent behavioral testing and intestinal dissection for gut microbiome profiling via high-throughput sequencing. We found that exposure affected larval zebrafish microbiome diversity and composition in a manner tied to behavioral development: increasing concentrations of BaP were associated with increased taxonomic diversity, exposure was associated with unweighted UniFrac distance, and microbiome diversity and exposure predicted larval behavior. Further, a gnotobiotic zebrafish experiment clarified whether microbiome presence was associated with BaP exposure response and behavioral changes. We found that gut microbiome state altered the relationship between BaP exposure concentration and behavioral response. These results support the idea that the zebrafish gut microbiome is a determinant of the developmental neurotoxicity that results from chemical exposure.
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Affiliation(s)
- Keaton Stagaman
- Department of Microbiology, Oregon State University, 226 Nash Hall, Corvallis, OR, 97331, USA
| | - Alexandra Alexiev
- Department of Microbiology, Oregon State University, 226 Nash Hall, Corvallis, OR, 97331, USA
| | - Michael J Sieler
- Department of Microbiology, Oregon State University, 226 Nash Hall, Corvallis, OR, 97331, USA
| | - Austin Hammer
- Department of Microbiology, Oregon State University, 226 Nash Hall, Corvallis, OR, 97331, USA
| | - Kristin D Kasschau
- Department of Microbiology, Oregon State University, 226 Nash Hall, Corvallis, OR, 97331, USA
| | - Lisa Truong
- Sinnhuber Aquatic Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA
| | - Robyn L Tanguay
- Sinnhuber Aquatic Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA
| | - Thomas J Sharpton
- Department of Microbiology, Oregon State University, 226 Nash Hall, Corvallis, OR, 97331, USA.
- Department of Statistics, Oregon State University, Corvallis, OR, USA.
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10
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Whiley L, Lawler NG, Zeng AX, Lee A, Chin ST, Bizkarguenaga M, Bruzzone C, Embade N, Wist J, Holmes E, Millet O, Nicholson JK, Gray N. Cross-Validation of Metabolic Phenotypes in SARS-CoV-2 Infected Subpopulations Using Targeted Liquid Chromatography-Mass Spectrometry (LC-MS). J Proteome Res 2024; 23:1313-1327. [PMID: 38484742 PMCID: PMC11002931 DOI: 10.1021/acs.jproteome.3c00797] [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: 11/17/2023] [Revised: 02/21/2024] [Accepted: 02/23/2024] [Indexed: 04/06/2024]
Abstract
To ensure biological validity in metabolic phenotyping, findings must be replicated in independent sample sets. Targeted workflows have long been heralded as ideal platforms for such validation due to their robust quantitative capability. We evaluated the capability of liquid chromatography-mass spectrometry (LC-MS) assays targeting organic acids and bile acids to validate metabolic phenotypes of SARS-CoV-2 infection. Two independent sample sets were collected: (1) Australia: plasma, SARS-CoV-2 positive (n = 20), noninfected healthy controls (n = 22) and COVID-19 disease-like symptoms but negative for SARS-CoV-2 infection (n = 22). (2) Spain: serum, SARS-CoV-2 positive (n = 33) and noninfected healthy controls (n = 39). Multivariate modeling using orthogonal projections to latent structures discriminant analyses (OPLS-DA) classified healthy controls from SARS-CoV-2 positive (Australia; R2 = 0.17, ROC-AUC = 1; Spain R2 = 0.20, ROC-AUC = 1). Univariate analyses revealed 23 significantly different (p < 0.05) metabolites between healthy controls and SARS-CoV-2 positive individuals across both cohorts. Significant metabolites revealed consistent perturbations in cellular energy metabolism (pyruvic acid, and 2-oxoglutaric acid), oxidative stress (lactic acid, 2-hydroxybutyric acid), hypoxia (2-hydroxyglutaric acid, 5-aminolevulinic acid), liver activity (primary bile acids), and host-gut microbial cometabolism (hippuric acid, phenylpropionic acid, indole-3-propionic acid). These data support targeted LC-MS metabolic phenotyping workflows for biological validation in independent sample sets.
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Affiliation(s)
- Luke Whiley
- Australian
National Phenome Centre, Health Futures Institute Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
- Centre
for Computational and Systems Medicine, Health Futures Institute Harry
Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
| | - Nathan G. Lawler
- Australian
National Phenome Centre, Health Futures Institute Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
- Centre
for Computational and Systems Medicine, Health Futures Institute Harry
Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
| | - Annie Xu Zeng
- Australian
National Phenome Centre, Health Futures Institute Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
| | - Alex Lee
- Australian
National Phenome Centre, Health Futures Institute Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
| | - Sung-Tong Chin
- Australian
National Phenome Centre, Health Futures Institute Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
| | - Maider Bizkarguenaga
- Centro
de Investigación Cooperativa en Biociencias—CIC bioGUNE,
Precision Medicine and Metabolism Laboratory, Basque Research and
Technology Alliance, Bizkaia Science and
Technology Park, Building
800, 48160 Derio, Spain
| | - Chiara Bruzzone
- Centro
de Investigación Cooperativa en Biociencias—CIC bioGUNE,
Precision Medicine and Metabolism Laboratory, Basque Research and
Technology Alliance, Bizkaia Science and
Technology Park, Building
800, 48160 Derio, Spain
| | - Nieves Embade
- Centro
de Investigación Cooperativa en Biociencias—CIC bioGUNE,
Precision Medicine and Metabolism Laboratory, Basque Research and
Technology Alliance, Bizkaia Science and
Technology Park, Building
800, 48160 Derio, Spain
| | - Julien Wist
- Australian
National Phenome Centre, Health Futures Institute Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
- Centre
for Computational and Systems Medicine, Health Futures Institute Harry
Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
- Chemistry
Department, Universidad del Valle, Cali 76001, Colombia
| | - Elaine Holmes
- Australian
National Phenome Centre, Health Futures Institute Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
- Centre
for Computational and Systems Medicine, Health Futures Institute Harry
Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
- Department
of Metabolism Digestion and Reproduction, Faculty of Medicine, Imperial
College London, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, U.K.
| | - Oscar Millet
- Centro
de Investigación Cooperativa en Biociencias—CIC bioGUNE,
Precision Medicine and Metabolism Laboratory, Basque Research and
Technology Alliance, Bizkaia Science and
Technology Park, Building
800, 48160 Derio, Spain
| | - Jeremy K. Nicholson
- Australian
National Phenome Centre, Health Futures Institute Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
- Centre
for Computational and Systems Medicine, Health Futures Institute Harry
Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
- Institute
of Global Health Innovation, Faculty Building South Kensington Campus, Imperial College London, London SW7 2AZ, U.K.
| | - Nicola Gray
- Australian
National Phenome Centre, Health Futures Institute Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
- Centre
for Computational and Systems Medicine, Health Futures Institute Harry
Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
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11
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Zhou L, Lu G, Nie Y, Ren Y, Shi JS, Xue Y, Xu ZH, Geng Y. Restricted intake of sulfur-containing amino acids reversed the hepatic injury induced by excess Desulfovibrio through gut-liver axis. Gut Microbes 2024; 16:2370634. [PMID: 38935546 PMCID: PMC11212577 DOI: 10.1080/19490976.2024.2370634] [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: 02/01/2024] [Accepted: 06/17/2024] [Indexed: 06/29/2024] Open
Abstract
Diet is a key player in gut-liver axis. However, the effect of different dietary patterns on gut microbiota and liver functions remains unclear. Here, we used rodent standard chow and purified diet to mimic two common human dietary patterns: grain and plant-based diet and refined-food-based diet, respectively and explored their impacts on gut microbiota and liver. Gut microbiota experienced a great shift with notable increase in Desulfovibrio, gut bile acid (BA) levels elevated significantly, and liver inflammation was observed in mice fed with the purified diet. Liver inflammation and elevated gut BA levels also occurred in mice fed with the chow diet after receiving Desulfovibrio desulfuricans ATCC 29,577 (DSV). Restriction of sulfur-containing amino acids (SAAs) prevented liver injury mainly through higher hepatic antioxidant and detoxifying ability and reversed the elevated BA levels due to excess Desulfovibrio. Ex vivo fermentation of human fecal microbiota with primary BAs demonstrated that DSV enhanced production of secondary BAs. Higher concentration of both primary and secondary BAs were found in the gut of germ-free mice after receiving DSV. In conclusion, Restriction of SAAs in diet may become an effective dietary intervention to prevent liver injury associated with excess Desulfovibrio in the gut.
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Affiliation(s)
- Lingxi Zhou
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu, China
| | - Gexue Lu
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China
| | - Yawen Nie
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China
| | - Yilin Ren
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Jin-Song Shi
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China
| | - Yuzheng Xue
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Zheng-Hong Xu
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu, China
- College of Biomass Science and Engineering, Sichuan University, Chengdu, China
| | - Yan Geng
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi, China
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12
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Carson MD, Westwater C, Novince CM. Adolescence and the Microbiome: Implications for Healthy Growth and Maturation. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1900-1909. [PMID: 37673331 PMCID: PMC10699129 DOI: 10.1016/j.ajpath.2023.07.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 07/19/2023] [Accepted: 07/26/2023] [Indexed: 09/08/2023]
Abstract
The gut microbiota was initially thought to develop into a stable, adult-like profile during early postnatal life. The formation of the gut microbiota during early life has been shown to contribute to healthy growth and has lifelong implications for host health. Adolescence, the developmental period between childhood and adulthood, is a critical window for healthy growth and maturation. The composition of the gut microbiota in adolescents is distinct from that of children and adults, which supports the premise that the gut microbiota continues to develop during adolescence toward an adult-like profile. Research has begun to shift its focus from understanding the gut microbiome at the extremes of the life span to evaluating the importance of the gut microbiome during adolescence and its role in healthy development. This article provides an overview of adolescent development, host-microbiota interactions, and experimental models used to discern effects of gut microbiota on health and disease. Herein, the role of the gut microbiota is reviewed as it relates to adolescent: i) brain development, cognition, and behavior; ii) metabolism and adiposity; and iii) skeletal growth and bone mass accrual. Future directions are addressed, including omics investigations defining mechanisms through which the gut microbiota influences adolescent development. Furthermore, we discuss advancing noninvasive interventions targeting the adolescent gut microbiota that could be employed to support healthy growth and maturation.
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Affiliation(s)
- Matthew D Carson
- Departments of Oral Health Sciences, College of Dental Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Caroline Westwater
- Departments of Oral Health Sciences, College of Dental Medicine, Medical University of South Carolina, Charleston, South Carolina; Department of Microbiology and Immunology, College of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Chad M Novince
- Departments of Oral Health Sciences, College of Dental Medicine, Medical University of South Carolina, Charleston, South Carolina; Division of Endocrinology, Department of Pediatrics, College of Medicine, Medical University of South Carolina, Charleston, South Carolina; Division of Periodontics, Department of Stomatology, College of Dental Medicine, Medical University of South Carolina, Charleston, South Carolina.
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13
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Larivière-Gauthier G, Kerouanton A, Mompelat S, Bougeard S, Denis M, Fravalo P. Monophasic Variant of Salmonella Typhimurium Infection Affects the Serum Metabolome in Swine. Microorganisms 2023; 11:2565. [PMID: 37894223 PMCID: PMC10608901 DOI: 10.3390/microorganisms11102565] [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: 09/22/2023] [Revised: 10/10/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Salmonella is the most relevant foodborne zoonotic agent found in swine, and its presence in French herds is significant. Its carriage is asymptomatic, which makes it difficult to detect during rearing, thus increasing the risk of its presence on pork meat. Studies have shown that enteric infection in animals could be associated with changes in the serum metabolome composition, through the immune response or changes in the digestive microbiota composition. We hypothesized that these changes in the serum metabolome composition could be used as markers for the detection of asymptomatic animals infected by Salmonella. Using untargeted analysis by liquid chromatography coupled with mass spectrometry, we showed that significant differences in the composition of the serum metabolome could be detected between infected or noninfected animals both 1 and 21 days after experimental infection. This serum metabolome composition significantly changed during the 21 days postinfection in the infected animal groups, suggesting an evolution of the impact of infection with time. Despite this evolution, differences in the serum metabolome composition persisted between infected and noninfected animals 21 days after the initial infection. We also showed a possible difference between high-shedding and low-shedding animals 21 days postinfection. Finally, some of the variations in the metabolome were found to be significantly associated with variations of specific members of the fecal microbiota. Thus, excreting and asymptomatic animals, but also high-shedding animals, could be identified on the basis of their serum metabolome composition.
