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Jaworska K, Kuś M, Ufnal M. TMAO and diabetes: from the gut feeling to the heart of the problem. Nutr Diabetes 2025; 15:21. [PMID: 40393987 DOI: 10.1038/s41387-025-00377-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 04/30/2025] [Accepted: 05/06/2025] [Indexed: 05/22/2025] Open
Abstract
Elevated plasma levels of trimethylamine N-oxide (TMAO)-a compound derived from diet and the gut microbiome-have been widely studied for their association with diabetes risk and their potential role in disease pathophysiology and complications. However, clinical studies, both prospective and retrospective, have yielded conflicting results. For example, elevated levels of TMAO are frequently linked to an increased risk of cardiovascular and renal complications in individuals with diabetes. However, the robustness and independence of these associations differ across study populations and are influenced by the degree of adjustment for confounding risk factors. Considering insulin's regulatory effect on FMO3 activity in liver cells, TMAO may serve as a marker of hepatic insulin resistance, which could partially explain its association with diabetes risk. The role of TMAO in diabetes pathology remains controversial; while some studies emphasize its detrimental impact on insulin sensitivity and the progression of diabetes-related complications, others suggest potential protective effects. Investigating the largely unexplored role of TMAO's precursor, trimethylamine, may help elucidate these discrepancies. This review consolidates clinical and experimental findings to clarify TMAO's complex mechanistic contributions to diabetes pathology.
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Affiliation(s)
- Kinga Jaworska
- Department of Experimental Physiology and Pathophysiology, Laboratory of the Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland.
| | - Monika Kuś
- Department of Experimental Physiology and Pathophysiology, Laboratory of the Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Marcin Ufnal
- Department of Experimental Physiology and Pathophysiology, Laboratory of the Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
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Li X, Ren Y, Gao X, Wang H, Zhang J, Xie J, Liang J, Zhao B, Zhou H, Yin J. Gut microbiota-mediated choline metabolism exacerbates cognitive impairment induced by chronic cerebral hypoperfusion. J Cereb Blood Flow Metab 2025; 45:989-1004. [PMID: 39719076 PMCID: PMC12035329 DOI: 10.1177/0271678x241309777] [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: 07/11/2024] [Revised: 11/01/2024] [Accepted: 12/11/2024] [Indexed: 12/26/2024]
Abstract
Chronic cerebral hypoperfusion (CCH) is a crucial mechanism causing vascular cognitive impairment (VCI). Choline is metabolized by gut microbiota into trimethylamine N-oxide (TMAO), a risk factor of cardiovascular diseases and cognitive impairment. However, the impact of choline-TMAO pathway on CCH-induced VCI is elusive. We performed a cross-sectional clinical study to investigate the relationship between the choline-TMAO pathway and cognitive outcome and used a bilateral common carotid artery occlusion rat model to explore the effect of a choline-rich diet on cognition and underlying mechanisms. Plasma choline and TMAO levels were negatively correlated with cognitive scores in CCH patients. A choline-rich diet exacerbated CCH-induced cognitive impairment by encouraging the proliferation of choline-metabolizing bacteria in the gut and subsequent generation of TMAO. The choline-TMAO pathway, mediated by gut microbiota, exacerbates cognitive impairment induced by CCH. Targeted dietary choline regulation based on gut microbiota modulation may ameliorate long-term cognitive impairment.
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Affiliation(s)
- Xiao Li
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yueran Ren
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuxuan Gao
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huidi Wang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jiafeng Zhang
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiahui Xie
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jingru Liang
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Boxin Zhao
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hongwei Zhou
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jia Yin
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Iorra FDQ, Rodrigues PG, Bock PM, Guahnon MP, Eller S, de Oliveira TF, Birk L, Schwarz PDS, Drehmer M, Bloch KV, Cureau FV, Schaan BD. Gut Microbiota Metabolite TMAO and Adolescent Cardiometabolic Health: A Cross-sectional Analysis. J Endocr Soc 2025; 9:bvaf055. [PMID: 40242209 PMCID: PMC12000724 DOI: 10.1210/jendso/bvaf055] [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: 12/26/2024] [Indexed: 04/18/2025] Open
Abstract
Background Trimethylamine N-oxide (TMAO) is a metabolite derived from gut microbiota that has been associated with cardiovascular and metabolic disease risk in adults. However, its role in assessing cardiometabolic risk in adolescents is unclear. Objective This study investigates the association between serum TMAO levels and cardiometabolic health indicators in Brazilian adolescents. Materials and Methods This is a multicenter, cross-sectional analysis involving 4446 participants aged 12 to 17 years from four Brazilian cities. Serum TMAO levels were quantified using liquid chromatography-tandem mass spectrometry, and associations with clinical, metabolic, and inflammatory variables were evaluated through multivariate linear regression analyses. Results After adjusting for potential confounders, being in the highest tertile of serum TMAO was positively associated with waist circumference [β 1.45; 95% confidence interval (CI) 0.77, 2.14; P < .001], body mass index Z-score (β .19; 95% CI 0.10, 0.27; P < .001), and C-reactive protein (β .24; 95% CI 0.13, 0.34; P < .001). A negative association between the highest tertile of TMAO and fasting plasma glucose was also observed (β -1.22; 95% CI -1.77, -0.66; P < .001). Conclusion TMAO may serve as an emerging biomarker for cardiometabolic risk assessment in adolescents.
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Affiliation(s)
- Fernando de Quadros Iorra
- Postgraduate Program in Medical Sciences: Endocrinology, Federal University of Rio Grande do Sul, Porto Alegre 90035-903, Brazil
| | | | - Patrícia Martins Bock
- Post-Graduate Program in Pharmacology and Therapeutics, Federal University of Rio Grande do Sul, Porto Alegre 90035-903, Brazil
- Institute of Biological Sciences, Federal University of Rio Grande, Rio Grande 96203-900, Brazil
| | - Marina Petrasi Guahnon
- Postgraduate Program in Epidemiology, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre 90035-903, Brazil
| | - Sarah Eller
- Pharmacosciences Department, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
| | - Tiago Franco de Oliveira
- Pharmacosciences Department, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
| | - Leticia Birk
- Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
| | - Patricia de Souza Schwarz
- Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
| | - Michele Drehmer
- Postgraduate Program in Epidemiology, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre 90035-903, Brazil
- Postgraduate Program in Food, Nutrition and Health, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre 90035-903, Brazil
| | - Katia V Bloch
- Institute of Studies in Public Health, Federal University of Rio de Janeiro, Rio de Janeiro 20271-062, Brazil
| | - Felipe Vogt Cureau
- Graduate Program in Cardiology and Cardiovascular Sciences, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre 90035-903, Brazil
| | - Beatriz D Schaan
- Postgraduate Program in Medical Sciences: Endocrinology, Federal University of Rio Grande do Sul, Porto Alegre 90035-903, Brazil
- Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Brazil
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Rakhshandehroo M, Harvey L, de Bruin A, Timmer E, Lohr J, Tims S, Schipper L. Maternal exposure to purified versus grain-based diet during early lactation in mice affects offspring growth and reduces responsivity to Western-style diet challenge in adulthood. J Dev Orig Health Dis 2025; 16:e3. [PMID: 39780545 DOI: 10.1017/s2040174424000436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
The nutritional environment during fetal and early postnatal life has a long-term impact on growth, development, and metabolic health of the offspring, a process termed "nutritional programming." Rodent models studying programming effects of nutritional interventions use either purified or grain-based rodent diets as background diets. However, the impact of these diets on phenotypic outcomes in these models has not been comprehensively investigated. We used a previously validated (C57BL/6J) mouse model to investigate the effects of infant milk formula (IMF) interventions on nutritional programming. Specifically, we investigated the effects of maternal diet type (i.e., grain-based vs purified) during early lactation and prior to the intervention on offspring growth, metabolic phenotype, and gut microbiota profile. Maternal exposure to purified diet led to an increased post-weaning growth velocity in the offspring and reduced adult diet-induced obesity. Further, maternal exposure to purified diet reduced the offspring gut microbiota diversity and modified its composition post-weaning. These data not only reinforce the notion that maternal nutrition significantly influences the programming of offspring vulnerability to an obesogenic diet in adulthood but emphasizes the importance of careful selection of standard background diet type when designing any preclinical study with (early life) nutritional interventions.