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Affiliation(s)
- Guillaume Larivière-Gauthier
- USC Metabiot, Cnam, 22440 Ploufragan, France;
- USC Metabiot, Anses, Ploufragan-Plouzané-Niort Laboratory, Hygiene and Quality of Poultry and Pig Products Unit, 22440 Ploufragan, France;
| | - Annaëlle Kerouanton
- USC Metabiot, Anses, Ploufragan-Plouzané-Niort Laboratory, Hygiene and Quality of Poultry and Pig Products Unit, 22440 Ploufragan, France;
| | - Sophie Mompelat
- Anses, Fougères Laboratory, Analysis of Residues and Contaminants Unit, 35133 Fougères, France;
| | - Stéphanie Bougeard
- Anses, Ploufragan-Plouzané-Niort Laboratory, Epidemiology, Health and Welfare Unit, 22440 Ploufragan, France;
| | - Martine Denis
- USC Metabiot, Anses, Ploufragan-Plouzané-Niort Laboratory, Hygiene and Quality of Poultry and Pig Products Unit, 22440 Ploufragan, France;
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14
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Kayama H, Takeda K. Emerging roles of host and microbial bioactive lipids in inflammatory bowel diseases. Eur J Immunol 2023; 53:e2249866. [PMID: 37191284 DOI: 10.1002/eji.202249866] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 04/11/2023] [Accepted: 05/15/2023] [Indexed: 05/17/2023]
Abstract
The intestinal tract harbors diverse microorganisms, host- and microbiota-derived metabolites, and potentially harmful dietary antigens. The epithelial barrier separates the mucosa, where diverse immune cells exist, from the lumen to avoid excessive immune reactions against microbes and dietary antigens. Inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease, is characterized by a chronic and relapsing disorder of the gastrointestinal tract. Although the precise etiology of IBD is still largely unknown, accumulating evidence suggests that IBD is multifactorial, involving host genetics and microbiota. Alterations in the metabolomic profiles and microbial community are features of IBD. Advances in mass spectrometry-based lipidomic technologies enable the identification of changes in the composition of intestinal lipid species in IBD. Because lipids have a wide range of functions, including signal transduction and cell membrane formation, the dysregulation of lipid metabolism drastically affects the physiology of the host and microorganisms. Therefore, a better understanding of the intimate interactions of intestinal lipids with host cells that are implicated in the pathogenesis of intestinal inflammation might aid in the identification of novel biomarkers and therapeutic targets for IBD. This review summarizes the current knowledge on the mechanisms by which host and microbial lipids control and maintain intestinal health and diseases.
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Affiliation(s)
- Hisako Kayama
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- WPI, Osaka University, Suita, Osaka, Japan
- Institute for Advanced Co-Creation Studies, Osaka University, Suita, Osaka, Japan
| | - Kiyoshi Takeda
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- WPI, Osaka University, Suita, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan
- Center for Infection Disease Education and Research, Osaka University, Suita, Japan
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15
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Zhao R, Cheng W, Shen J, Liang W, Zhang Z, Sheng Y, Chai T, Chen X, Zhang Y, Huang X, Yang H, Song C, Pang L, Nan C, Zhang Y, Chen R, Mei J, Wei H, Fang X. Single-cell and spatiotemporal transcriptomic analyses reveal the effects of microorganisms on immunity and metabolism in the mouse liver. Comput Struct Biotechnol J 2023; 21:3466-3477. [PMID: 38152123 PMCID: PMC10751235 DOI: 10.1016/j.csbj.2023.06.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 06/28/2023] [Accepted: 06/28/2023] [Indexed: 12/29/2023] Open
Abstract
The gut-liver axis is a complex bidirectional communication pathway between the intestine and the liver in which microorganisms and their metabolites flow from the intestine through the portal vein to the liver and influence liver function. In a sterile environment, the phenotype or function of the liver is altered, but few studies have investigated the specific cellular and molecular effects of microorganisms on the liver. To this end, we constructed single-cell and spatial transcriptomic (ST) profiles of germ-free (GF) and specific-pathogen-free (SPF) mouse livers. Single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) revealed that the ratio of most immune cells was altered in the liver of GF mice; in particular, natural killer T (NKT) cells, IgA plasma cells (IgAs) and Kupffer cells (KCs) were significantly reduced in GF mice. Spatial enhanced resolution omics sequencing (Stereo-seq) confirmed that microorganisms mediated the accumulation of Kupffer cells in the periportal zone. Unexpectedly, IgA plasma cells were more numerous and concentrated in the periportal vein in liver sections from SPF mice but less numerous and scattered in GF mice. ST technology also enables the precise zonation of liver lobules into eight layers and three patterns based on the gene expression level in each layer, allowing us to further investigate the effects of microbes on gene zonation patterns and functions. Furthermore, untargeted metabolism experiments of the liver revealed that the propionic acid levels were significantly lower in GF mice, and this reduction may be related to the control of genes involved in bile acid and fatty acid metabolism. In conclusion, the combination of sc/snRNA-seq, Stereo-seq, and untargeted metabolomics revealed immune system defects as well as altered bile acid and lipid metabolic processes at the single-cell and spatial levels in the livers of GF mice. This study will be of great value for understanding host-microbiota interactions.
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Affiliation(s)
- Ruizhen Zhao
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
- BGI-Shenzhen, Shenzhen 518083, China
| | - Wei Cheng
- College of Animal Sciences and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Juan Shen
- BGI-Shenzhen, Shenzhen 518083, China
| | | | - Zhao Zhang
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
- BGI-Shenzhen, Shenzhen 518083, China
| | - Yifei Sheng
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
- BGI-Shenzhen, Shenzhen 518083, China
| | - Tailiang Chai
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
- BGI-Shenzhen, Shenzhen 518083, China
| | - Xueting Chen
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
- BGI-Shenzhen, Shenzhen 518083, China
| | - Yin Zhang
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
- BGI-Shenzhen, Shenzhen 518083, China
| | - Xiang Huang
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | | | - Chunqing Song
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China
| | - Li Pang
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
| | - Cuoji Nan
- BGI-Shenzhen, Shenzhen 518083, China
| | | | - Rouxi Chen
- BGI-Sanya, BGI-Shenzhen, Sanya 572025, China
| | - Junpu Mei
- BGI-Shenzhen, Shenzhen 518083, China
- BGI-Sanya, BGI-Shenzhen, Sanya 572025, China
| | - Hong Wei
- Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Xiaodong Fang
- BGI-Shenzhen, Shenzhen 518083, China
- BGI-Sanya, BGI-Shenzhen, Sanya 572025, China
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16
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Zhu F, Zheng S, Zhao M, Shi F, Zheng L, Wang H. The regulatory role of bile acid microbiota in the progression of liver cirrhosis. Front Pharmacol 2023; 14:1214685. [PMID: 37416060 PMCID: PMC10320161 DOI: 10.3389/fphar.2023.1214685] [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: 05/02/2023] [Accepted: 06/12/2023] [Indexed: 07/08/2023] Open
Abstract
Bile acids (BAs) are synthesized in liver tissue from cholesterol and are an important endocrine regulator and signaling molecule in the liver and intestine. It maintains BAs homeostasis, and the integrity of intestinal barrier function, and regulates enterohepatic circulation in vivo by modulating farnesoid X receptors (FXR) and membrane receptors. Cirrhosis and its associated complications can lead to changes in the composition of intestinal micro-ecosystem, resulting in dysbiosis of the intestinal microbiota. These changes may be related to the altered composition of BAs. The BAs transported to the intestinal cavity through the enterohepatic circulation are hydrolyzed and oxidized by intestinal microorganisms, resulting in changes in their physicochemical properties, which can also lead to dysbiosis of intestinal microbiota and overgrowth of pathogenic bacteria, induction of inflammation, and damage to the intestinal barrier, thus aggravating the progression of cirrhosis. In this paper, we review the discussion of BAs synthesis pathway and signal transduction, the bidirectional regulation of bile acids and intestinal microbiota, and further explore the role of reduced total bile acid concentration and dysregulated intestinal microbiota ratio in the development of cirrhosis, in order to provide a new theoretical basis for the clinical treatment of cirrhosis and its complications.
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Affiliation(s)
- Feng Zhu
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Shudan Zheng
- First Clinical School of Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Mei Zhao
- First Clinical School of Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Fan Shi
- First Clinical School of Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Lihong Zheng
- Department of Gastroenterology, Fourth Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Haiqiang Wang
- Department of Gastroenterology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
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17
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Matsuzaki R, Gunnigle E, Geissen V, Clarke G, Nagpal J, Cryan JF. Pesticide exposure and the microbiota-gut-brain axis. THE ISME JOURNAL 2023:10.1038/s41396-023-01450-9. [PMID: 37328570 DOI: 10.1038/s41396-023-01450-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 04/27/2023] [Accepted: 05/31/2023] [Indexed: 06/18/2023]
Abstract
The gut microbiota exist within a dynamic ecosystem shaped by various factors that includes exposure to xenobiotics such as pesticides. It is widely regarded that the gut microbiota plays an essential role in maintaining host health, including a major influence on the brain and behaviour. Given the widespread use of pesticides in modern agriculture practices, it is important to assess the long-term collateral effects these xenobiotic exposures have on gut microbiota composition and function. Indeed, exposure studies using animal models have shown that pesticides can induce negative impacts on the host gut microbiota, physiology and health. In tandem, there is a growing body of literature showing that the effects of pesticide exposure can be extended to the manifestation of behavioural impairments in the host. With the increasing appreciation of the microbiota-gut-brain axis, in this review we assess whether pesticide-induced changes in gut microbiota composition profiles and functions could be driving these behavioural alterations. Currently, the diversity of pesticide type, exposure dose and variation in experimental designs hinders direct comparisons of studies presented. Although many insights presented, the mechanistic connection between the gut microbiota and behavioural changes remains insufficiently explored. Future experiments should therefore focus on causal mechanisms to examine the gut microbiota as the mediator of the behavioural impairments observed in the host following pesticide exposure.
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Affiliation(s)
- Rie Matsuzaki
- APC Microbiome Ireland, University College Cork, T12 YT20, Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, T12 YT20, Cork, Ireland
| | - Eoin Gunnigle
- APC Microbiome Ireland, University College Cork, T12 YT20, Cork, Ireland
| | - Violette Geissen
- Department of Environmental Sciences, Wageningen University & Research, 6700AA, Wageningen, The Netherlands
| | - Gerard Clarke
- APC Microbiome Ireland, University College Cork, T12 YT20, Cork, Ireland
- Department of Psychiatry & Neurobehavioural Sciences, University College Cork, T12 YT20, Cork, Ireland
| | - Jatin Nagpal
- APC Microbiome Ireland, University College Cork, T12 YT20, Cork, Ireland
- School of Pharmacy and Department of Pharmacology & Therapeutics, University College Cork, T12 YT20, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, T12 YT20, Cork, Ireland.
- Department of Anatomy and Neuroscience, University College Cork, T12 YT20, Cork, Ireland.
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18
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Liu B, Yu L, Zhai Q, Li M, Li L, Tian F, Chen W. Effect of water-soluble polysaccharides from Morchella esculenta on high-fat diet-induced obese mice: changes in gut microbiota and metabolic functions. Food Funct 2023. [PMID: 37191147 DOI: 10.1039/d3fo00574g] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
Morchella esculenta polysaccharides exhibit numerous probiotic activities, but their regulatory effects on the gut microbiota are unclear. This study was conducted to explore whether M. esculenta polysaccharides can regulate dysbacteriosis caused by a high-fat diet and relieve obesity. We extracted a water-soluble polysaccharide from M. esculenta (MPF, purity: 96.19%, consisting of 55.97% glucose, 9.63% xylose, and 22% mannose) that reduces mouse fat accumulation, alleviates obesity, and relieves liver injury, after 90 days of high-fat diet intake. This polysaccharide reversed dysbiosis and regulated the abundance of gut microbiota caused by a high-fat diet (restoring the ratio of Firmicutes/Bacteroidetes and changing the abundances of Lactobacillus, Dubosiella, and Faecalibaculum), increasing short-chain fatty acids and decreasing gene expression in the liver (glucose 6-phosphatase, glucose transporter 1, peroxisome proliferator-activated receptor gamma (PPAR) receptor-1α, PPARα, PPARγ, and CCAAT enhancer binding protein α). We identified a regulatory relationship between polysaccharides, gut microbiota, and the liver as a potential mechanism by which polysaccharides can alleviate obesity.
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Affiliation(s)
- Bingshu Liu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, P. R. China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Leilei Yu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, P. R. China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Qixiao Zhai
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, P. R. China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Miaoyu Li
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, P. R. China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Liuruolan Li
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, P. R. China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Fengwei Tian
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, P. R. China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, P. R. China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, Jiangsu 214122, China
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19
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Feng Y, Zhang M, Liu Y, Yang X, Wei F, Jin X, Liu D, Guo Y, Hu Y. Quantitative microbiome profiling reveals the developmental trajectory of the chicken gut microbiota and its connection to host metabolism. IMETA 2023; 2:e105. [PMID: 38868437 PMCID: PMC10989779 DOI: 10.1002/imt2.105] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/06/2023] [Accepted: 03/15/2023] [Indexed: 06/14/2024]
Abstract
Revealing the assembly and succession of the chicken gut microbiota is critical for a better understanding of its role in chicken physiology and metabolism. However, few studies have examined dynamic changes of absolute chicken gut microbes using the quantitative microbiome profiling (QMP) method. Here, we revealed the developmental trajectory of the broiler chicken gut bacteriome and mycobiome by combining high-throughput sequencing with a microbial load quantification assay. We showed that chicken gut microbiota abundance and diversity reached a plateau at 7 days posthatch (DPH), forming segment-specific community types after 1 DPH. The bacteriome was more impacted by deterministic processes, and the mycobiome was more affected by stochastic processes. We also observed stage-specific microbes in different gut segments, and three microbial occurrence patterns including "colonization," "disappearance," and "core" were defined. The microbial co-occurrence networks were very different among gut segments, with more positive associations than negative associations. Furthermore, we provided links between the absolute changes in chicken gut microbiota and their serum metabolite variations. Time-course untargeted metabolomics revealed six metabolite clusters with different changing patterns of abundance. The foregut microbiota had more connections with chicken serum metabolites, and the gut microbes were closely related to chicken lipid and amino acid metabolism. The present study provided a full landscape of chicken gut microbiota development in a quantitative manner, and the associations between gut microbes and chicken serum metabolites further highlight the impact of gut microbiota in chicken growth and development.
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Affiliation(s)
- Yuqing Feng
- State Key Laboratory of Animal Nutrition, College of Animal Science and TechnologyChina Agricultural UniversityBeijingChina
| | - Meihong Zhang
- State Key Laboratory of Animal Nutrition, College of Animal Science and TechnologyChina Agricultural UniversityBeijingChina
| | - Yan Liu
- State Key Laboratory of Animal Nutrition, College of Animal Science and TechnologyChina Agricultural UniversityBeijingChina
| | - Xinyue Yang
- State Key Laboratory of Animal Nutrition, College of Animal Science and TechnologyChina Agricultural UniversityBeijingChina
| | - Fuxiao Wei
- State Key Laboratory of Animal Nutrition, College of Animal Science and TechnologyChina Agricultural UniversityBeijingChina
| | - Xiaolu Jin
- State Key Laboratory of Animal Nutrition, College of Animal Science and TechnologyChina Agricultural UniversityBeijingChina
| | - Dan Liu
- State Key Laboratory of Animal Nutrition, College of Animal Science and TechnologyChina Agricultural UniversityBeijingChina
| | - Yuming Guo
- State Key Laboratory of Animal Nutrition, College of Animal Science and TechnologyChina Agricultural UniversityBeijingChina
| | - Yongfei Hu
- State Key Laboratory of Animal Nutrition, College of Animal Science and TechnologyChina Agricultural UniversityBeijingChina
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20
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Microbiota alters the metabolome in an age- and sex- dependent manner in mice. Nat Commun 2023; 14:1348. [PMID: 36906623 PMCID: PMC10008592 DOI: 10.1038/s41467-023-37055-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 03/01/2023] [Indexed: 03/13/2023] Open
Abstract
Commensal bacteria are major contributors to mammalian metabolism. We used liquid chromatography mass spectrometry to study the metabolomes of germ-free, gnotobiotic, and specific-pathogen-free mice, while also evaluating the influence of age and sex on metabolite profiles. Microbiota modified the metabolome of all body sites and accounted for the highest proportion of variation within the gastrointestinal tract. Microbiota and age explained similar amounts of variation the metabolome of urine, serum, and peritoneal fluid, while age was the primary driver of variation in the liver and spleen. Although sex explained the least amount of variation at all sites, it had a significant impact on all sites except the ileum. Collectively, these data illustrate the interplay between microbiota, age, and sex in the metabolic phenotypes of diverse body sites. This provides a framework for interpreting complex metabolic phenotypes and will help guide future studies into the role that the microbiome plays in disease.
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21
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Chen W, Yan Q, Zhong R, Tan Z. Amino acid profiles, amino acid sensors and transporters expression and intestinal microbiota are differentially altered in goats infected with Haemonchus contortus. Amino Acids 2023; 55:371-384. [PMID: 36648537 DOI: 10.1007/s00726-023-03235-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 01/06/2023] [Indexed: 01/18/2023]
Abstract
Infection with the nematode Haemonchus contortus causes host malnutrition and gastrointestinal injuries. The objective of this study was to investigate the effects of H. contortus infection on gastrointestinal contents of free amino acids (AA), the expression of AA transporters and microbiota with a focus on amino acid metabolism. Twenty-four Xiangdong black goats (13 ± 1.5 kg, 6 months old) were randomly assigned into the control group (n = 8) and the infected group (n = 16). The results showed that H. contortus infection increased (P < 0.05) the free AA contents in jejunum and ileum digesta. The concentrations of blood threonine, phenylalanine and tyrosine were lower (P < 0.05) in the infected group as compared to the control group. In the jejunum and ileum epithelium, H. contortus infection significantly (P < 0.05) down-regulated the expression of AA transporter b0,+AT/rBAT and B0AT1, but up-regulated (P < 0.05) the expression of transporter CAT2 and xCT. Furthermore, microbiota in both jejunum (Bifidobacteriaceae, Lachnospiraceae, Bacteroidaceae, Enterobacteriaceae, and Micrococcaceae) and ileum (Acidaminococcaceae, Desulfovibrionaceae, Bacteroidaceae, and Peptostreptococcaceae) were also altered at the family level by H. contortus infection. The commensal bacteria of jejunum showed a close correlation with amino acids, AA transporters, and amino acid metabolism, especially cystine. In conclusion, H. contortus infection affected the intestinal AA contents and the expression of intestinal AA transporters, suggesting altered AA metabolism and absorption, which were accompanied by changes in the relative abundances of gut bacteria that mediate amino acid metabolism.
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Affiliation(s)
- Wenxun Chen
- CAS Key Laboratory for Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Hunan Provincial Key Laboratory of Nutritional Physiology and Metabolic Process, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, 410125, Hunan, People's Republic of China
- University of Chinese Academy of Science, Beijing, 100049, People's Republic of China
| | - Qiongxian Yan
- CAS Key Laboratory for Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Hunan Provincial Key Laboratory of Nutritional Physiology and Metabolic Process, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, 410125, Hunan, People's Republic of China.
| | - Rongzhen Zhong
- Jilin Provincial Key Laboratory of Grassland Farming, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Changchun, 130102, Jilin, People's Republic of China
| | - Zhiliang Tan
- CAS Key Laboratory for Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Hunan Provincial Key Laboratory of Nutritional Physiology and Metabolic Process, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, 410125, Hunan, People's Republic of China
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22
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Pruss KM, Chen H, Liu Y, Van Treuren W, Higginbottom SK, Jarman JB, Fischer CR, Mak J, Wong B, Cowan TM, Fischbach MA, Sonnenburg JL, Dodd D. Host-microbe co-metabolism via MCAD generates circulating metabolites including hippuric acid. Nat Commun 2023; 14:512. [PMID: 36720857 PMCID: PMC9889317 DOI: 10.1038/s41467-023-36138-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 01/17/2023] [Indexed: 02/01/2023] Open
Abstract
The human gut microbiota produces dozens of small molecules that circulate in blood, accumulate to comparable levels as pharmaceutical drugs, and influence host physiology. Despite the importance of these metabolites to human health and disease, the origin of most microbially-produced molecules and their fate in the host remains largely unknown. Here, we uncover a host-microbe co-metabolic pathway for generation of hippuric acid, one of the most abundant organic acids in mammalian urine. Combining stable isotope tracing with bacterial and host genetics, we demonstrate reduction of phenylalanine to phenylpropionic acid by gut bacteria; the host re-oxidizes phenylpropionic acid involving medium-chain acyl-CoA dehydrogenase (MCAD). Generation of germ-free male and female MCAD-/- mice enabled gnotobiotic colonization combined with untargeted metabolomics to identify additional microbial metabolites processed by MCAD in host circulation. Our findings uncover a host-microbe pathway for the abundant, non-toxic phenylalanine metabolite hippurate and identify β-oxidation via MCAD as a novel mechanism by which mammals metabolize microbiota-derived metabolites.
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Affiliation(s)
- Kali M Pruss
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Haoqing Chen
- Department of Pathology Stanford University School of Medicine, Stanford, CA, USA
| | - Yuanyuan Liu
- Department of Pathology Stanford University School of Medicine, Stanford, CA, USA
| | - William Van Treuren
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Steven K Higginbottom
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - John B Jarman
- Department of Pathology Stanford University School of Medicine, Stanford, CA, USA
| | - Curt R Fischer
- ChEM-H, Stanford University, Stanford, CA, USA
- Octant Bio, Emeryville, CA, USA
| | | | | | - Tina M Cowan
- Department of Pathology Stanford University School of Medicine, Stanford, CA, USA
| | - Michael A Fischbach
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
- ChEM-H, Stanford University, Stanford, CA, USA
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- Chan Zuckerberg Biohub, San Francisco, CA, USA
| | - Justin L Sonnenburg
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
- Chan Zuckerberg Biohub, San Francisco, CA, USA
- Center for Human Microbiome Studies, Stanford, CA, USA
| | - Dylan Dodd
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Pathology Stanford University School of Medicine, Stanford, CA, USA.
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23
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Protective Effects of Clinacanthus nutans (Burm.f.) Lindau Aqueous Extract on HBV Mouse Model by Modulating Gut Microbiota and Liver Metabolomics. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2023; 2023:5625222. [PMID: 36636608 PMCID: PMC9831714 DOI: 10.1155/2023/5625222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 12/04/2022] [Accepted: 12/13/2022] [Indexed: 01/14/2023]
Abstract
Background Clinacanthus nutans (Burm.f.) Lindau (C. nutans) has been used in the therapy of hepatitis B (HB) and is effective; however, the mechanism of action has not been elucidated. Objective To investigate the protective effects of C. nutans aqueous extract on the hepatitis B virus (HBV) mouse model based on correlation analysis between gut microbiota and liver metabolomics. Materials and Methods We firstly constructed the animal model by high-pressure injection of pcDNA3.1(+)/HBV plasmid into the tail vein and treated it with C. nutans. The biomarkers and inflammatory cytokines of HB were detected by enzyme-linked immunosorbent assay and quantitative PCR; the Illumina-MiSeq platform was used for investigating gut microbiota; the LC-MS/MS method was utilized on screening liver tissue metabolites; multiomics joint analysis was performed using the R program. Results Compared with the modeling group, C. nutans significantly decreased the expression levels of HBsAg, IL-1β, TNF-α(P < 0.05) in the serum, and cccDNA (P < 0.05) in the liver tissues of mice. C. nutans dramatically reduced the ratio of Firmicutes and Bacteroidetes (P < 0.05) and significantly declined the proportion of Lactobacillaceae and Lactobacillus(P < 0.05), dramatically increasing the relative abundance of Bacteroidales_S24-7_group, Rikenellaceae, and Alistipes(P < 0.05); LC-MS/MS analysis results showed that C. nutans dramatically upregulate hippuric acid, L-histidine, trehalose, D-threitol, and stachyose and downregulate uridine 5'-diphosphate, cholic acid, trimethylamine N-oxide, CDP-ethanolamine, and phosphorylcholine (P < 0.05). The correlation analysis revealed that C. nutans affects the related metabolite levels of hippuric acid and cholic acid through the modulation of crucial bacteria (Alistipes) (P < 0.01), exerting specific anti-inflammatory effects. Conclusion These results suggest that C. nutans exerts protective effects in HBV model mice, showing the therapeutic potential for anti-HBV infection.