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Affiliation(s)
| | - L Harvey
- Danone Research & Innovation Center, Utrecht, The Netherlands
| | - A de Bruin
- Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - E Timmer
- Danone Research & Innovation Center, Utrecht, The Netherlands
| | - J Lohr
- Danone Research & Innovation Center, Utrecht, The Netherlands
| | - S Tims
- Danone Research & Innovation Center, Utrecht, The Netherlands
| | - L Schipper
- Danone Research & Innovation Center, Utrecht, The Netherlands
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Termite F, Archilei S, D’Ambrosio F, Petrucci L, Viceconti N, Iaccarino R, Liguori A, Gasbarrini A, Miele L. Gut Microbiota at the Crossroad of Hepatic Oxidative Stress and MASLD. Antioxidants (Basel) 2025; 14:56. [PMID: 39857390 PMCID: PMC11759774 DOI: 10.3390/antiox14010056] [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: 12/13/2024] [Revised: 12/30/2024] [Accepted: 01/02/2025] [Indexed: 01/27/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition marked by excessive lipid accumulation in hepatic tissue. This disorder can lead to a range of pathological outcomes, including metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. Despite extensive research, the molecular mechanisms driving MASLD initiation and progression remain incompletely understood. Oxidative stress and lipid peroxidation are pivotal in the "multiple parallel hit model", contributing to hepatic cell death and tissue damage. Gut microbiota plays a substantial role in modulating hepatic oxidative stress through multiple pathways: impairing the intestinal barrier, which results in bacterial translocation and chronic hepatic inflammation; modifying bile acid structure, which impacts signaling cascades involved in lipidic metabolism; influencing hepatocytes' ferroptosis, a form of programmed cell death; regulating trimethylamine N-oxide (TMAO) metabolism; and activating platelet function, both recently identified as pathogenetic factors in MASH progression. Moreover, various exogenous factors impact gut microbiota and its involvement in MASLD-related oxidative stress, such as air pollution, physical activity, cigarette smoke, alcohol, and dietary patterns. This manuscript aims to provide a state-of-the-art overview focused on the intricate interplay between gut microbiota, lipid peroxidation, and MASLD pathogenesis, offering insights into potential strategies to prevent disease progression and its associated complications.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Luca Miele
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy (S.A.)
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Li Z, He X, Fang Q, Yin X. Gut Microbe-Generated Metabolite Trimethylamine-N-Oxide and Ischemic Stroke. Biomolecules 2024; 14:1463. [PMID: 39595639 PMCID: PMC11591650 DOI: 10.3390/biom14111463] [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: 10/13/2024] [Revised: 11/05/2024] [Accepted: 11/08/2024] [Indexed: 11/28/2024] Open
Abstract
Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite, the production of which in vivo is mainly regulated by dietary choices, gut microbiota, and the hepatic enzyme flavin monooxygenase (FMO), while its elimination occurs via the kidneys. The TMAO level is positively correlated with the risk of developing cardiovascular diseases. Recent studies have found that TMAO plays an important role in the development of ischemic stroke. In this review, we describe the relationship between TMAO and ischemic stroke risk factors (hypertension, diabetes, atrial fibrillation, atherosclerosis, thrombosis, etc.), disease risk, severity, prognostic outcomes, and recurrence and discuss the possible mechanisms by which they interact. Importantly, TMAO induces atherosclerosis and thrombosis through lipid metabolism, foam cell formation, endothelial dysfunction (via inflammation, oxidative stress, and pyroptosis), enhanced platelet hyper-reactivity, and the upregulation and activation of vascular endothelial tissue factors. Although the pathogenic mechanisms underlying TMAO's aggravation of disease severity and its effects on post-stroke neurological recovery and recurrence risk remain unclear, they may involve inflammation, astrocyte function, and pro-inflammatory monocytes. In addition, this paper provides a summary and evaluation of relevant preclinical and clinical studies on interventions regarding the gut-microbiota-dependent TMAO level to provide evidence for the prevention and treatment of ischemic stroke through the gut microbe-TMAO pathway.
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Affiliation(s)
| | | | - Qi Fang
- Department of Neurology, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Suzhou 215006, China; (Z.L.); (X.H.)
| | - Xulong Yin
- Department of Neurology, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Suzhou 215006, China; (Z.L.); (X.H.)
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Connell E, Le Gall G, McArthur S, Lang L, Breeze B, Pontifex MG, Sami S, Pourtau L, Gaudout D, Müller M, Vauzour D. (Poly)phenol-rich grape and blueberry extract prevents LPS-induced disruption of the blood-brain barrier through the modulation of the gut microbiota-derived uremic toxins. Neurochem Int 2024; 180:105878. [PMID: 39389472 DOI: 10.1016/j.neuint.2024.105878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 09/09/2024] [Accepted: 10/07/2024] [Indexed: 10/12/2024]
Abstract
The dynamic protective capacity of (poly)phenols, attributed to their potent antioxidant and anti-inflammatory properties, has been consistently reported. Due to their capacity to alter gut microbiome composition, further actions of (poly)phenols may be exerted through the modulation of the microbiota-gut-brain axis. However, the underlying mechanisms remain poorly defined. Here, we investigated the protective effect of a (poly)phenol-rich grape and blueberry extract (Memophenol™), on the microbiota-gut-brain axis in a model of chronic low-grade inflammation (0.5 mg/kg/wk lipopolysaccharide (LPS) for 8 weeks). Dietary supplementation of male C57BL/6 J mice with Memophenol™ prevented LPS-induced increases in the microbe-derived uremia-associated molecules, indoxyl sulfate (IS) and trimethylamine N-oxide (TMAO). These changes coincided with shifts in gut microbiome composition, notably Romboutsia and Desulfovibrio abundance, respectively. In the brain, LPS exposure disrupted the marginal localisation of the endothelial tight junction ZO-1 and downregulated ZO-1 mRNA expression to an extent closely correlated with TMAO and IS levels; a process prevented by Memophenol™ intake. Hippocampal mRNA sequencing analysis revealed significant downregulation in regulatory pathways of neurodegeneration with Memophenol™ intake. These findings may indicate a novel protective role of the (poly)phenol-rich grape and blueberry extract on the endothelial tight junction component ZO-1, acting through modulation of gut microbial metabolism.
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Affiliation(s)
- Emily Connell
- Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, NR4 7TJ, United Kingdom
| | - Gwénaëlle Le Gall
- Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, NR4 7TJ, United Kingdom
| | - Simon McArthur
- Institute of Dentistry, Faculty of Medicine & Dentistry, Queen Mary University of London, Blizard Institute, London, E1 2AT, United Kingdom
| | - Leonie Lang
- Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, NR4 7TJ, United Kingdom
| | - Bernadette Breeze
- Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, NR4 7TJ, United Kingdom
| | - Matthew G Pontifex
- Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, NR4 7TJ, United Kingdom
| | - Saber Sami
- Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, NR4 7TJ, United Kingdom
| | | | | | - Michael Müller
- Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, NR4 7TJ, United Kingdom
| | - David Vauzour
- Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, NR4 7TJ, United Kingdom.
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Schneider E, O'Riordan KJ, Clarke G, Cryan JF. Feeding gut microbes to nourish the brain: unravelling the diet-microbiota-gut-brain axis. Nat Metab 2024; 6:1454-1478. [PMID: 39174768 DOI: 10.1038/s42255-024-01108-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 07/15/2024] [Indexed: 08/24/2024]
Abstract
The prevalence of brain disorders, including stress-related neuropsychiatric disorders and conditions with cognitive dysfunction, is rising. Poor dietary habits contribute substantially to this accelerating trend. Conversely, healthy dietary intake supports mood and cognitive performance. Recently, the communication between the microorganisms within the gastrointestinal tract and the brain along the gut-brain axis has gained prominence as a potential tractable target to modulate brain health. The composition and function of the gut microbiota is robustly influenced by dietary factors to alter gut-brain signalling. To reflect this interconnection between diet, gut microbiota and brain functioning, we propose that a diet-microbiota-gut-brain axis exists that underpins health and well-being. In this Review, we provide a comprehensive overview of the interplay between diet and gut microbiota composition and function and the implications for cognition and emotional functioning. Important diet-induced effects on the gut microbiota for the development, prevention and maintenance of neuropsychiatric disorders are described. The diet-microbiota-gut-brain axis represents an uncharted frontier for brain health diagnostics and therapeutics across the lifespan.
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Affiliation(s)
| | | | - Gerard Clarke
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
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Ma R, Shi G, Li Y, Shi H. Trimethylamine N-oxide, choline and its metabolites are associated with the risk of non-alcoholic fatty liver disease. Br J Nutr 2024; 131:1915-1923. [PMID: 38443197 DOI: 10.1017/s0007114524000631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2024]
Abstract
It is inconclusive whether trimethylamine N-oxide (TMAO) and choline and related metabolites, namely trimethylamine (TMA), l-carnitine, betaine and dimethylglycine (DMG), are associated with non-alcoholic fatty liver disease (NAFLD). Our objective was to investigate these potential associations. Additionally, we sought to determine the mediating role of TMAO. In this 1:1 age- and sex-matched case-control study, a total of 150 pairs comprising NAFLD cases and healthy controls were identified. According to the fully adjusted model, after the highest tertile was compared with the lowest tertile, the plasma TMAO concentration (OR = 2·02 (95 % CI 1·04, 3·92); P trend = 0·003), l-carnitine concentration (OR = 1·79 (1·01, 3·17); P trend = 0·020) and DMG concentration (OR = 1·81 (1·00, 3·28); P trend = 0·014) were significantly positively associated with NAFLD incidence. However, a significantly negative association was found for plasma betaine (OR = 0. 50 (0·28, 0·88); P trend = 0·001). The restricted cubic splines model consistently indicated positive dose-response relationships between exposure to TMAO, l-carnitine, and DMG and NAFLD risk, with a negative association being observed for betaine. The corresponding AUC increased significantly from 0·685 (0·626, 0·745) in the traditional risk factor model to 0·769 (0·716, 0·822) when TMAO and its precursors were included (l-carnitine, betaine and choline) (P = 0·032). Mediation analyses revealed that 14·7 and 18·6 % of the excess NAFLD risk associated with l-carnitine and DMG, respectively, was mediated by TMAO (the P values for the mediating effects were 0·021 and 0·036, respectively). These results suggest that a higher concentration of TMAO is associated with increased NAFLD risk among Chinese adults and provide evidence of the possible mediating role of TMAO.
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Affiliation(s)
- Rong Ma
- Department of Infectious Diseases, the First Affiliated Hospital of Chengdu Medical College, Chengdu610500, People's Republic of China
| | - Guangying Shi
- Department of Hepatology, Xinjiang Corps Hospital, Xinjiang832104, People's Republic of China
| | - Yanfang Li
- Department of Infectious Diseases, the First Affiliated Hospital of Chengdu Medical College, Chengdu610500, People's Republic of China
| | - Han Shi
- Department of Infectious Diseases, the First Affiliated Hospital of Chengdu Medical College, Chengdu610500, People's Republic of China
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Morais LH, Boktor JC, MahmoudianDehkordi S, Kaddurah-Daouk R, Mazmanian SK. α-Synuclein Overexpression and the Microbiome Shape the Gut and Brain Metabolome in Mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.07.597975. [PMID: 38915679 PMCID: PMC11195096 DOI: 10.1101/2024.06.07.597975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Pathological forms of the protein α-synuclein contribute to a family of disorders termed synucleinopathies, which includes Parkinson's disease (PD). Most cases of PD are believed to arise from gene-environment interactions. Microbiome composition is altered in PD, and gut bacteria are causal to symptoms and pathology in animal models. To explore how the microbiome may impact PD-associated genetic risks, we quantitatively profiled nearly 630 metabolites from 26 biochemical classes in the gut, plasma, and brain of α-synuclein-overexpressing (ASO) mice with or without microbiota. We observe tissue-specific changes driven by genotype, microbiome, and their interaction. Many differentially expressed metabolites in ASO mice are also dysregulated in human PD patients, including amine oxides, bile acids and indoles. Notably, levels of the microbial metabolite trimethylamine N-oxide (TMAO) strongly correlate from the gut to the plasma to the brain, identifying a product of gene-environment interactions that may influence PD-like outcomes in mice. TMAO is elevated in the blood and cerebral spinal fluid of PD patients. These findings uncover broad metabolomic changes that are influenced by the intersection of host genetics and the microbiome in a mouse model of PD.
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Affiliation(s)
- Livia H. Morais
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815
| | - Joseph C. Boktor
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815
| | | | - Rima Kaddurah-Daouk
- Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
- Duke Institute of Brain Sciences, Duke University, Durham, NC, USA
- Department of Medicine, Duke University, Durham, NC, USA
| | - Sarkis K. Mazmanian
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815
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11
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Miyata M, Takeda K, Nagira S, Sugiura Y. Trimethylamine N-oxide ameliorates hepatic damage including reduction of hepatic bile acids and cholesterol in Fxr-null mice. Int J Food Sci Nutr 2024; 75:385-395. [PMID: 38690724 DOI: 10.1080/09637486.2024.2346765] [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: 10/31/2023] [Accepted: 04/17/2024] [Indexed: 05/02/2024]
Abstract
There are conflicting animal experiments on the effect of trimethylamine N-oxide (TMAO), the dietary metabolite, on non-alcoholic fatty liver disease (NAFLD). This study aims to determine the effect of TMAO on NAFLD. A diet containing 0.3% TMAO was fed to farnesoid X receptor (Fxr)-null mice, a model of NAFLD, for 13 weeks. Fxr-null mice fed TMAO showed significant reductions in liver damage markers but not wild-type mice. Hepatic bile acid and cholesterol levels were significantly decreased, and triacylglycerol levels tended to decrease in TMAO-fed Fxr-null mice. Changes in mRNA levels of hepatic bile acid and cholesterol transporters and synthetic enzymes were observed, which could explain the decreased hepatic bile acid and cholesterol levels in Fxr-null mice given the TMAO diet but not in the wild-type mice. These results suggest that TMAO intake ameliorates liver damage in Fxr-null mice, further altering bile acid/cholesterol metabolism in an FXR-independent manner.
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Affiliation(s)
- Masaaki Miyata
- Department of Food Science and Technology, National Research and Development Agency, Japan Fisheries Research and Education Agency, National Fisheries University, Shimonoseki, Japan
| | - Kento Takeda
- Department of Food Science and Technology, National Research and Development Agency, Japan Fisheries Research and Education Agency, National Fisheries University, Shimonoseki, Japan
| | - Sayuri Nagira
- Department of Food Science and Technology, National Research and Development Agency, Japan Fisheries Research and Education Agency, National Fisheries University, Shimonoseki, Japan
| | - Yoshimasa Sugiura
- Department of Food Science and Technology, National Research and Development Agency, Japan Fisheries Research and Education Agency, National Fisheries University, Shimonoseki, Japan
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Lützhøft DO, Bækgård C, Wimborne E, Straarup EM, Pedersen KM, Swann JR, Pedersen HD, Kristensen K, Morgills L, Nielsen DS, Hansen AK, Bracken MK, Cirera S, Christoffersen BØ. High fat diet is associated with gut microbiota dysbiosis and decreased gut microbial derived metabolites related to metabolic health in young Göttingen Minipigs. PLoS One 2024; 19:e0298602. [PMID: 38427692 PMCID: PMC10906878 DOI: 10.1371/journal.pone.0298602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 01/26/2024] [Indexed: 03/03/2024] Open
Abstract
The objectives were 1) to characterize a Göttingen Minipig model of metabolic syndrome regarding its colon microbiota and circulating microbial products, and 2) to assess whether ovariectomized female and castrated male minipigs show similar phenotypes. Twenty-four nine-week-old Göttingen Minipigs were allocated to four groups based on sex and diet: ovariectomized females and castrated males fed either chow or high-fat diet (HFD) for 12 weeks. At study end, body composition and plasma biomarkers were measured, and a mixed meal tolerance test (MMT) and an intravenous glucose tolerance test (IVGTT) were performed. The HFD groups had significantly higher weight gain, fat percentage, fasting plasma insulin and glucagon compared to the chow groups. Homeostatic model assessment of insulin resistance index (HOMA-IR) was increased and glucose effectiveness derived from the IVGTT and Matsuda´s insulin sensitivity index from the MMT were decreased in the HFD groups. The HFD groups displayed dyslipidemia, with significantly increased total-, LDL- and HDL-cholesterol, and decreased HDL/non-HDL cholesterol ratio. The colon microbiota of HFD minipigs clearly differed from the lean controls (GuniFrac distance matrix). The main bacteria families driving this separation were Clostridiaceae, Fibrobacteraceae, Flavobacteriaceae and Porphyromonadaceae. Moreover, the species richness was significantly decreased by HFD. In addition, HFD decreased the circulating level of short chain fatty acids and beneficial microbial metabolites hippuric acid, xanthine and trigonelline, while increasing the level of branched chain amino acids. Six and nine metabolically relevant genes were differentially expressed between chow-fed and HFD-fed animals in liver and omental adipose tissue, respectively. The HFD-fed pigs presented with metabolic syndrome, gut microbial dysbiosis and a marked decrease in healthy gut microbial products and thus displayed marked parallels to human obesity and insulin resistance. HFD-fed Göttingen Minipig therefore represents a relevant animal model for studying host-microbiota interactions. No significant differences between the castrated and ovariectomized minipigs were observed.
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Affiliation(s)
- Ditte Olsen Lützhøft
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Cecilie Bækgård
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Elizabeth Wimborne
- School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | | | | | - Jonathan R. Swann
- School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | | | | | | | - Dennis Sandris Nielsen
- Department of Food Science, Faculty of Science, University of Copenhagen, Frederiksberg C, Denmark
| | - Axel Kornerup Hansen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | | | - Susanna Cirera
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
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13
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Maksymiuk KM, Szudzik M, Samborowska E, Chabowski D, Konop M, Ufnal M. Mice, rats, and guinea pigs differ in FMOs expression and tissue concentration of TMAO, a gut bacteria-derived biomarker of cardiovascular and metabolic diseases. PLoS One 2024; 19:e0297474. [PMID: 38266015 PMCID: PMC10807837 DOI: 10.1371/journal.pone.0297474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 01/06/2024] [Indexed: 01/26/2024] Open
Abstract
INTRODUCTION Increased plasma trimethylamine oxide (TMAO) is observed in cardiovascular and metabolic diseases, originating from the gut microbiota product, trimethylamine (TMA), via flavin-containing monooxygenases (FMOs)-dependent oxidation. Numerous studies have investigated the association between plasma TMAO and various pathologies, yet limited knowledge exists regarding tissue concentrations of TMAO, TMAO precursors, and interspecies variability. METHODS Chromatography coupled with mass spectrometry was employed to evaluate tissue concentrations of TMAO and its precursors in adult male mice, rats, and guinea pigs. FMO mRNA and protein levels were assessed through PCR and Western blot, respectively. RESULTS Plasma TMAO levels were similar among the studied species. However, significant differences in tissue concentrations of TMAO were observed between mice, rats, and guinea pigs. The rat renal medulla exhibited the highest TMAO concentration, while the lowest was found in the mouse liver. Mice demonstrated significantly higher plasma TMA concentrations compared to rats and guinea pigs, with the highest TMA concentration found in the mouse renal medulla and the lowest in the rat lungs. FMO5 exhibited the highest expression in mouse liver, while FMO3 was highly expressed in rats. Guinea pigs displayed low expression of FMOs in this tissue. CONCLUSION Despite similar plasma TMAO levels, mice, rats, and guinea pigs exhibited significant differences in tissue concentrations of TMA, TMAO, and FMO expression. These interspecies variations should be considered in the design and interpretation of experimental studies. Furthermore, these findings may suggest a diverse importance of the TMAO pathway in the physiology of the evaluated species.