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24
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Wang D, Russel WA, Sun Y, Belanger KD, Ay A. Machine learning and network analysis of the gut microbiome from patients with schizophrenia and non-psychiatric subject controls reveal behavioral risk factors and bacterial interactions. Schizophr Res 2023; 251:49-58. [PMID: 36577234 DOI: 10.1016/j.schres.2022.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 11/15/2022] [Accepted: 12/11/2022] [Indexed: 12/27/2022]
Abstract
Recent findings have supported an association between deviations in gut microbiome composition and schizophrenia. However, the extent to which the gut microbiota contributes to schizophrenia remains unclear. Moreover, studies have yet to explore variations in ecological associations among bacterial types in subjects with schizophrenia, which can reveal differences in community interactions and gut stability. We examined the dataset collected by Nguyen et al. (2021) to investigate the similarities and differences in gut microbial constituents between 48 subjects with schizophrenia and 48 matched non-psychiatric comparison cases. We re-analyzed alpha- and beta-diversity differences and completed modified differential abundance analyses and confirmed the findings of Nguyen et al. (2021) that there was little variation in alpha-diversity but significant differences in beta-diversity between individuals with schizophrenia and non-psychiatric subjects. We also conducted mediation analysis, developed a machine learning (ML) model to predict schizophrenia, and completed network analysis to examine community-level interactions among bacterial taxa. Our study offers new insights, suggesting that the gut microbiome mediates the effects between schizophrenia and smoking status, BMI, anxiety score, and depression score. Our differential abundance and network analysis findings suggest that the differential abundance of Lachnospiraceae and Ruminococcaceae taxa fosters a decrease in stabilizing competitive interactions in the gut microbiome of subjects with schizophrenia. Loss of this competition may promote ecological instability and dysbiosis, altering gut-brain axis interactions in these subjects.
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Affiliation(s)
- Dong Wang
- Department of Computer Science, Colgate University, Hamilton, NY 13346, USA; Department of Mathematics, Colgate University, Hamilton, NY 13346, USA.
| | - William A Russel
- Department of Biology, Colgate University, Hamilton, NY 13346, USA.
| | - Yuntong Sun
- Department of Biology, Colgate University, Hamilton, NY 13346, USA.
| | | | - Ahmet Ay
- Department of Mathematics, Colgate University, Hamilton, NY 13346, USA; Department of Biology, Colgate University, Hamilton, NY 13346, USA.
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25
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Zhang N, Wang J, Bakker W, Zheng W, Baccaro M, Murali A, van Ravenzwaay B, Rietjens IMCM. In vitro models to detect in vivo bile acid changes induced by antibiotics. Arch Toxicol 2022; 96:3291-3303. [PMID: 36074177 PMCID: PMC9584874 DOI: 10.1007/s00204-022-03373-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 08/25/2022] [Indexed: 11/20/2022]
Abstract
Bile acid homeostasis plays an important role in many biological activities through the bile-liver-gut axis. In this study, two in vitro models were applied to further elucidate the mode of action underlying reported in vivo bile acid changes induced by antibiotics (colistin sulfate, tobramycin, meropenem trihydrate, and doripenem hydrate). 16S rRNA analysis of rat fecal samples anaerobically incubated with these antibiotics showed that especially tobramycin induced changes in the gut microbiota. Furthermore, tobramycin was shown to inhibit the microbial deconjugation of taurocholic acid (TCA) and the transport of TCA over an in vitro Caco-2 cell layer used as a model to mimic intestinal bile acid reuptake. The effects induced by the antibiotics in the in vitro model systems provide novel and complementary insight explaining the effects of the antibiotics on microbiota and fecal bile acid levels upon 28-day in vivo treatment of rats. In particular, our results provide insight in the mode(s) of action underlying the increased levels of TCA in the feces upon tobramycin exposure. Altogether, the results of the present study provide a proof-of-principle on how in vitro models can be used to elucidate in vivo effects on bile acid homeostasis, and to obtain insight in the mode(s) of action underlying the effect of an antibiotic, in this case tobramycin, on bile acid homeostasis via effects on intestinal bile acid metabolism and reuptake.
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Affiliation(s)
- Nina Zhang
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
| | - Jingxuan Wang
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Wouter Bakker
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Weijia Zheng
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Marta Baccaro
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | | | | | - Ivonne M C M Rietjens
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
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26
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Cuesta S, Burdisso P, Segev A, Kourrich S, Sperandio V. Gut colonization by Proteobacteria alters host metabolism and modulates cocaine neurobehavioral responses. Cell Host Microbe 2022; 30:1615-1629.e5. [PMID: 36323315 PMCID: PMC9669251 DOI: 10.1016/j.chom.2022.09.014] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 07/22/2022] [Accepted: 09/14/2022] [Indexed: 11/11/2022]
Abstract
Gut-microbiota membership is associated with diverse neuropsychological outcomes, including substance use disorders (SUDs). Here, we use mice colonized with Citrobacter rodentium or the human γ-Proteobacteria commensal Escherichia coli HS as a model to examine the mechanistic interactions between gut microbes and host responses to cocaine. We find that cocaine exposure increases intestinal norepinephrine levels that are sensed through the bacterial adrenergic receptor QseC to promote intestinal colonization of γ-Proteobacteria. Colonized mice show enhanced host cocaine-induced behaviors. The neuroactive metabolite glycine, a bacterial nitrogen source, is depleted in the gut and cerebrospinal fluid of colonized mice. Systemic glycine repletion reversed, and γ-Proteobacteria mutated for glycine uptake did not alter the host response to cocaine. γ-Proteobacteria modulated glycine levels are linked to cocaine-induced transcriptional plasticity in the nucleus accumbens through glutamatergic transmission. The mechanism outline here could potentially be exploited to modulate reward-related brain circuits that contribute to SUDs.
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Affiliation(s)
- Santiago Cuesta
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
| | - Paula Burdisso
- Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET-UNR) and Plataforma Argentina de Biología Estructural y Metabolómica (PLABEM), Rosario, Santa Fe, Argentina
| | - Amir Segev
- Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, TX 75390, USA
| | - Saïd Kourrich
- Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, Canada; The Center of Excellence in Research on Orphan Diseases - Foundation Courtois, Université du Québec à Montréal, Montréal, QC, Canada; Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, QC, Canada
| | - Vanessa Sperandio
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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27
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Diether NE, Nam SL, Fouhse J, Le Thanh BV, Stothard P, Zijlstra RT, Harynuk J, de la Mata P, Willing BP. Dietary benzoic acid and supplemental enzymes alter fiber-fermenting taxa and metabolites in the cecum of weaned pigs. J Anim Sci 2022; 100:skac324. [PMID: 36205053 PMCID: PMC9683507 DOI: 10.1093/jas/skac324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 10/05/2022] [Indexed: 11/13/2022] Open
Abstract
Inclusion of enzymes and organic acids in pig diets is an important strategy supporting decreased antibiotic usage in pork production. However, limited knowledge exists about how these additives impact intestinal microbes and their metabolites. To examine the effects of benzoic acid and enzymes on gut microbiota and metabolome, 160 pigs were assigned to one of four diets 7 days after weaning: a control diet or the addition of 0.5% benzoic acid, 0.045% dietary enzymes (phytase, β-glucanase, xylanase, and α-amylase), or both and fed ad libitum for 21 to 22 d. Individual growth performance and group diarrhea incidence data were collected throughout the experimental period. A decrease of 20% in pen-level diarrhea incidence from days 8 to 14 in pigs-fed both benzoic acid and enzymes compared to the control diet (P = 0.047). Cecal digesta samples were collected at the end of the experimental period from 40 piglets (n = 10 per group) and evaluated for differences using 16S rRNA sequencing and two-dimensional gas chromatography and time-of-flight mass spectrometry (GCxGC-TOFMS). Analysis of cecal microbiota diversity revealed that benzoic acid altered microbiota composition (Unweighted Unifrac, P = 0.047, r2 = 0.07) and decreased α-diversity (Shannon, P = 0.041; Faith's Phylogenetic Diversity, P = 0.041). Dietary enzymes increased fiber-fermenting bacterial taxa such as Prevotellaceae. Two-step feature selection identified 17 cecal metabolites that differed among diets, including increased microbial cross-feeding product 1,2-propanediol in pigs-fed benzoic acid-containing diets. In conclusion, dietary benzoic acid and enzymes affected the gut microbiota and metabolome of weaned pigs and may support the health and resolution of postweaning diarrhea.
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Affiliation(s)
- Natalie E Diether
- Department of Agricultural, Food & Nutritional Science, University of Alberta, Edmonton, Alberta T6G 2P5, Canada
| | - Seo Lin Nam
- Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2P5, Canada
| | - Janelle Fouhse
- Department of Agricultural, Food & Nutritional Science, University of Alberta, Edmonton, Alberta T6G 2P5, Canada
| | - Bich V Le Thanh
- Department of Agricultural, Food & Nutritional Science, University of Alberta, Edmonton, Alberta T6G 2P5, Canada
| | - Paul Stothard
- Department of Agricultural, Food & Nutritional Science, University of Alberta, Edmonton, Alberta T6G 2P5, Canada
| | - Ruurd T Zijlstra
- Department of Agricultural, Food & Nutritional Science, University of Alberta, Edmonton, Alberta T6G 2P5, Canada
| | - James Harynuk
- Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2P5, Canada
| | - Paulina de la Mata
- Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2P5, Canada
| | - Benjamin P Willing
- Department of Agricultural, Food & Nutritional Science, University of Alberta, Edmonton, Alberta T6G 2P5, Canada
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28
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Metabolic reconstitution of germ-free mice by a gnotobiotic microbiota varies over the circadian cycle. PLoS Biol 2022; 20:e3001743. [PMID: 36126044 PMCID: PMC9488797 DOI: 10.1371/journal.pbio.3001743] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 07/06/2022] [Indexed: 12/17/2022] Open
Abstract
The capacity of the intestinal microbiota to degrade otherwise indigestible diet components is known to greatly improve the recovery of energy from food. This has led to the hypothesis that increased digestive efficiency may underlie the contribution of the microbiota to obesity. OligoMM12-colonized gnotobiotic mice have a consistently higher fat mass than germ-free (GF) or fully colonized counterparts. We therefore investigated their food intake, digestion efficiency, energy expenditure, and respiratory quotient using a novel isolator-housed metabolic cage system, which allows long-term measurements without contamination risk. This demonstrated that microbiota-released calories are perfectly balanced by decreased food intake in fully colonized versus gnotobiotic OligoMM12 and GF mice fed a standard chow diet, i.e., microbiota-released calories can in fact be well integrated into appetite control. We also observed no significant difference in energy expenditure after normalization by lean mass between the different microbiota groups, suggesting that cumulative small differences in energy balance, or altered energy storage, must underlie fat accumulation in OligoMM12 mice. Consistent with altered energy storage, major differences were observed in the type of respiratory substrates used in metabolism over the circadian cycle: In GF mice, the respiratory exchange ratio (RER) was consistently lower than that of fully colonized mice at all times of day, indicative of more reliance on fat and less on glucose metabolism. Intriguingly, the RER of OligoMM12-colonized gnotobiotic mice phenocopied fully colonized mice during the dark (active/eating) phase but phenocopied GF mice during the light (fasting/resting) phase. Further, OligoMM12-colonized mice showed a GF-like drop in liver glycogen storage during the light phase and both liver and plasma metabolomes of OligoMM12 mice clustered closely with GF mice. This implies the existence of microbiota functions that are required to maintain normal host metabolism during the resting/fasting phase of circadian cycle and which are absent in the OligoMM12 consortium.
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Gadaleta RM, Cariello M, Crudele L, Moschetta A. Bile Salt Hydrolase-Competent Probiotics in the Management of IBD: Unlocking the "Bile Acid Code". Nutrients 2022; 14:3212. [PMID: 35956388 PMCID: PMC9370712 DOI: 10.3390/nu14153212] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/02/2022] [Accepted: 08/03/2022] [Indexed: 01/18/2023] Open
Abstract
Bile acid (BA) species and the gut microbiota (GM) contribute to intestinal mucosa homeostasis. BAs shape the GM and, conversely, intestinal bacteria with bile salt hydrolase (BSH) activity modulate the BA pool composition. The mutual interaction between BAs and intestinal microorganisms also influences mucosal barrier integrity, which is important for inflammatory bowel disease (IBD) pathogenesis, prevention and therapy. High levels of secondary BAs are detrimental for the intestinal barrier and increase the intestinal inflammatory response and dysbiosis. Additionally, a lack of BSH-active bacteria plays a role in intestinal inflammation and BA dysmetabolism. Thus, BSH-competent bacteria in probiotic formulations are being actively studied in IBD. At the same time, studies exploring the modulation of the master regulator of BA homeostasis, the Farnesoid X Receptor (FXR), in intestinal inflammation and how this impacts the GM are gaining significant momentum. Overall, the choice of probiotic supplementation should be a peculiar issue of personalized medicine, considering not only the disease but also the specific BA and metabolic signatures of a given patient.