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Affiliation(s)
- Klaudia M. Maksymiuk
- Laboratory of the Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Warsaw, Poland
| | - Mateusz Szudzik
- Laboratory of the Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Warsaw, Poland
| | - Emilia Samborowska
- Mass spectrometry Laboratory, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Dawid Chabowski
- Laboratory of the Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Warsaw, Poland
| | - Marek Konop
- Laboratory of the Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Warsaw, Poland
| | - Marcin Ufnal
- Laboratory of the Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Warsaw, Poland
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14
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Janeiro MH, Solas M, Orbe J, Rodríguez JA, Sanchez de Muniain L, Escalada P, Yip PK, Ramirez MJ. Trimethylamine N-Oxide as a Mediator Linking Peripheral to Central Inflammation: An In Vitro Study. Int J Mol Sci 2023; 24:17557. [PMID: 38139384 PMCID: PMC10743393 DOI: 10.3390/ijms242417557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
In this study, the plausible role of trimethylamine N-oxide (TMAO), a microbiota metabolite, was investigated as a link between peripheral inflammation and the inflammation of the central nervous system using different cell lines. TMAO treatment favored the differentiation of adipocytes from preadipocytes (3T3-L1 cell line). In macrophages (RAW 264.7 cell line), which infiltrate adipose tissue in obesity, TMAO increased the expression of pro-inflammatory cytokines. The treatment with 200 μM of TMAO seemed to disrupt the blood-brain barrier as it induced a significant decrease in the expression of occludin in hCMECs. TMAO also increased the expression of pro-inflammatory cytokines in primary neuronal cultures, induced a pro-inflammatory state in primary microglial cultures, and promoted phagocytosis. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between peripheral and central inflammation. Thus, TMAO-decreasing compounds may be a promising therapeutic strategy for neurodegenerative diseases.
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Affiliation(s)
- Manuel H. Janeiro
- Department of Pharmacology and Toxicology, University of Navarra, 31008 Pamplona, Spain; (M.H.J.); (M.S.); (L.S.d.M.); (P.E.)
| | - Maite Solas
- Department of Pharmacology and Toxicology, University of Navarra, 31008 Pamplona, Spain; (M.H.J.); (M.S.); (L.S.d.M.); (P.E.)
- IdISNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
| | - Josune Orbe
- IdISNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- Laboratory of Atherothrombosis, CIMA, 31008 Pamplona, Spain;
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS)-Ictus, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Jose A. Rodríguez
- Laboratory of Atherothrombosis, CIMA, 31008 Pamplona, Spain;
- CIBER Cardiovascular (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Leyre Sanchez de Muniain
- Department of Pharmacology and Toxicology, University of Navarra, 31008 Pamplona, Spain; (M.H.J.); (M.S.); (L.S.d.M.); (P.E.)
| | - Paula Escalada
- Department of Pharmacology and Toxicology, University of Navarra, 31008 Pamplona, Spain; (M.H.J.); (M.S.); (L.S.d.M.); (P.E.)
| | - Ping K. Yip
- Centre for Neuroscience, Surgery & Trauma, Blizard Institute, Queen Mary University of London, London EC1M 6BQ, UK;
| | - Maria J. Ramirez
- Department of Pharmacology and Toxicology, University of Navarra, 31008 Pamplona, Spain; (M.H.J.); (M.S.); (L.S.d.M.); (P.E.)
- IdISNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
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15
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Yadav H, Jaldhi, Bhardwaj R, Anamika, Bakshi A, Gupta S, Maurya SK. Unveiling the role of gut-brain axis in regulating neurodegenerative diseases: A comprehensive review. Life Sci 2023; 330:122022. [PMID: 37579835 DOI: 10.1016/j.lfs.2023.122022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/06/2023] [Accepted: 08/10/2023] [Indexed: 08/16/2023]
Abstract
Emerging evidence have shown the importance of gut microbiota in regulating brain functions. The diverse molecular mechanisms involved in cross-talk between gut and brain provide insight into importance of this communication in maintenance of brain homeostasis. It has also been observed that disturbed gut microbiota contributes to neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and aging. Recently, gut microbiome-derived exosomes have also been reported to play an essential role in the development and progression of neurodegenerative diseases and could thereby act as a therapeutic target. Further, pharmacological interventions including antibiotics, prebiotics and probiotics can influence gut microbiome-mediated management of neurological diseases. However, extensive research is warranted to better comprehend this interconnection in maintenance of brain homeostasis and its implication in neurological diseases. Thus, the present review is aimed to provide a detailed understanding of gut-brain axis followed by possibilities to target the gut microbiome for improving neurological health.
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Affiliation(s)
- Himanshi Yadav
- Biochemistry and Molecular Biology Laboratory, Department of Zoology, Faculty of Science, University of Delhi, Delhi, India
| | - Jaldhi
- Biochemistry and Molecular Biology Laboratory, Department of Zoology, Faculty of Science, University of Delhi, Delhi, India
| | - Rati Bhardwaj
- Department of Biotechnology, Delhi Technical University, Delhi, India
| | - Anamika
- Department of Zoology, Ramjas College, University of Delhi, Delhi, India
| | - Amrita Bakshi
- Department of Zoology, Ramjas College, University of Delhi, Delhi, India
| | - Suchi Gupta
- Tech Cell Innovations Private Limited, Centre for Medical Innovation and Entrepreneurship (CMIE), All India Institute of Medical Sciences, New Delhi, India
| | - Shashank Kumar Maurya
- Biochemistry and Molecular Biology Laboratory, Department of Zoology, Faculty of Science, University of Delhi, Delhi, India.
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16
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Lei D, Yu W, Liu Y, Jiang Y, Li X, Lv J, Li Y. Trimethylamine N-Oxide (TMAO) Inducing Endothelial Injury: UPLC-MS/MS-Based Quantification and the Activation of Cathepsin B-Mediated NLRP3 Inflammasome. Molecules 2023; 28:molecules28093817. [PMID: 37175227 PMCID: PMC10180140 DOI: 10.3390/molecules28093817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 03/25/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
TMAO is a new risk biomarker for cardiovascular disease. With trimethylammonium as its main chemical skeleton, TMAO is structurally similar to many endogenous metabolites, such as acetylcholine, carnitine, phosphorylcholine, etc. The mechanism of TMAO on the pathological process of CVD is still unclear. In this study, the quantitative analysis of plasma TMAO is conducted, and the contribution of Cathepsin B and NLRP3 inflammasome during the process of TMAO-induced endothelial injury was proposed and investigated at animal and cellular levels. Immunofluorescence assay was applied to represent the protein expression of Cathepsin B and NLRP3 inflammasome located at endothelial cells. The results showed that TMAO could disrupt endothelial cells permeability to induce endothelial injury, meanwhile, TMAO could increase NLRP3 inflammasome activation and promote the activity and expression of Cathepsin B in vitro and in vivo, whereas inhibition of NLRP3 inflammasome activation by MCC950 could protect the endothelial cells from TMAO associated endothelial injury via Cathepsin B. The study reveals that TMAO can cause endothelial injury via Cathepsin B-dependent NLRP3 inflammasome, and inhibition of Cathepsin B and NLRP3 inflammasome can reduce the TMAO-induced damage. The results provide new insight into the role of TMAO in CVD, which can be a potential therapeutic target for disease treatment and drug design.
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Affiliation(s)
- Dongyu Lei
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
- Department of Physiology, School of Basic Medicine, Xinjiang Medical University, Urumqi 830017, China
| | - Wenbo Yu
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Yi Liu
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Yujie Jiang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Xiaohui Li
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Jing Lv
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Ying Li
- Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha 410013, China
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17
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Agostini D, Gervasi M, Ferrini F, Bartolacci A, Stranieri A, Piccoli G, Barbieri E, Sestili P, Patti A, Stocchi V, Donati Zeppa S. An Integrated Approach to Skeletal Muscle Health in Aging. Nutrients 2023; 15:nu15081802. [PMID: 37111021 PMCID: PMC10141535 DOI: 10.3390/nu15081802] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 03/31/2023] [Accepted: 04/04/2023] [Indexed: 04/29/2023] Open
Abstract
A decline in muscle mass and function represents one of the most problematic changes associated with aging, and has dramatic effects on autonomy and quality of life. Several factors contribute to the inexorable process of sarcopenia, such as mitochondrial and autophagy dysfunction, and the lack of regeneration capacity of satellite cells. The physiologic decline in muscle mass and in motoneuron functionality associated with aging is exacerbated by the sedentary lifestyle that accompanies elderly people. Regular physical activity is beneficial to most people, but the elderly need well-designed and carefully administered training programs that improve muscle mass and, consequently, both functional ability and quality of life. Aging also causes alteration in the gut microbiota composition associated with sarcopenia, and some advances in research have elucidated that interventions via the gut microbiota-muscle axis have the potential to ameliorate the sarcopenic phenotype. Several mechanisms are involved in vitamin D muscle atrophy protection, as demonstrated by the decreased muscular function related to vitamin D deficiency. Malnutrition, chronic inflammation, vitamin deficiencies, and an imbalance in the muscle-gut axis are just a few of the factors that can lead to sarcopenia. Supplementing the diet with antioxidants, polyunsaturated fatty acids, vitamins, probiotics, prebiotics, proteins, kefir, and short-chain fatty acids could be potential nutritional therapies against sarcopenia. Finally, a personalized integrated strategy to counteract sarcopenia and maintain the health of skeletal muscles is suggested in this review.