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Affiliation(s)
- Raffaella Maria Gadaleta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Marica Cariello
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Lucilla Crudele
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
- INBB National Instituto for Biostructure and Biosystems, Viale delle Medaglie d’Oro 305, 00136 Rome, Italy
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Liu B, Yu D, Sun J, Wu X, Xin Z, Deng B, Fan L, Fu J, Ge L, Ren W. Characterizing the influence of gut microbiota on host tryptophan metabolism with germ-free pigs. ANIMAL NUTRITION 2022; 11:190-200. [PMID: 36263410 PMCID: PMC9562448 DOI: 10.1016/j.aninu.2022.07.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 07/13/2022] [Accepted: 07/18/2022] [Indexed: 11/07/2022]
Abstract
Intestinal microbes are closely associated with host health, depending on metabolic crosstalk between the microbiota and host. Tryptophan metabolism is one of the best examples of metabolic crosstalk between intestinal microbiota and host; however, our understanding about the influence of intestinal microbiota on host tryptophan metabolism is limited. Thus, we established germ-free (GF) pig models to systemically explore the influence of intestinal microbiota on tryptophan metabolism. Five GF pigs were kept in GF conditions throughout the experiment (GF group). Six GF pigs were transplanted with fecal microbiota from donor sows to act as control pigs. Compared with control pigs, the GF pigs had remarkable alterations in tryptophan metabolism. The differential metabolites (P < 0.05) were mainly found in the liver, circulation system and large intestine. Notably, the alteration of metabolites in tryptophan metabolism varied among organs, especially for the serotonin pathway. In GF pigs, tryptophan and kynurenine in the large intestine and 5-hydroxytryptophan in most organs were increased (P < 0.05), while metabolites in the indole pathway in most organs were decreased (P < 0.05). Collectively, our study reveals changes in tryptophan metabolism in GF pigs, highlighting the critical role of gut microbes in shaping host tryptophan metabolism.
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Shute A, Bihan DG, Lewis IA, Nasser Y. Metabolomics: The Key to Unraveling the Role of the Microbiome in Visceral Pain Neurotransmission. Front Neurosci 2022; 16:917197. [PMID: 35812241 PMCID: PMC9260117 DOI: 10.3389/fnins.2022.917197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 05/30/2022] [Indexed: 11/29/2022] Open
Abstract
Inflammatory bowel disease (IBD), comprising Crohn's disease and Ulcerative colitis, is a relapsing and remitting disease of the gastrointestinal tract, presenting with chronic inflammation, ulceration, gastrointestinal bleeding, and abdominal pain. Up to 80% of patients suffering from IBD experience acute pain, which dissipates when the underlying inflammation and tissue damage resolves. However, despite achieving endoscopic remission with no signs of ongoing intestinal inflammation or damage, 30-50% of IBD patients in remission experience chronic abdominal pain, suggesting altered sensory neuronal processing in this disorder. Furthermore, effective treatment for chronic pain is limited such that 5-25% of IBD outpatients are treated with narcotics, with associated morbidity and mortality. IBD patients commonly present with substantial alterations to the microbial community structure within the gastrointestinal tract, known as dysbiosis. The same is also true in irritable bowel syndrome (IBS), a chronic disorder characterized by altered bowel habits and abdominal pain, in the absence of inflammation. An emerging body of literature suggests that the gut microbiome plays an important role in visceral hypersensitivity. Specific microbial metabolites have an intimate relationship with host receptors that are highly expressed on host cell and neurons, suggesting that microbial metabolites play a key role in visceral hypersensitivity. In this review, we will discuss the techniques used to analysis the metabolome, current potential metabolite targets for visceral hypersensitivity, and discuss the current literature that evaluates the role of the post-inflammatory microbiota and metabolites in visceral hypersensitivity.
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Affiliation(s)
- Adam Shute
- Department of Medicine, Cumming School of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
| | - Dominique G. Bihan
- Department of Biological Sciences, University of Calgary, Calgary, AB, Canada
| | - Ian A. Lewis
- Department of Biological Sciences, University of Calgary, Calgary, AB, Canada
| | - Yasmin Nasser
- Department of Medicine, Cumming School of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
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Moving beyond descriptive studies: harnessing metabolomics to elucidate the molecular mechanisms underpinning host-microbiome phenotypes. Mucosal Immunol 2022; 15:1071-1084. [PMID: 35970917 DOI: 10.1038/s41385-022-00553-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 07/04/2022] [Accepted: 07/20/2022] [Indexed: 02/04/2023]
Abstract
Advances in technology and software have radically expanded the scope of metabolomics studies and allow us to monitor a broad transect of central carbon metabolism in routine studies. These increasingly sophisticated tools have shown that many human diseases are modulated by microbial metabolism. Despite this, it remains surprisingly difficult to move beyond these statistical associations and identify the specific molecular mechanisms that link dysbiosis to the progression of human disease. This difficulty stems from both the biological intricacies of host-microbiome dynamics as well as the analytical complexities inherent to microbiome metabolism research. The primary objective of this review is to examine the experimental and computational tools that can provide insights into the molecular mechanisms at work in host-microbiome interactions and to highlight the undeveloped frontiers that are currently holding back microbiome research from fully leveraging the benefits of modern metabolomics.
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Sun Y, Sun P, Hu Y, Shan L, Geng Q, Gong Y, Fan H, Zhang T, Zhou Y. Elevated testicular apoptosis is associated with elevated sphingosine driven by gut microbiota in prediabetic sheep. BMC Biol 2022; 20:121. [PMID: 35606800 PMCID: PMC9128135 DOI: 10.1186/s12915-022-01326-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 05/09/2022] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Men with prediabetes often exhibit concomitant low-quality sperm production or even infertility, problems which urgently require improved therapeutic options. In this study, we have established a sheep model of diet-induced prediabetes that is associated with spermatogenic defects and have explored the possible underlying metabolic causes. RESULTS We compared male sheep fed a normal diet with those in which prediabetes was induced by a rich diet and with a third group in which the rich diet was supplemented by melatonin. Only the rich diet group had symptoms of prediabetes, and in these sheep, we found impaired spermatogenesis characterized by a block in the development of round spermatids and an increased quantity of testicular apoptotic cells. Comparing the gut microbiomes and intestinal digest metabolomes of the three groups revealed a distinctive difference in the taxonomic composition of the microbiota in prediabetic sheep, and an altered metabolome, whose most significant feature was altered sphingosine metabolism; elevated sphingosine was also found in blood and testes. Administration of melatonin alleviated the symptoms of prediabetes, including those of impaired spermatogenesis, while restoring a more normal microbiota and metabolic levels of sphingosine. Fecal microbiota transplantation from prediabetic sheep induced elevated sphingosine levels and impaired spermatogenesis in recipient mice, indicating a causal role of gut microbiota in these phenotypes. CONCLUSIONS Our results point to a key role of sphingosine in the disruption of spermatogenesis in prediabetic sheep and suggest it could be a useful disease marker; furthermore, melatonin represents a potential prebiotic agent for the treatment of male infertility caused by prediabetes.
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Affiliation(s)
- Yuanchao Sun
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, 010070, China
- The Affiliated Hospital of Qingdao University and The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, 266003, China
| | - Peng Sun
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, 010070, China
- Laboratory of Microbiology and Immunology, College of Basic Medicine, Inner Mongolia Medical University, Hohhot, 010059, China
| | - Yanting Hu
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, 010070, China
| | - Liying Shan
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, 010070, China
| | - Qi Geng
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, 010070, China
| | - Yutian Gong
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, 010070, China
| | - Haitao Fan
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, 010070, China
| | - Teng Zhang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, 010070, China.
| | - Yang Zhou
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, 010070, China.
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Liu Y, Chen H, Van Treuren W, Hou BH, Higginbottom SK, Dodd D. Clostridium sporogenes uses reductive Stickland metabolism in the gut to generate ATP and produce circulating metabolites. Nat Microbiol 2022; 7:695-706. [PMID: 35505245 PMCID: PMC9089323 DOI: 10.1038/s41564-022-01109-9] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/24/2022] [Indexed: 11/30/2022]
Abstract
Gut bacteria face a key problem in how they capture enough energy to sustain their growth and physiology. The gut bacterium Clostridium sporogenes obtains its energy by utilizing amino acids in pairs, coupling the oxidation of one to the reduction of another-the Stickland reaction. Oxidative pathways produce ATP via substrate-level phosphorylation, whereas reductive pathways are thought to balance redox. In the present study, we investigated whether these reductive pathways are also linked to energy generation and the production of microbial metabolites that may circulate and impact host physiology. Using metabolomics, we find that, during growth in vitro, C. sporogenes produces 15 metabolites, 13 of which are present in the gut of C. sporogenes-colonized mice. Four of these compounds are reductive Stickland metabolites that circulate in the blood of gnotobiotic mice and are also detected in plasma from healthy humans. Gene clusters for reductive Stickland pathways suggest involvement of electron transfer proteins, and experiments in vitro demonstrate that reductive metabolism is coupled to ATP formation and not just redox balance. Genetic analysis points to the broadly conserved Rnf complex as a key coupling site for energy transduction. Rnf complex mutants show aberrant amino acid metabolism in a defined medium and are attenuated for growth in the mouse gut, demonstrating a role of the Rnf complex in Stickland metabolism and gut colonization. Our findings reveal that the production of circulating metabolites by a commensal bacterium within the host gut is linked to an ATP-yielding redox process.
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Affiliation(s)
- Yuanyuan Liu
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Haoqing Chen
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - William Van Treuren
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Bi-Huei Hou
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Steven K Higginbottom
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Dylan Dodd
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
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Exploring the Gut Microbiome in Myasthenia Gravis. Nutrients 2022; 14:nu14081647. [PMID: 35458209 PMCID: PMC9027283 DOI: 10.3390/nu14081647] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/10/2022] [Accepted: 04/12/2022] [Indexed: 12/13/2022] Open
Abstract
The human gut microbiota is vital for maintaining human health in terms of immune system homeostasis. Perturbations in the composition and function of microbiota have been associated with several autoimmune disorders, including myasthenia gravis (MG), a neuromuscular condition associated with varying weakness and rapid fatigue of the skeletal muscles triggered by the host’s antibodies against the acetylcholine receptor (AChR) in the postsynaptic muscle membrane at the neuromuscular junction (NMJ). It is hypothesized that perturbation of the gut microbiota is associated with the pathogenesis of MG. The gut microbiota community profiles are usually generated using 16S rRNA gene sequencing. Compared to healthy individuals, MG participants had an altered gut microbiota’s relative abundance of bacterial taxa, particularly with a drop in Clostridium. The microbial diversity related to MG severity and the overall fecal short-chain fatty acids (SCFAs) were lower in MG subjects. Changes were also found in terms of serum biomarkers and fecal metabolites. A link was found between the bacterial Operational Taxonomic Unit (OTU), some metabolite biomarkers, and MG’s clinical symptoms. There were also variations in microbial and metabolic markers, which, in combination, could be used as an MG diagnostic tool, and interventions via fecal microbiota transplant (FMT) could affect MG development. Probiotics may influence MG by restoring the gut microbiome imbalance, aiding the prevention of MG, and lowering the risk of gut inflammation by normalizing serum biomarkers. Hence, this review will discuss how alterations of gut microbiome composition and function relate to MG and the benefits of gut modulation.
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Zheng L, Wen XL, Duan SL. Role of metabolites derived from gut microbiota in inflammatory bowel disease. World J Clin Cases 2022; 10:2660-2677. [PMID: 35434116 PMCID: PMC8968818 DOI: 10.12998/wjcc.v10.i9.2660] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 12/12/2021] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
Over the past two decades, it is improved gut microbiota plays an important role in the health and disease pathogenesis. Metabolites, small molecules produced as intermediate or end products of microbial metabolism, is considered as one of the major interaction way for gut microbiota with the host. Bacterial metabolisms of dietary substrates, modification of host molecules or bacteria are the major source of metabolites. Signals from microbial metabolites affect immune maturation and homeostasis, host energy metabolism as well as mucosal integrity maintenance. Based on many researches, the composition and function of the microbiota can be changed, which is also seen in the metabolite profiles of patients with inflammatory bowel disease (IBD). Additionally, some specific classes of metabolites also can trigger IBD. In this paper, definition of the key classes of microbial-derived metabolites which are changed in IBD, description of the pathophysiological basis of association and identification of the precision therapeutic modulation in the future are the major contents.