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Affiliation(s)
- Deborah Agostini
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Marco Gervasi
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Fabio Ferrini
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Alessia Bartolacci
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Alessandro Stranieri
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Giovanni Piccoli
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Elena Barbieri
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Piero Sestili
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Antonino Patti
- Sport and Exercise Sciences Research Unit, Department of Psychology, Educational Science and Human Movement, University of Palermo, 90128 Palermo, Italy
| | - Vilberto Stocchi
- Department of Human Science for Promotion of Quality of Life, Università Telematica San Raffaele, 00166 Rome, Italy
| | - Sabrina Donati Zeppa
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
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18
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Zhang L, Yu F, Xia J. Trimethylamine N-oxide: role in cell senescence and age-related diseases. Eur J Nutr 2023; 62:525-541. [PMID: 36219234 DOI: 10.1007/s00394-022-03011-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 09/21/2022] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Hayflick and Moorhead first demonstrated cell senescence as the irreversible growth arrest of cells after prolonged cultivation. Telomere shortening and oxidative stress are the fundamental mechanisms that drive cell senescence. Increasing studies have shown that TMAO is closely associated with cellular aging and age-related diseases. An emerging body of evidence from animal models, especially mice, has identified that TMAO contributes to senescence from multiple pathways and appears to accelerate many neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. However, the specific mechanism of how TMAO speeds aging is still not completely clear. MATERIAL AND METHODS In this review, we summarize some key findings in TMAO, cell senescence, and age-related diseases. We focused particular attention on the potential mechanisms for clinical transformation to find ways to interfere with the aging process. CONCLUSION TMAO can accelerate cell senescence by causing mitochondrial damage, superoxide formation, and promoting the generation of pro-inflammatory factors.
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Affiliation(s)
- Lin Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.,Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Fang Yu
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Jian Xia
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China. .,Clinical Research Center for Cerebrovascular Disease of Hunan Province, Central South University, Changsha, Hunan, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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19
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The role of gut-dependent molecule trimethylamine N-oxide as a novel target for the treatment of chronic kidney disease. Int Urol Nephrol 2023:10.1007/s11255-023-03500-9. [PMID: 36797553 DOI: 10.1007/s11255-023-03500-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 01/09/2023] [Indexed: 02/18/2023]
Abstract
Trimethylamine N-oxide (TMAO) is an intestinal uremic toxin molecule mainly excreted by the kidney. Therefore, the plasma TMAO concentration is significantly increased in chronic kidney disease (CKD) patients, and plasma TMAO can be cleared by dialysis. Furthermore, TMAO damage the kidney mainly through three mechanisms: oxidative stress, inflammation and endoplasmic reticulum stress. Clinical experiments have indicated that higher TMAO levels are strongly related to the elevated incidence and mortality of cardiovascular (CV) events in CKD patients. Moreover, experimental data have shown that high levels of TMAO directly aggravate atherosclerosis, thrombosis and enhance myocardial contractility, resulting in myocardial ischemia and stroke. Specially, there are currently four potential ways to reduce blood TMAO concentration or block the effect of TMAO, including reducing the intake of trimethylamine (TMA) precursors in the diet, regulating the intestinal flora to reduce TMA production, interrupting the role of flavin-dependent monooxygenase isoforms (FMOs) to reduce the generation of TMAO, and blocking the TMAO receptor protein kinase R-like endoplasmic reticulum kinase (PERK). We hope that more clinical studies and clinicians will focus on clinical treatment to reduce the concentration of TMAO and alleviate renal damage.
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20
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McArthur S. Regulation of Physiological Barrier Function by the Commensal Microbiota. Life (Basel) 2023; 13:life13020396. [PMID: 36836753 PMCID: PMC9964120 DOI: 10.3390/life13020396] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 01/27/2023] [Accepted: 01/29/2023] [Indexed: 02/04/2023] Open
Abstract
A fundamental characteristic of living organisms is their ability to separate the internal and external environments, a function achieved in large part through the different physiological barrier systems and their component junctional molecules. Barrier integrity is subject to multiple influences, but one that has received comparatively little attention to date is the role of the commensal microbiota. These microbes, which represent approximately 50% of the cells in the human body, are increasingly recognized as powerful physiological modulators in other systems, but their role in regulating barrier function is only beginning to be addressed. Through comparison of the impact commensal microbes have on cell-cell junctions in three exemplar physiological barriers-the gut epithelium, the epidermis and the blood-brain barrier-this review will emphasize the important contribution microbes and microbe-derived mediators play in governing barrier function. By extension, this will highlight the critical homeostatic role of commensal microbes, as well as identifying the puzzles and opportunities arising from our steadily increasing knowledge of this aspect of physiology.
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Affiliation(s)
- Simon McArthur
- Institute of Dentistry, Faculty of Medicine & Dentistry, Queen Mary University of London, Blizard Institute, 4, Newark Street, London E1 2AT, UK
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21
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He GD, Liu XC, Hou XH, Feng YQ. The effect of trimethylamine N-oxide on the metabolism of visceral white adipose tissue in spontaneously hypertensive rat. Adipocyte 2022; 11:420-433. [PMID: 35975941 PMCID: PMC9387326 DOI: 10.1080/21623945.2022.2104783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Strong links have been reported among trimethylamine N-oxide (TMAO), visceral white adipose tissue (vWAT), and cardiometabolic diseases. However, the effects of TMAO on vWAT in hypertension remained incompletely explored. The impact of a chronic 22-week-long treatment with 1 g/L TMAO on vWAT, and its transcriptional and metabolic changes in spontaneously hypertensive rats (SHRs) were evaluated by serum cytokine measurements, histological analysis, fatty acid determinations, and co-expression network analyses. TMAO increased the serum interleukin-6 levels and insulin secretion in SHRs. The adipocyte size was diminished in the SHR 1 g/L TMAO group. In addition, one kind of monounsaturated fatty acids (cis-15-tetracosenoate) and four kinds of polyunsaturated fatty acids (cis-11,14,17-eicosatrienoic acid, docosatetraenoate, docosapentaenoate n-3, and docosapentaenoate n-6) were elevated by TMAO treatment. Three co-expression modules significantly related to TMAO treatment were identified and pathway enrichment analyses indicated that phagosome, lysosome, fatty acid metabolism, valine, leucine, and isoleucine degradation and metabolic pathways were the most significantly altered biological pathways. This study shed new light on the metabolic roles of TMAO on the vWAT of SHRs. TMAO regulated the metabolic status of vWAT, including reduced lipogenesis and an improved specific fatty acid composition. The mechanisms underlying these effects likely involve phagosome and lysosome pathways.
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Affiliation(s)
- Guo-Dong He
- School of Medicine, South China University of Technology, Guangzhou, 510006, China.,Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Xiao-Cong Liu
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Xing-Hua Hou
- Research Department of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Ying-Qing Feng
- School of Medicine, South China University of Technology, Guangzhou, 510006, China.,Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
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22
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Wen Y, Sun Z, Xie S, Hu Z, Lan Q, Sun Y, Yuan L, Zhai C. Intestinal Flora Derived Metabolites Affect the Occurrence and Development of Cardiovascular Disease. J Multidiscip Healthc 2022; 15:2591-2603. [PMID: 36388628 PMCID: PMC9656419 DOI: 10.2147/jmdh.s367591] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 08/10/2022] [Indexed: 10/31/2023] Open
Abstract
In recent years, increasing evidence has shown that the gut microbiota and their metabolites play a pivotal role in human health and diseases, especially the cardiovascular diseases (CVDs). Intestinal flora imbalance (changes in the composition and function of intestinal flora) accelerates the progression of CVDs. The intestinal flora breaks down the food ingested by the host into a series of metabolically active products, including trimethylamine N-Oxide (TMAO), short-chain fatty acids (SCFAs), primary and secondary bile acids, tryptophan and indole derivatives, phenylacetylglutamine (PAGln) and branched chain amino acids (BCAA). These metabolites participate in the occurrence and development of CVDs via abnormally activating these signaling pathways more swiftly when the gut barrier integrity is broken down. This review focuses on the production and metabolism of TMAO and SCFAs. At the same time, we summarize the roles of intestinal flora metabolites in the occurrence and development of coronary heart disease and hypertension, pulmonary hypertension and other CVDs. The theories of "gut-lung axis" and "gut-heart axis" are provided, aiming to explore the potential targets for the treatment of CVDs based on the roles of the intestinal flora in the CVDs.
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Affiliation(s)
- Yinuo Wen
- The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- The First Clinical College, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China
| | - Zefan Sun
- The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
| | - Shuoyin Xie
- The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- The First Clinical College, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China
| | - Zixuan Hu
- The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- The First Clinical College, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China
| | - Qicheng Lan
- The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- The First Clinical College, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China
| | - Yupeng Sun
- The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- The First Clinical College, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China
| | - Linbo Yuan
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China
| | - Changlin Zhai
- The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- The First Clinical College, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China
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23
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Penney NC, Yeung DKT, Garcia-Perez I, Posma JM, Kopytek A, Garratt B, Ashrafian H, Frost G, Marchesi JR, Purkayastha S, Hoyles L, Darzi A, Holmes E. Multi-omic phenotyping reveals host-microbe responses to bariatric surgery, glycaemic control and obesity. COMMUNICATIONS MEDICINE 2022; 2:127. [PMID: 36217535 PMCID: PMC9546886 DOI: 10.1038/s43856-022-00185-6] [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: 12/14/2021] [Accepted: 09/12/2022] [Indexed: 11/05/2022] Open
Abstract
Background Resolution of type 2 diabetes (T2D) is common following bariatric surgery, particularly Roux-en-Y gastric bypass. However, the underlying mechanisms have not been fully elucidated. Methods To address this we compare the integrated serum, urine and faecal metabolic profiles of participants with obesity ± T2D (n = 80, T2D = 42) with participants who underwent Roux-en-Y gastric bypass or sleeve gastrectomy (pre and 3-months post-surgery; n = 27), taking diet into account. We co-model these data with shotgun metagenomic profiles of the gut microbiota to provide a comprehensive atlas of host-gut microbe responses to bariatric surgery, weight-loss and glycaemic control at the systems level. Results Here we show that bariatric surgery reverses several disrupted pathways characteristic of T2D. The differential metabolite set representative of bariatric surgery overlaps with both diabetes (19.3% commonality) and body mass index (18.6% commonality). However, the percentage overlap between diabetes and body mass index is minimal (4.0% commonality), consistent with weight-independent mechanisms of T2D resolution. The gut microbiota is more strongly correlated to body mass index than T2D, although we identify some pathways such as amino acid metabolism that correlate with changes to the gut microbiota and which influence glycaemic control. Conclusion We identify multi-omic signatures associated with responses to surgery, body mass index, and glycaemic control. Improved understanding of gut microbiota - host co-metabolism may lead to novel therapies for weight-loss or diabetes. However, further experiments are required to provide mechanistic insight into the role of the gut microbiota in host metabolism and establish proof of causality.
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Affiliation(s)
- Nicholas C. Penney
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, SW7 2AZ UK
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W2 1NY UK
| | - Derek K. T. Yeung
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, SW7 2AZ UK
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W2 1NY UK
| | - Isabel Garcia-Perez
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, SW7 2AZ UK
| | - Joram M. Posma
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, SW7 2AZ UK
- Health Data Research UK, London, NW1 2BE UK
| | - Aleksandra Kopytek
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, SW7 2AZ UK
| | - Bethany Garratt
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W2 1NY UK
| | - Hutan Ashrafian
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, SW7 2AZ UK
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W2 1NY UK
| | - Gary Frost
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, SW7 2AZ UK
| | - Julian R. Marchesi
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, SW7 2AZ UK
| | - Sanjay Purkayastha
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W2 1NY UK
| | - Lesley Hoyles
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, SW7 2AZ UK
- Department of Biosciences, Nottingham Trent University, Nottingham, NG11 8NS UK
| | - Ara Darzi
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W2 1NY UK
- Institute of Global Health Innovation, Imperial College London, London, W2 1NY UK
| | - Elaine Holmes
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, SW7 2AZ UK
- Centre for Computational & Systems Medicine, Health Futures Institute, Murdoch University, Perth, WA 6150 Australia
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24
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Spivak I, Fluhr L, Elinav E. Local and systemic effects of microbiome‐derived metabolites. EMBO Rep 2022; 23:e55664. [PMID: 36031866 PMCID: PMC9535759 DOI: 10.15252/embr.202255664] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/10/2022] [Accepted: 08/16/2022] [Indexed: 12/12/2022] Open
Abstract
Commensal microbes form distinct ecosystems within their mammalian hosts, collectively termed microbiomes. These indigenous microbial communities broadly expand the genomic and functional repertoire of their host and contribute to the formation of a “meta‐organism.” Importantly, microbiomes exert numerous biochemical reactions synthesizing or modifying multiple bioactive small molecules termed metabolites, which impact their host's physiology in a variety of contexts. Identifying and understanding molecular mechanisms of metabolite–host interactions, and how their disrupted signaling can contribute to diseases, may enable their therapeutic application, a modality termed “postbiotic” therapy. In this review, we highlight key examples of effects of bioactive microbe‐associated metabolites on local, systemic, and immune environments, and discuss how these may impact mammalian physiology and associated disorders. We outline the challenges and perspectives in understanding the potential activity and function of this plethora of microbially associated small molecules as well as possibilities to harness them toward the promotion of personalized precision therapeutic interventions.
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Affiliation(s)
- Igor Spivak
- Systems Immunology Department Weizmann Institute of Science Rehovot Israel
- Medical Clinic III University Hospital Aachen Aachen Germany
| | - Leviel Fluhr
- Systems Immunology Department Weizmann Institute of Science Rehovot Israel
| | - Eran Elinav
- Systems Immunology Department Weizmann Institute of Science Rehovot Israel
- Microbiome & Cancer Division, DKFZ Heidelberg Germany
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25
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Association of Choline Intake with Blood Pressure and Effects of Its Microbiota-Dependent Metabolite Trimethylamine-N-Oxide on Hypertension. Cardiovasc Ther 2022; 2022:9512401. [PMID: 36082192 PMCID: PMC9436605 DOI: 10.1155/2022/9512401] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/26/2022] [Accepted: 08/02/2022] [Indexed: 12/01/2022] Open
Abstract
Background The association of total choline (TC) intake and its metabolite trimethylamine-N-oxide (TMAO) with hypertension and blood pressure (BP) has not been elucidated. Methods For the population study, the association of TC intake with hypertension, as well as blood pressure, was determined through logistic along with multiple linear regression analysis from the National Health and Nutrition Examination Survey 2007 to 2018, respectively. For the animal experimental study, spontaneously hypertensive rats (SHRs) were assigned to the water group or water containing 333 mg/L or 1 g/L TMAO group. After 22 weeks treatment of TMAO, blood pressure measurement, echocardiography, and histopathology of the heart and arteries were evaluated. Results No significant association of TC with hypertension was observed but the trend for ORs of hypertension was decreased with the increased level of TC. Negative association between TC and BP was significant in quintile 4 and quintile 5 range of TC, and the negative trend was significant. The SHR-TMAO groups showed significant higher urine output levels in contrast with the SHR-water group. No difference of diastolic BP was observed, but there was a trend towards lower systolic BP with the increase doses of TMAO in the SHR group. The SHR 1 g/L TMAO rats had a remarkably lower systolic blood pressure than the SHR-water group. Echocardiography showed a diastolic dysfunction alleviating effect in the 1 g/L TMAO group. Conclusion High TC intake was not linked to elevated risk of hypertension. An inverse relationship of choline intake with systolic BP was observed. The mechanism for the beneficial effect of TC might be associated with the diuretic effect of its metabolite TMAO.
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Zhou D, Zhang J, Xiao C, Mo C, Ding BS. Trimethylamine-N-oxide (TMAO) mediates the crosstalk between the gut microbiota and hepatic vascular niche to alleviate liver fibrosis in nonalcoholic steatohepatitis. Front Immunol 2022; 13:964477. [PMID: 36072588 PMCID: PMC9441952 DOI: 10.3389/fimmu.2022.964477] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/04/2022] [Indexed: 11/13/2022] Open
Abstract
Liver fibrosis is one main histological characteristic of nonalcoholic steatohepatitis (NASH), a disease paralleling a worldwide surge in metabolic syndromes with no approved therapies. The role of the gut microbiota in NASH pathogenesis has not been thoroughly illustrated, especially how the gut microbiota derives metabolites to influence the distal liver in NASH. Here, we performed 16S rDNA amplicon sequencing analysis of feces from a mouse NASH model induced by a Western diet and CCl4 injury and found genera under Streptococcaceae, Alcaligenaceae, Oscillibacter, and Pseudochrobactrum, which are related metabolites of TMAO. Injection of the gut microbial metabolite TMAO reduced the progression of liver fibrosis in the mouse NASH model. Further analysis revealed that the anti-fibrotic TMAO normalized gut microbiota diversity and preserved liver sinusoidal endothelial cell integrity by inhibiting endothelial beta 1-subunit of Na (+), K (+)-ATPase (ATP1B1) expression. Collectively, our findings suggest TMAO-mediated crosstalk between microbiota metabolites and hepatic vasculature, and perturbation of this crosstalk disrupts sinusoidal vasculature to promote liver fibrosis in NASH.