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Affiliation(s)
- Lie Zheng
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 710003, Shaanxi Province, China
| | - Xin-Li Wen
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 710003, Shaanxi Province, China
| | - Sheng-Lei Duan
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 710003, Shaanxi Province, China
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Zheng L, Wen XL, Duan SL. Role of metabolites derived from gut microbiota in inflammatory bowel disease. World J Clin Cases 2022; 10:2658-2675. [DOI: 10.12998/wjcc.v10.i9.2658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Over the past two decades, it is improved gut microbiota plays an important role in the health and disease pathogenesis. Metabolites, small molecules produced as intermediate or end products of microbial metabolism, is considered as one of the major interaction way for gut microbiota with the host. Bacterial metabolisms of dietary substrates, modification of host molecules or bacteria are the major source of metabolites. Signals from microbial metabolites affect immune maturation and homeostasis, host energy metabolism as well as mucosal integrity maintenance. Based on many researches, the composition and function of the microbiota can be changed, which is also seen in the metabolite profiles of patients with inflammatory bowel disease (IBD). Additionally, some specific classes of metabolites also can trigger IBD. In this paper, definition of the key classes of microbial-derived metabolites which are changed in IBD, description of the pathophysiological basis of association and identification of the precision therapeutic modulation in the future are the major contents.
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Affiliation(s)
- Lie Zheng
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 710003, Shaanxi Province, China
| | - Xin-Li Wen
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 710003, Shaanxi Province, China
| | - Sheng-Lei Duan
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 710003, Shaanxi Province, China
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Meliț LE, Mărginean CO, Săsăran MO. The Yin-Yang Concept of Pediatric Obesity and Gut Microbiota. Biomedicines 2022; 10:biomedicines10030645. [PMID: 35327446 PMCID: PMC8945275 DOI: 10.3390/biomedicines10030645] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/05/2022] [Accepted: 03/07/2022] [Indexed: 02/04/2023] Open
Abstract
The era of pediatric obesity is no longer a myth. Unfortunately, pediatric obesity has reached alarming incidence levels worldwide and the factors that contribute to its development have been intensely studied in multiple recent and emerging studies. Gut microbiota was recently included in the wide spectrum of factors implicated in the determination of obesity, but its role in pediatric obese patients is far from being fully understood. In terms of the infant gut microbiome, multiple factors have been demonstrated to shape its content, including maternal diet and health, type of delivery, feeding patterns, weaning and dietary habits. Nevertheless, the role of the intrauterine environment, such as the placental microbial community, cannot be completely excluded. Most studies have identified Firmicutes and Bacteroidetes as the most important players related to obesity risk in gut microbiota reflecting an increase of Firmicutes and a decrease in Bacteroidetes in the context of obesity; however, multiple inconsistencies between studies were recently reported, especially in pediatric populations, and there is a scarcity of studies performed in this age group.
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Affiliation(s)
- Lorena Elena Meliț
- Department of Pediatrics I, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș, Gheorghe Marinescu Street No 38, 540136 Târgu Mureș, Romania;
| | - Cristina Oana Mărginean
- Department of Pediatrics I, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș, Gheorghe Marinescu Street No 38, 540136 Târgu Mureș, Romania;
- Correspondence:
| | - Maria Oana Săsăran
- Department of Pediatrics III, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș, Gheorghe Marinescu Street No 38, 540136 Târgu Mureș, Romania;
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Xu SS, Zhang XL, Liu SS, Feng ST, Xiang GM, Xu CJ, Fan ZY, Xu K, Wang N, Wang Y, Che JJ, Liu ZG, Mu YL, Li K. Multi-Omic Analysis in a Metabolic Syndrome Porcine Model Implicates Arachidonic Acid Metabolism Disorder as a Risk Factor for Atherosclerosis. Front Nutr 2022; 9:807118. [PMID: 35284467 PMCID: PMC8906569 DOI: 10.3389/fnut.2022.807118] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/10/2022] [Indexed: 11/25/2022] Open
Abstract
Background The diet-induced gut microbiota dysbiosis has been suggested as a major risk factor for atherothrombosis, however, the detailed mechanism linking these conditions is yet to be fully understood. Methods We established a long-term excessive-energy diet-induced metabolic syndrome (MetS) inbred Wuzhishan minipig model, which is characterized by its genetic stability, small size, and human-like physiology. The metabolic parameters, atherosclerotic lesions, gut microbiome, and host transcriptome were analyzed. Metabolomics profiling revealed a linkage between gut microbiota and atherothrombosis. Results We showed that white atheromatous plaque was clearly visible on abdominal aorta in the MetS model. Furthermore, using metagenome and metatranscriptome sequencing, we discovered that the long-term excessive energy intake altered the local intestinal microbiota composition and transcriptional profile, which was most dramatically illustrated by the reduced abundance of SCFAs-producing bacteria including Bacteroides, Lachnospiraceae, and Ruminococcaceae in the MetS model. Liver and abdominal aorta transcriptomes in the MetS model indicate that the diet-induced gut microbiota dysbiosis activated host chronic inflammatory responses and significantly upregulated the expression of genes related to arachidonic acid-dependent signaling pathways. Notably, metabolomics profiling further revealed an intimate linkage between arachidonic acid metabolism and atherothrombosis in the host-gut microbial metabolism axis. Conclusions These findings provide new insights into the relationship between atherothrombosis and regulation of gut microbiota via host metabolomes and will be of potential value for the treatment of cardiovascular diseases in MetS.
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Affiliation(s)
- Song-Song Xu
- State Key Laboratory of Animal Nutrition and Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China
| | - Xiu-Ling Zhang
- State Key Laboratory of Animal Nutrition and Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Sha-Sha Liu
- State Key Laboratory of Animal Nutrition and Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
- Animal Husbandry and Veterinary Department, Beijing Vocational College of Agriculture, Beijing, China
| | - Shu-Tang Feng
- State Key Laboratory of Animal Nutrition and Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Guang-Ming Xiang
- State Key Laboratory of Animal Nutrition and Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Chang-Jiang Xu
- State Key Laboratory of Animal Nutrition and Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Zi-Yao Fan
- State Key Laboratory of Animal Nutrition and Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Kui Xu
- State Key Laboratory of Animal Nutrition and Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Nan Wang
- State Key Laboratory of Animal Nutrition and Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Yue Wang
- State Key Laboratory of Animal Nutrition and Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Jing-Jing Che
- State Key Laboratory of Animal Nutrition and Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Zhi-Guo Liu
- State Key Laboratory of Animal Nutrition and Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Yu-Lian Mu
- State Key Laboratory of Animal Nutrition and Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
- *Correspondence: Yu-Lian Mu
| | - Kui Li
- State Key Laboratory of Animal Nutrition and Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China
- Kui Li
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Lan Y, Sun Q, Ma Z, Peng J, Zhang M, Wang C, Zhang X, Yan X, Chang L, Hou X, Qiao R, Mulati A, Zhou Y, Zhang Q, Liu Z, Liu X. Seabuckthorn polysaccharide ameliorates high-fat diet-induced obesity by gut microbiota-SCFAs-liver axis. Food Funct 2022; 13:2925-2937. [PMID: 35191457 DOI: 10.1039/d1fo03147c] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Obesity has been reported to be associated with gut microbiome dysbiosis. seabuckthorn fruits have traditionally been used in Tibetan foods and medicines for thousands of years. Seabuckthorn polysaccharide (SP) is one of the main functional components in seabuckthorn fruits. However, the effects of SP on a high-fat diet (HFD)-induced obesity have not yet been elucidated. The purpose of this study is to explore the amelioration effect of SP on obesity induced by HFD and to reveal its mechanism of gut microbiota and its metabolites. Results showed that 12-week SP (0.1%, w/w) dietary supplementation could significantly reduce body weight gain, serum lipid level and liver triglycerides level in obese mice. Notably, the SP treatment elevated p-AMPKα and PPARα proteins expression stimulated the phosphorylation of ACC1 and inhibited the protein expression of FAS, PPARγ, and CD36 in the mice liver. Further, SP also reorganized the gut microbiome by up-regulating the proportion of Muribaculaceae_unclassified, Bifidobacterium, Rikenellaceae_RC9_gut_group, Alistipes, and Bacteroides, and down-regulating the abundance of Lactobacillus, Firmicutes_unclassified, Dubosiella Bilophila, and Streptococcus in HFD-induced obese mice. Moreover, the production of microbial metabolites short-chain fatty acids (SCFAs) in feces has also increased. In addition, correlation analysis results showed that obesity-ameliorating effects of SP were highly associated with levels of SCFAs in feces. Therefore, the regulation of SP on liver lipid metabolism may be due to the variation of the gut microbiome and raised production of SCFAs. These results indicate that SP could play the part of a potential nutraceutical for ameliorating obesity through regulation of the gut-liver axis.
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Affiliation(s)
- Ying Lan
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, China.
| | - Qingyang Sun
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, China.
| | - Zhiyuan Ma
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, China.
| | - Jing Peng
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, China.
| | - Mengqi Zhang
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, China.
| | - Chi Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Xiaotian Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Xianfang Yan
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Lili Chang
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, China.
| | - Xinglin Hou
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, China.
| | - Ruixue Qiao
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, China.
| | - Aiziguli Mulati
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, China.
| | - Yuan Zhou
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, China.
| | - Qiang Zhang
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, China.
| | - Zhigang Liu
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, China.
| | - Xuebo Liu
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, China.
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Zhang T, Sun P, Geng Q, Fan H, Gong Y, Hu Y, Shan L, Sun Y, Shen W, Zhou Y. Disrupted spermatogenesis in a metabolic syndrome model: the role of vitamin A metabolism in the gut-testis axis. Gut 2022; 71:78-87. [PMID: 33504491 PMCID: PMC8666830 DOI: 10.1136/gutjnl-2020-323347] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 01/11/2021] [Accepted: 01/11/2021] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Effects of the diet-induced gut microbiota dysbiosis reach far beyond the gut. We aim to uncover the direct evidence involving the gut-testis axis in the aetiology of impaired spermatogenesis. DESIGN An excessive-energy diet-induced metabolic syndrome (MetS) sheep model was established. The testicular samples, host metabolomes and gut microbiome were analysed. Faecal microbiota transplantation (FMT) confirmed the linkage between gut microbiota and spermatogenesis. RESULTS We demonstrated that the number of arrested spermatogonia was markedly elevated by using 10× single-cell RNA-seq in the MetS model. Furthermore, through using metabolomics profiling and 16S rDNA-seq, we discovered that the absorption of vitamin A in the gut was abolished due to a notable reduction of bile acid levels, which was significantly associated with reduced abundance of Ruminococcaceae_NK4A214_group. Notably, the abnormal metabolic effects of vitamin A were transferable to the testicular cells through the circulating blood, which contributed to abnormal spermatogenesis, as confirmed by FMT. CONCLUSION These findings define a starting point for linking the testicular function and regulation of gut microbiota via host metabolomes and will be of potential value for the treatment of male infertility in MetS.
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Affiliation(s)
- Teng Zhang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Peng Sun
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Qi Geng
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Haitao Fan
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Yutian Gong
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Yanting Hu
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Liying Shan
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Yuanchao Sun
- The Affiliated Hospital of Qingdao University and The Biomedical Sciences Institute of Qingdao University, Qingdao University, Qingdao, China
| | - Wei Shen
- College of Life Sciences, Qingdao Agricultural University, Qingdao, China
| | - Yang Zhou
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, China
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Dai Z, Wu Z, Zhu W, Wu G. Amino Acids in Microbial Metabolism and Function. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1354:127-143. [PMID: 34807440 DOI: 10.1007/978-3-030-85686-1_7] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Amino acids (AAs) not only serve as building blocks for protein synthesis in microorganisms but also play important roles in their metabolism, survival, inter-species crosstalk, and virulence. Different AAs have their distinct functions in microbes of the digestive tract and this in turn has important impacts on host nutrition and physiology. Deconjugation and re-conjugation of glycine- or taurine- conjugated bile acids in the process of their enterohepatic recycling is a good example of the bacterial adaptation to harsh gut niches, inter-kingdom cross-talk with AA metabolism, and cell signaling as the critical control point. It is also a big challenge for scientists to modulate the homeostasis of the pools of AAs and their metabolites in the digestive tract with the aim to improve nutrition and regulate AA metabolism related to anti-virulence reactions. Diversity of the metabolic pathways of AAs and their multi-functions in modulating bacterial growth and survival in the digestive tract should be taken into consideration in recommending nutrient requirements for animals. Thus, the concept of functional amino acids can guide not only microbiological studies but also nutritional and physiological investigations. Cutting edge discoveries in this research area will help to better understand the mechanisms responsible for host-microbe interactions and develop new strategies for improving the nutrition, health, and well-being of both animals and humans.