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Affiliation(s)
- Dengcheng Zhou
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Jing Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Chengju Xiao
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Chunheng Mo
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
- *Correspondence: Bi-Sen Ding, ; Chunheng Mo,
| | - Bi-Sen Ding
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
- Fibrosis Research Program, Division of Pulmonary and Critical Care Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Division of Regenerative Medicine, Weill Cornell Medicine, New York, NY, United States
- *Correspondence: Bi-Sen Ding, ; Chunheng Mo,
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27
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The Role of a Gut Microbial-Derived Metabolite, Trimethylamine N-Oxide (TMAO), in Neurological Disorders. Mol Neurobiol 2022; 59:6684-6700. [DOI: 10.1007/s12035-022-02990-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 08/07/2022] [Indexed: 10/15/2022]
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Ahmed H, Leyrolle Q, Koistinen V, Kärkkäinen O, Layé S, Delzenne N, Hanhineva K. Microbiota-derived metabolites as drivers of gut-brain communication. Gut Microbes 2022; 14:2102878. [PMID: 35903003 PMCID: PMC9341364 DOI: 10.1080/19490976.2022.2102878] [Citation(s) in RCA: 168] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Alterations in the gut microbiota composition have been associated with a range of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. The gut microbes transform and metabolize dietary- and host-derived molecules generating a diverse group of metabolites with local and systemic effects. The bi-directional communication between brain and the microbes residing in the gut, the so-called gut-brain axis, consists of a network of immunological, neuronal, and endocrine signaling pathways. Although the full variety of mechanisms of the gut-brain crosstalk is yet to be established, the existing data demonstrates that a single metabolite or its derivatives are likely among the key inductors within the gut-brain axis communication. However, more research is needed to understand the molecular mechanisms underlying how gut microbiota associated metabolites alter brain functions, and to examine if different interventional approaches targeting the gut microbiota could be used in prevention and treatment of neurological disorders, as reviewed herein.Abbreviations:4-EPS 4-ethylphenylsulfate; 5-AVA(B) 5-aminovaleric acid (betaine); Aβ Amyloid beta protein; AhR Aryl hydrocarbon receptor; ASD Autism spectrum disorder; BBB Blood-brain barrier; BDNF Brain-derived neurotrophic factor; CNS Central nervous system; GABA ɣ-aminobutyric acid; GF Germ-free; MIA Maternal immune activation; SCFA Short-chain fatty acid; 3M-4-TMAB 3-methyl-4-(trimethylammonio)butanoate; 4-TMAP 4-(trimethylammonio)pentanoate; TMA(O) Trimethylamine(-N-oxide); TUDCA Tauroursodeoxycholic acid; ZO Zonula occludens proteins.
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Affiliation(s)
- Hany Ahmed
- Food Sciences Unit, Department of Life Technologies, University of Turku, Turku, Finland,CONTACT Hany Ahmed Food Chemistry and Food Development Unit, Department of Life Technologies, University of Turku, Turku, Finland
| | - Quentin Leyrolle
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
| | - Ville Koistinen
- Food Sciences Unit, Department of Life Technologies, University of Turku, Turku, Finland,School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Olli Kärkkäinen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Sophie Layé
- Laboratoire NutriNeuro, UMR INRAE 1286, Bordeaux INP, Université de Bordeaux, Bordeaux, France
| | - Nathalie Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
| | - Kati Hanhineva
- Food Sciences Unit, Department of Life Technologies, University of Turku, Turku, Finland,School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland,Department of Biology and Biological Engineering, Division of Food and Nutrition Science, Chalmers University of Technology, Gothenburg, Sweden
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29
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Koppe L, Soulage CO. The impact of dietary nutrient intake on gut microbiota in the progression and complications of chronic kidney disease. Kidney Int 2022; 102:728-739. [PMID: 35870642 DOI: 10.1016/j.kint.2022.06.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 06/02/2022] [Accepted: 06/10/2022] [Indexed: 11/29/2022]
Abstract
Chronic kidney disease (CKD) has been associated with changes in the function and composition of the gut microbiota. The ecosystem of the human gut consists of trillions of microorganisms forming an authentic metabolically active organ that is fueled by nutrients to produce bioactive compounds. These microbiota-derived metabolites may be protective for kidney function (e.g. short-chain fatty acids from fermentation of dietary fibers) or deleterious (e.g. gut-derived uremic toxins such as trimethylamine N-oxide, p-cresyl sulfate, and indoxyl sulfate from fermentation of amino acids). Although diet is the cornerstone of the management of the patient with CKD, it remains a relatively underused component of the clinician's armamentarium. In this review, we describe the latest advances in understanding diet-microbiota crosstalk in a uremic context, and how this communication might contribute to CKD progression and complications. We then discuss how this knowledge could be harnessed for personalized nutrition strategies to prevent patients with CKD progressing to end-stage kidney disease and its detrimental consequences.
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Affiliation(s)
- Laetitia Koppe
- Department of Nephrology, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, F-69495 Pierre-Bénite, France; Univ. Lyon, CarMeN lab, INSA-Lyon, INSERM U1060, INRA, Université Claude Bernard Lyon 1, F-69621 Villeurbanne, France.
| | - Christophe O Soulage
- Univ. Lyon, CarMeN lab, INSA-Lyon, INSERM U1060, INRA, Université Claude Bernard Lyon 1, F-69621 Villeurbanne, France
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30
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Brial F, Matsuda F, Gauguier D. Diet dependent impact of benzoate on diabetes and obesity in mice. Biochimie 2021; 194:35-42. [PMID: 34965461 DOI: 10.1016/j.biochi.2021.12.010] [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: 09/06/2021] [Revised: 10/29/2021] [Accepted: 12/22/2021] [Indexed: 11/17/2022]
Abstract
The gut microbiota contributes to mammalian host biology by supplying metabolites from nutrients and pro-inflammatory molecules. We have recently shown that urinary hippurate is associated with reduced risk of obesity, increased gut microbiome diversity and gene richness, and functional modules for microbial production of its precursor benzoate. Obese mice infused with hippurate exhibit profound alterations of glucose homeostasis. Here, we tested the biological effects of chronic administration of benzoate on cardiometabolic phenotypes in lean and obese mice. Benzoate induced glucose intolerance, enhanced insulin secretion, increased adiposity and stimulated liver inflammation in lean mice fed control diet. In contrast, in condition of obesity and diabetes induced by high fat diet feeding, benzoate infusion resulted in reduction of glucose intolerance, stimulation of both glucose-induced insulin secretion and β-cell proliferation, and reduction of liver triglyceride and collagen accumulation. These results combined with those previously obtained in mice treated with hippurate underline the importance of the benzoate-hippurate pathway in cardiometabolic diseases and pave the way to diagnostic and therapeutic solutions.
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Affiliation(s)
- Francois Brial
- Université de Paris, INSERM UMR 1124, 45 rue des Saints Pères, 75006, Paris, France; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, 53 Shogoin Kawahara-cho, Sakyo, 606-8507, Kyoto, Japan
| | - Fumihiko Matsuda
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, 53 Shogoin Kawahara-cho, Sakyo, 606-8507, Kyoto, Japan
| | - Dominique Gauguier
- Université de Paris, INSERM UMR 1124, 45 rue des Saints Pères, 75006, Paris, France; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, 53 Shogoin Kawahara-cho, Sakyo, 606-8507, Kyoto, Japan; McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.
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31
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Gut Metabolite Trimethylamine N-Oxide Protects INS-1 β-Cell and Rat Islet Function under Diabetic Glucolipotoxic Conditions. Biomolecules 2021; 11:biom11121892. [PMID: 34944536 PMCID: PMC8699500 DOI: 10.3390/biom11121892] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/11/2021] [Accepted: 12/14/2021] [Indexed: 12/14/2022] Open
Abstract
Serum accumulation of the gut microbial metabolite trimethylamine N-oxide (TMAO) is associated with high caloric intake and type 2 diabetes (T2D). Impaired pancreatic β-cell function is a hallmark of diet-induced T2D, which is linked to hyperglycemia and hyperlipidemia. While TMAO production via the gut microbiome-liver axis is well defined, its molecular effects on metabolic tissues are unclear, since studies in various tissues show deleterious and beneficial TMAO effects. We investigated the molecular effects of TMAO on functional β-cell mass. We hypothesized that TMAO may damage functional β-cell mass by inhibiting β-cell viability, survival, proliferation, or function to promote T2D pathogenesis. We treated INS-1 832/13 β-cells and primary rat islets with physiological TMAO concentrations and compared functional β-cell mass under healthy standard cell culture (SCC) and T2D-like glucolipotoxic (GLT) conditions. GLT significantly impeded β-cell mass and function by inducing oxidative and endoplasmic reticulum (ER) stress. TMAO normalized GLT-mediated damage in β-cells and primary islet function. Acute 40µM TMAO recovered insulin production, insulin granule formation, and insulin secretion by upregulating the IRE1α unfolded protein response to GLT-induced ER and oxidative stress. These novel results demonstrate that TMAO protects β-cell function and suggest that TMAO may play a beneficial molecular role in diet-induced T2D conditions.