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Affiliation(s)
- Zhaolai Dai
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
| | - Zhenlong Wu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Weiyun Zhu
- National Center for International Research On Animal Gut Nutrition, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, China
| | - Guoyao Wu
- Department of Animal Science, Texas A&M University, College Station, 77843, TX, USA
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Darnaud M, De Vadder F, Bogeat P, Boucinha L, Bulteau AL, Bunescu A, Couturier C, Delgado A, Dugua H, Elie C, Mathieu A, Novotná T, Ouattara DA, Planel S, Saliou A, Šrůtková D, Yansouni J, Stecher B, Schwarzer M, Leulier F, Tamellini A. A standardized gnotobiotic mouse model harboring a minimal 15-member mouse gut microbiota recapitulates SOPF/SPF phenotypes. Nat Commun 2021; 12:6686. [PMID: 34795236 PMCID: PMC8602333 DOI: 10.1038/s41467-021-26963-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 10/28/2021] [Indexed: 01/14/2023] Open
Abstract
Mus musculus is the classic mammalian model for biomedical research. Despite global efforts to standardize breeding and experimental procedures, the undefined composition and interindividual diversity of the microbiota of laboratory mice remains a limitation. In an attempt to standardize the gut microbiome in preclinical mouse studies, here we report the development of a simplified mouse microbiota composed of 15 strains from 7 of the 20 most prevalent bacterial families representative of the fecal microbiota of C57BL/6J Specific (and Opportunistic) Pathogen-Free (SPF/SOPF) animals and the derivation of a standardized gnotobiotic mouse model called GM15. GM15 recapitulates extensively the functionalities found in the C57BL/6J SOPF microbiota metagenome, and GM15 animals are phenotypically similar to SOPF or SPF animals in two different facilities. They are also less sensitive to the deleterious effects of post-weaning malnutrition. In this work, we show that the GM15 model provides increased reproducibility and robustness of preclinical studies by limiting the confounding effect of fluctuation in microbiota composition, and offers opportunities for research focused on how the microbiota shapes host physiology in health and disease.
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Affiliation(s)
- Marion Darnaud
- BIOASTER, Institut de Recherche Technologique, 40 avenue Tony Garnier, 69007, Lyon, France.
| | - Filipe De Vadder
- Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Université Claude Bernard Lyon 1, Unité Mixte de Recherche 5242, 46 Allée d'Italie, 69364, Lyon, Cedex, 07, France
| | - Pascaline Bogeat
- BIOASTER, Institut de Recherche Technologique, 40 avenue Tony Garnier, 69007, Lyon, France
| | - Lilia Boucinha
- BIOASTER, Institut de Recherche Technologique, 40 avenue Tony Garnier, 69007, Lyon, France
| | - Anne-Laure Bulteau
- Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Université Claude Bernard Lyon 1, Unité Mixte de Recherche 5242, 46 Allée d'Italie, 69364, Lyon, Cedex, 07, France
| | - Andrei Bunescu
- BIOASTER, Institut de Recherche Technologique, 40 avenue Tony Garnier, 69007, Lyon, France
| | - Céline Couturier
- BIOASTER, Institut de Recherche Technologique, 40 avenue Tony Garnier, 69007, Lyon, France
| | - Ana Delgado
- BIOASTER, Institut de Recherche Technologique, 40 avenue Tony Garnier, 69007, Lyon, France
| | - Hélène Dugua
- BIOASTER, Institut de Recherche Technologique, 40 avenue Tony Garnier, 69007, Lyon, France
| | - Céline Elie
- BIOASTER, Institut de Recherche Technologique, 40 avenue Tony Garnier, 69007, Lyon, France
| | - Alban Mathieu
- BIOASTER, Institut de Recherche Technologique, 40 avenue Tony Garnier, 69007, Lyon, France
| | - Tereza Novotná
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922, Nový Hrádek, Czech Republic
| | | | - Séverine Planel
- BIOASTER, Institut de Recherche Technologique, 40 avenue Tony Garnier, 69007, Lyon, France
| | - Adrien Saliou
- BIOASTER, Institut de Recherche Technologique, 40 avenue Tony Garnier, 69007, Lyon, France
| | - Dagmar Šrůtková
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922, Nový Hrádek, Czech Republic
| | - Jennifer Yansouni
- BIOASTER, Institut de Recherche Technologique, 40 avenue Tony Garnier, 69007, Lyon, France
| | - Bärbel Stecher
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Ludwig-Maximilians-University of Munich, 80336, Munich, Germany
- German Center for Infection Research (DZIF), Partner Site, Munich, Germany
| | - Martin Schwarzer
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922, Nový Hrádek, Czech Republic
| | - François Leulier
- BIOASTER, Institut de Recherche Technologique, 40 avenue Tony Garnier, 69007, Lyon, France
- Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Université Claude Bernard Lyon 1, Unité Mixte de Recherche 5242, 46 Allée d'Italie, 69364, Lyon, Cedex, 07, France
| | - Andrea Tamellini
- BIOASTER, Institut de Recherche Technologique, 40 avenue Tony Garnier, 69007, Lyon, France
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Karlsen TR, Kong XY, Holm S, Quiles-Jiménez A, Dahl TB, Yang K, Sagen EL, Skarpengland T, S Øgaard JD, Holm K, Vestad B, Olsen MB, Aukrust P, Bjørås M, Hov JR, Halvorsen B, Gregersen I. NEIL3-deficiency increases gut permeability and contributes to a pro-atherogenic metabolic phenotype. Sci Rep 2021; 11:19749. [PMID: 34611194 PMCID: PMC8492623 DOI: 10.1038/s41598-021-98820-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 09/09/2021] [Indexed: 12/12/2022] Open
Abstract
Atherosclerosis and its consequences cause considerable morbidity and mortality world-wide. We have previously shown that expression of the DNA glycosylase NEIL3 is regulated in human atherosclerotic plaques, and that NEIL3-deficiency enhances atherogenesis in Apoe-/- mice. Herein, we identified a time point prior to quantifiable differences in atherosclerosis between Apoe-/-Neil3-/- mice and Apoe-/- mice. Mice at this age were selected to explore the metabolic and pathophysiological processes preceding extensive atherogenesis in NEIL3-deficient mice. Untargeted metabolomic analysis of young Apoe-/-Neil3-/- mice revealed significant metabolic disturbances as compared to mice expressing NEIL3, particularly in metabolites dependent on the gut microbiota. 16S rRNA gene sequencing of fecal bacterial DNA indeed confirmed that the NEIL3-deficient mice had altered gut microbiota, as well as increased circulating levels of the bacterially derived molecule LPS. The mice were challenged with a FITC-conjugated dextran to explore gut permeability, which was significantly increased in the NEIL3-deficient mice. Further, immunohistochemistry showed increased levels of the proliferation marker Ki67 in the colonic epithelium of NEIL3-deficient mice, suggesting increased proliferation of intestinal cells and gut leakage. We suggest that these metabolic alterations serve as drivers of atherosclerosis in NEIL3-deficient mice.
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Affiliation(s)
- Tom Rune Karlsen
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Xiang Yi Kong
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Sverre Holm
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Ana Quiles-Jiménez
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Tuva B Dahl
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Department of Research and Development, Division of Emergencies and Critical Care, Oslo University Hospital HF, Rikshospitalet, Oslo, Norway
| | - Kuan Yang
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Ellen L Sagen
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Tonje Skarpengland
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Jonas D S Øgaard
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Kristian Holm
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Beate Vestad
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Maria B Olsen
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Pål Aukrust
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Magnar Bjørås
- Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Johannes R Hov
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Bente Halvorsen
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Ida Gregersen
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
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45
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Eshleman EM, Alenghat T. Epithelial sensing of microbiota-derived signals. Genes Immun 2021; 22:237-246. [PMID: 33824498 PMCID: PMC8492766 DOI: 10.1038/s41435-021-00124-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/10/2021] [Accepted: 03/16/2021] [Indexed: 02/01/2023]
Abstract
The gastrointestinal tract harbors trillions of microbial species, collectively termed the microbiota, which establish a symbiotic relationship with the host. Decades of research have emphasized the necessity of microbial signals in the development, maturation, and function of host physiology. However, changes in the composition or containment of the microbiota have been linked to the development of several chronic inflammatory diseases, including inflammatory bowel diseases. Intestinal epithelial cells (IECs) are in constant contact with the microbiota and are critical for maintaining intestinal homeostasis. Signals from the microbiota are directly sensed by IECs and influence intestinal health by calibrating immune cell responses and fortifying intestinal barrier function. IECs detect commensal microbes through engagement of common pattern recognition receptors or by sensing the production of microbial-derived metabolites. Deficiencies in these microbial-detecting pathways in IECs leads to impaired epithelial barrier function and altered intestinal homeostasis. This Review aims to highlight the pathways by which IECs sense microbiota-derived signals and the necessity of these detection pathways in maintaining epithelial barrier integrity.
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Affiliation(s)
- Emily M Eshleman
- Division of Immunobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Theresa Alenghat
- Division of Immunobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
- Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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Pekarsky S, Corl A, Turjeman S, Kamath PL, Getz WM, Bowie RCK, Markin Y, Nathan R. Drivers of change and stability in the gut microbiota of an omnivorous avian migrant exposed to artificial food supplementation. Mol Ecol 2021; 30:4723-4739. [PMID: 34260783 DOI: 10.1111/mec.16079] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 06/14/2021] [Accepted: 07/01/2021] [Indexed: 12/21/2022]
Abstract
Human activities shape resources available to wild animals, impacting diet and probably altering their microbiota and overall health. We examined drivers shaping microbiota profiles of common cranes (Grus grus) in agricultural habitats by comparing gut microbiota and crane movement patterns (GPS-tracking) over three periods of their migratory cycle, and by analysing the effect of artificially supplemented food provided as part of a crane-agriculture management programme. We sampled faecal droppings in Russia (nonsupplemented, premigration) and in Israel in late autumn (nonsupplemented, postmigration) and winter (supplemented and nonsupplemented, wintering). As supplemented food is typically homogenous, we predicted lower microbiota diversity and different composition in birds relying on supplementary feeding. We did not observe changes in microbial diversity with food supplementation, as diversity differed only in samples from nonsupplemented wintering sites. However, both food supplementation and season affected bacterial community composition and led to increased abundance of specific genera (mostly Firmicutes). Cranes from the nonsupplemented groups spent most of their time in agricultural fields, probably feeding on residual grain when available, while food-supplemented cranes spent most of their time at the feeding station. Thus, nonsupplemented and food-supplemented diets probably diverge only in winter, when crop rotation and depletion of anthropogenic resources may lead to a more variable diet in nonsupplemented sites. Our results support the role of diet in structuring bacterial communities and show that they undergo both seasonal and human-induced shifts. Movement analyses provide important clues regarding host diet and behaviour towards understanding how human-induced changes shape the gut microbiota in wild animals.
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Affiliation(s)
- Sasha Pekarsky
- Movement Ecology Laboratory, Department of Ecology, Evolution & Behavior, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Ammon Corl
- Museum of Vertebrate Zoology, University of California, Berkeley, Berkeley, California, USA
| | - Sondra Turjeman
- Movement Ecology Laboratory, Department of Ecology, Evolution & Behavior, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Pauline L Kamath
- School of Food and Agriculture, University of Maine, Orono, Maine, USA
| | - Wayne M Getz
- Department of Environmental Science, Policy & Management, University of California, Berkeley, California, USA.,School Mathematical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Rauri C K Bowie
- Museum of Vertebrate Zoology, University of California, Berkeley, Berkeley, California, USA.,Department of Integrative Biology, University of California, Berkeley, California, USA
| | - Yuri Markin
- Oksky State Reserve, pos. Brykin Bor, Spassky raion, Ryazanskaya oblast, Russia
| | - Ran Nathan
- Movement Ecology Laboratory, Department of Ecology, Evolution & Behavior, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
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Kayani MUR, Yu K, Qiu Y, Shen Y, Gao C, Feng R, Zeng X, Wang W, Chen L, Su HL. Environmental concentrations of antibiotics alter the zebrafish gut microbiome structure and potential functions. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2021; 278:116760. [PMID: 33725532 DOI: 10.1016/j.envpol.2021.116760] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 01/31/2021] [Accepted: 02/14/2021] [Indexed: 06/12/2023]
Abstract
A paradoxical impact of high rates of production and consumption of antibiotics is their widespread release in the environment. Consequently, low concentrations of antibiotics and their byproducts have been routinely identified from various environmental settings especially from aquatic environments. However, the impact of such low concentrations of antibiotics on the exposed host especially in early life remains poorly understood. We exposed zebrafish to two different environmental concentrations of oxytetracycline and sulfamethoxazole, from larval stage to adulthood (∼120 days) and characterized their impact on the taxonomic diversity, antibiotic resistance genes, and metabolic pathways of the gut microbiome using metagenomic shotgun sequencing and analysis. Long term exposure of environmental concentrations of oxytetracycline and sulfamethoxazole significantly impacted the taxonomic composition and metabolic pathways of zebrafish gut microbiome. The antibiotic exposed samples exhibited significant enrichment of multiple flavobacterial species, including Flavobacterium sp. F52, Flavobacterium johnsoniae and Flavobacterium sp. Fl, which are well known pathogenic bacteria. The relative abundance of antibiotic resistance genes, especially several tetratcycline and sulfonamide resistance genes were significantly higher in the exposed samples and showed a linear correlation with the antibiotic concentrations. Furthermore, several metabolic pathways, including folate biosynthesis, oxidative phosphorylation, and biotin metabolism pathways, showed significant enrichment in the antibiotic exposed samples. Collectively, our results suggest that early life exposure of the environmental concentrations of antibiotics can increase the abundance of unfavorable bacteria, antibiotic resistance genes and associated pathways in the gut microbiome of zebrafish.
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Affiliation(s)
- Masood Ur Rehman Kayani
- Department of Pediatrics Infectious Diseases, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China; Center for Microbiota and Immunological Diseases, Shanghai General Hospital, Shanghai Institute of Immunology, Shanghai Jiao Tong University, School of Medicine, Shanghai, 2000025, China
| | - Kan Yu
- Department of Pediatrics Infectious Diseases, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China; School of Bioengineering, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China
| | - Yushu Qiu
- Department of Pediatrics Infectious Diseases, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yao Shen
- Center for Microbiota and Immunological Diseases, Shanghai General Hospital, Shanghai Institute of Immunology, Shanghai Jiao Tong University, School of Medicine, Shanghai, 2000025, China
| | - Caixia Gao
- Center for Microbiota and Immunological Diseases, Shanghai General Hospital, Shanghai Institute of Immunology, Shanghai Jiao Tong University, School of Medicine, Shanghai, 2000025, China
| | - Ru Feng
- Center for Microbiota and Immunological Diseases, Shanghai General Hospital, Shanghai Institute of Immunology, Shanghai Jiao Tong University, School of Medicine, Shanghai, 2000025, China
| | - Xinxin Zeng
- Department of Pediatrics Infectious Diseases, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Weiye Wang
- Municipal Key Lab of Environment and Children's Health, Xinhua Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Lei Chen
- Center for Microbiota and Immunological Diseases, Shanghai General Hospital, Shanghai Institute of Immunology, Shanghai Jiao Tong University, School of Medicine, Shanghai, 2000025, China
| | - Huang Li Su
- Department of Pediatrics Infectious Diseases, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
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Su X, Yu J, Wang N, Zhao S, Han W, Chen D, Li L, Li L. High-Coverage Metabolome Analysis Reveals Significant Diet Effects of Autoclaved and Irradiated Feed on Mouse Fecal and Urine Metabolomics. Mol Nutr Food Res 2021; 65:e2100110. [PMID: 33861501 DOI: 10.1002/mnfr.202100110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/02/2021] [Indexed: 12/17/2022]
Abstract
SCOPE Using metabolomics to study the relations of nutrition and health requires stringent control of the experimental conditions used in an animal model. This work investigates the diet effects of autoclaved and irradiated feed on mouse urine and fecal metabolomics. METHODS AND RESULTS C57BL/6 mice are fed normal-irradiation sterilized diet (n = 9), autoclave sterilized diet (n = 9), and high-irradiation sterilized diet (n = 9) for 4 weeks. Differential chemical isotope labeling liquid chromatography mass spectrometry is used to quantify the metabolome variations of urine and feces collected at five time points. Significant differences are observed in urine or fecal metabolomes of mice fed autoclaved diet versus mice fed high-irradiation diet or fed normal-irradiation diet, while the differences are small between the mice fed normal-irradiation and high-irradiation diet. Correlation studies of metabolite changes of diet- and aging-related biomarkers indicate a large overlap of significantly affected metabolites by the two factors. CONCLUSIONS Diet can be a confounding factor that needs to be carefully considered when a metabolomics study is designed and metabolomic results of a mouse model of nutritional or other biological study are interpreted. Using the same sterilized diet for a given metabolomics project is essential to control the diet effect.
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Affiliation(s)
- Xiaoling Su
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Jiong Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Nan Wang
- Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada
| | - Shuang Zhao
- Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada
| | - Wei Han
- Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada
| | - Deying Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Liang Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
- Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
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Bisht V, Nash K, Xu Y, Agarwal P, Bosch S, Gkoutos GV, Acharjee A. Integration of the Microbiome, Metabolome and Transcriptomics Data Identified Novel Metabolic Pathway Regulation in Colorectal Cancer. Int J Mol Sci 2021; 22:5763. [PMID: 34071236 PMCID: PMC8198673 DOI: 10.3390/ijms22115763] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/25/2021] [Accepted: 05/26/2021] [Indexed: 12/12/2022] Open
Abstract
Integrative multiomics data analysis provides a unique opportunity for the mechanistic understanding of colorectal cancer (CRC) in addition to the identification of potential novel therapeutic targets. In this study, we used public omics data sets to investigate potential associations between microbiome, metabolome, bulk transcriptomics and single cell RNA sequencing datasets. We identified multiple potential interactions, for example 5-aminovalerate interacting with Adlercreutzia; cholesteryl ester interacting with bacterial genera Staphylococcus, Blautia and Roseburia. Using public single cell and bulk RNA sequencing, we identified 17 overlapping genes involved in epithelial cell pathways, with particular significance of the oxidative phosphorylation pathway and the ACAT1 gene that indirectly regulates the esterification of cholesterol. These findings demonstrate that the integration of multiomics data sets from diverse populations can help us in untangling the colorectal cancer pathogenesis as well as postulate the disease pathology mechanisms and therapeutic targets.
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Affiliation(s)
- Vartika Bisht
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TH, UK; (V.B.); (Y.X.); (G.V.G.)
- MRC Health Data Research UK (HDR UK), Midlands B15 2TT, UK
| | - Katrina Nash
- College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK;
| | - Yuanwei Xu
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TH, UK; (V.B.); (Y.X.); (G.V.G.)
- MRC Health Data Research UK (HDR UK), Midlands B15 2TT, UK
- Institute of Translational Medicine, University Hospitals Birmingham NHS, Foundation Trust, Birmingham B15 2TT, UK
| | - Prasoon Agarwal
- KTH Royal Institute of Technology, School of Electrical Engineering and Computer Science, 100 44 Stockholm, Sweden;
- Science for Life Laboratory, 171 65 Solna, Sweden
| | - Sofie Bosch
- Department of Gastroenterology and Hepatology, AG&M research institute, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands;
| | - Georgios V. Gkoutos
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TH, UK; (V.B.); (Y.X.); (G.V.G.)
- MRC Health Data Research UK (HDR UK), Midlands B15 2TT, UK
- Institute of Translational Medicine, University Hospitals Birmingham NHS, Foundation Trust, Birmingham B15 2TT, UK
- NIHR Surgical Reconstruction and Microbiology Research Centre, University Hospital Birmingham, Birmingham B15 2WB, UK
- NIHR Experimental Cancer Medicine Centre, Birmingham B15 2TT, UK
- NIHR Biomedical Research Centre, University Hospital Birmingham, Birmingham B15 2TT, UK
| | - Animesh Acharjee
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TH, UK; (V.B.); (Y.X.); (G.V.G.)
- MRC Health Data Research UK (HDR UK), Midlands B15 2TT, UK
- Institute of Translational Medicine, University Hospitals Birmingham NHS, Foundation Trust, Birmingham B15 2TT, UK
- NIHR Surgical Reconstruction and Microbiology Research Centre, University Hospital Birmingham, Birmingham B15 2WB, UK
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Stergiadis S, Cabeza-Luna I, Mora-Ortiz M, Stewart RD, Dewhurst RJ, Humphries DJ, Watson M, Roehe R, Auffret MD. Unravelling the Role of Rumen Microbial Communities, Genes, and Activities on Milk Fatty Acid Profile Using a Combination of Omics Approaches. Front Microbiol 2021; 11:590441. [PMID: 33552010 PMCID: PMC7859430 DOI: 10.3389/fmicb.2020.590441] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 12/21/2020] [Indexed: 12/01/2022] Open
Abstract
Milk products are an important component of human diets, with beneficial effects for human health, but also one of the major sources of nutritionally undesirable saturated fatty acids (SFA). Recent discoveries showing the importance of the rumen microbiome on dairy cattle health, metabolism and performance highlight that milk composition, and potentially milk SFA content, may also be associated with microorganisms, their genes and their activities. Understanding these mechanisms can be used for the development of cost-effective strategies for the production of milk with less SFA. This work aimed to compare the rumen microbiome between cows producing milk with contrasting FA profile and identify potentially responsible metabolic-related microbial mechanisms. Forty eight Holstein dairy cows were fed the same total mixed ration under the same housing conditions. Milk and rumen fluid samples were collected from all cows for the analysis of fatty acid profiles (by gas chromatography), the abundances of rumen microbiome communities and genes (by whole-genome-shotgun metagenomics), and rumen metabolome (using 500 MHz nuclear magnetic resonance). The following groups: (i) 24 High-SFA (66.9-74.4% total FA) vs. 24 Low-SFA (60.2-66.6%% total FA) cows, and (ii) 8 extreme High-SFA (69.9-74.4% total FA) vs. 8 extreme Low-SFA (60.2-64.0% total FA) were compared. Rumen of cows producing milk with more SFA were characterized by higher abundances of the lactic acid bacteria Lactobacillus, Leuconostoc, and Weissella, the acetogenic Proteobacteria Acetobacter and Kozakia, Mycobacterium, two fungi (Cutaneotrichosporon and Cyphellophora), and at a lesser extent Methanobrevibacter and the protist Nannochloropsis. Cows carrying genes correlated with milk FA also had higher concentrations of butyrate, propionate and tyrosine and lower concentrations of xanthine and hypoxanthine in the rumen. Abundances of rumen microbial genes were able to explain between 76 and 94% on the variation of the most abundant milk FA. Metagenomics and metabolomics analyses highlighted that cows producing milk with contrasting FA profile under the same diet, also differ in their rumen metabolic activities in relation to adaptation to reduced rumen pH, carbohydrate fermentation, and protein synthesis and metabolism.
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Affiliation(s)
- Sokratis Stergiadis
- School of Agriculture, Policy and Development, Department of Animal Sciences, University of Reading, Animal, Dairy and Food Chain Sciences, Reading, United Kingdom
| | - Irene Cabeza-Luna
- School of Agriculture, Policy and Development, Department of Animal Sciences, University of Reading, Animal, Dairy and Food Chain Sciences, Reading, United Kingdom
- Beef and Sheep Research Centre, Scotland's Rural College (SRUC), Roslin Institute Building, Edinburgh, United Kingdom
| | - Marina Mora-Ortiz
- School of Agriculture, Policy and Development, Department of Animal Sciences, University of Reading, Animal, Dairy and Food Chain Sciences, Reading, United Kingdom
| | - Robert D. Stewart
- The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Richard J. Dewhurst
- Dairy Research and Innovation Centre, Scotland's Rural College (SRUC), Dumfries, United Kingdom
| | - David J. Humphries
- Centre for Dairy Research, University of Reading, Reading, United Kingdom
| | - Mick Watson
- The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Rainer Roehe
- Beef and Sheep Research Centre, Scotland's Rural College (SRUC), Roslin Institute Building, Edinburgh, United Kingdom
| | - Marc D. Auffret
- Beef and Sheep Research Centre, Scotland's Rural College (SRUC), Roslin Institute Building, Edinburgh, United Kingdom
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