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Hoyles L, Pontifex MG, Rodriguez-Ramiro I, Anis-Alavi MA, Jelane KS, Snelling T, Solito E, Fonseca S, Carvalho AL, Carding SR, Müller M, Glen RC, Vauzour D, McArthur S. Regulation of blood-brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide. MICROBIOME 2021; 9:235. [PMID: 34836554 PMCID: PMC8626999 DOI: 10.1186/s40168-021-01181-z] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 10/18/2021] [Indexed: 05/09/2023]
Abstract
BACKGROUND Communication between the gut microbiota and the brain is primarily mediated via soluble microbe-derived metabolites, but the details of this pathway remain poorly defined. Methylamines produced by microbial metabolism of dietary choline and L-carnitine have received attention due to their proposed association with vascular disease, but their effects upon the cerebrovascular circulation have hitherto not been studied. RESULTS Here, we use an integrated in vitro/in vivo approach to show that physiologically relevant concentrations of the dietary methylamine trimethylamine N-oxide (TMAO) enhanced blood-brain barrier (BBB) integrity and protected it from inflammatory insult, acting through the tight junction regulator annexin A1. In contrast, the TMAO precursor trimethylamine (TMA) impaired BBB function and disrupted tight junction integrity. Moreover, we show that long-term exposure to TMAO protects murine cognitive function from inflammatory challenge, acting to limit astrocyte and microglial reactivity in a brain region-specific manner. CONCLUSION Our findings demonstrate the mechanisms through which microbiome-associated methylamines directly interact with the mammalian BBB, with consequences for cerebrovascular and cognitive function. Video abstract.
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Affiliation(s)
- Lesley Hoyles
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK.
| | | | - Ildefonso Rodriguez-Ramiro
- Norwich Medical School, University of East Anglia, Norwich, UK
- Metabolic Syndrome Group, Madrid Institute for Advanced Studies (IMDEA) in Food, E28049, Madrid, Spain
| | - M Areeb Anis-Alavi
- Institute of Dentistry, Faculty of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Khadija S Jelane
- Institute of Dentistry, Faculty of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Tom Snelling
- Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Egle Solito
- William Harvey Research Institute, Faculty of Medicine & Dentistry, Queen Mary University of London, London, UK
- Dipartimento di Medicina molecolare e Biotecnologie mediche, Federico II University, Naples, Italy
| | - Sonia Fonseca
- The Gut Microbes and Health Research Programme, The Quadram Institute, Norwich Research Park, Norwich, UK
| | - Ana L Carvalho
- The Gut Microbes and Health Research Programme, The Quadram Institute, Norwich Research Park, Norwich, UK
| | - Simon R Carding
- Norwich Medical School, University of East Anglia, Norwich, UK
- The Gut Microbes and Health Research Programme, The Quadram Institute, Norwich Research Park, Norwich, UK
| | - Michael Müller
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Robert C Glen
- Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, UK
| | - David Vauzour
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Simon McArthur
- Institute of Dentistry, Faculty of Medicine & Dentistry, Queen Mary University of London, London, UK.
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Prokopidis K, Chambers E, Ni Lochlainn M, Witard OC. Mechanisms Linking the Gut-Muscle Axis With Muscle Protein Metabolism and Anabolic Resistance: Implications for Older Adults at Risk of Sarcopenia. Front Physiol 2021; 12:770455. [PMID: 34764887 PMCID: PMC8576575 DOI: 10.3389/fphys.2021.770455] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 10/07/2021] [Indexed: 12/13/2022] Open
Abstract
Aging is associated with a decline in skeletal muscle mass and function-termed sarcopenia-as mediated, in part, by muscle anabolic resistance. This metabolic phenomenon describes the impaired response of muscle protein synthesis (MPS) to the provision of dietary amino acids and practice of resistance-based exercise. Recent observations highlight the gut-muscle axis as a physiological target for combatting anabolic resistance and reducing risk of sarcopenia. Experimental studies, primarily conducted in animal models of aging, suggest a mechanistic link between the gut microbiota and muscle atrophy, mediated via the modulation of systemic amino acid availability and low-grade inflammation that are both physiological factors known to underpin anabolic resistance. Moreover, in vivo and in vitro studies demonstrate the action of specific gut bacteria (Lactobacillus and Bifidobacterium) to increase systemic amino acid availability and elicit an anti-inflammatory response in the intestinal lumen. Prospective lifestyle approaches that target the gut-muscle axis have recently been examined in the context of mitigating sarcopenia risk. These approaches include increasing dietary fiber intake that promotes the growth and development of gut bacteria, thus enhancing the production of short-chain fatty acids (SCFA) (acetate, propionate, and butyrate). Prebiotic/probiotic/symbiotic supplementation also generates SCFA and may mitigate low-grade inflammation in older adults via modulation of the gut microbiota. Preliminary evidence also highlights the role of exercise in increasing the production of SCFA. Accordingly, lifestyle approaches that combine diets rich in fiber and probiotic supplementation with exercise training may serve to produce SCFA and increase microbial diversity, and thus may target the gut-muscle axis in mitigating anabolic resistance in older adults. Future mechanistic studies are warranted to establish the direct physiological action of distinct gut microbiota phenotypes on amino acid utilization and the postprandial stimulation of muscle protein synthesis in older adults.
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Affiliation(s)
- Konstantinos Prokopidis
- Department of Musculoskeletal Biology, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Edward Chambers
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College, London, United Kingdom
| | - Mary Ni Lochlainn
- Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
| | - Oliver C. Witard
- Faculty of Life Sciences and Medicine, Centre for Human and Applied Physiological Sciences, King’s College London, London, United Kingdom
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Zhou L, Yu D, Zheng S, Ouyang R, Wang Y, Xu G. Gut microbiota-related metabolome analysis based on chromatography-mass spectrometry. Trends Analyt Chem 2021. [DOI: 10.1016/j.trac.2021.116375] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Krueger ES, Lloyd TS, Tessem JS. The Accumulation and Molecular Effects of Trimethylamine N-Oxide on Metabolic Tissues: It's Not All Bad. Nutrients 2021; 13:nu13082873. [PMID: 34445033 PMCID: PMC8400152 DOI: 10.3390/nu13082873] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/15/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023] Open
Abstract
Since elevated serum levels of trimethylamine N-oxide (TMAO) were first associated with increased risk of cardiovascular disease (CVD), TMAO research among chronic diseases has grown exponentially. We now know that serum TMAO accumulation begins with dietary choline metabolism across the microbiome-liver-kidney axis, which is typically dysregulated during pathogenesis. While CVD research links TMAO to atherosclerotic mechanisms in vascular tissue, its molecular effects on metabolic tissues are unclear. Here we report the current standing of TMAO research in metabolic disease contexts across relevant tissues including the liver, kidney, brain, adipose, and muscle. Since poor blood glucose management is a hallmark of metabolic diseases, we also explore the variable TMAO effects on insulin resistance and insulin production. Among metabolic tissues, hepatic TMAO research is the most common, whereas its effects on other tissues including the insulin producing pancreatic β-cells are largely unexplored. Studies on diseases including obesity, diabetes, liver diseases, chronic kidney disease, and cognitive diseases reveal that TMAO effects are unique under pathologic conditions compared to healthy controls. We conclude that molecular TMAO effects are highly context-dependent and call for further research to clarify the deleterious and beneficial molecular effects observed in metabolic disease research.
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Affiliation(s)
- Emily S. Krueger
- Department of Nutrition, Dietetics and Food Science, Brigham Young University, Provo, UT 84602, USA; (E.S.K.); (T.S.L.)
| | - Trevor S. Lloyd
- Department of Nutrition, Dietetics and Food Science, Brigham Young University, Provo, UT 84602, USA; (E.S.K.); (T.S.L.)
- Medical Education Program, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Jeffery S. Tessem
- Department of Nutrition, Dietetics and Food Science, Brigham Young University, Provo, UT 84602, USA; (E.S.K.); (T.S.L.)
- Correspondence: ; Tel.: +1-801-422-9082
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He S, Jiang H, Zhuo C, Jiang W. Trimethylamine/Trimethylamine-N-Oxide as a Key Between Diet and Cardiovascular Diseases. Cardiovasc Toxicol 2021; 21:593-604. [PMID: 34003426 DOI: 10.1007/s12012-021-09656-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 04/27/2021] [Indexed: 02/08/2023]
Abstract
Trimethylamine (TMA) is a gut microbiota-derived metabolite which comes from diets rich of choline, betaine or L-carnitine and could be further converted to Trimethylamine-N-oxide (TMAO) in the liver. As the function of gut microbiota and its metabolites being explored so far, studies suggest that TMAO may be a potential risk factor of cardiovascular diseases independent of other traditional risk factors. However, the precise role of TMAO is controversial as some converse results were discovered. In recent studies, it is hypothesized that TMA may also participate in the progression of cardiovascular diseases and some cytotoxic effect of TMA has been discovered. Thus, exploring the relationship between TMA, TMAO and CVD may bring a novel insight into the diagnosis and therapy of cardiovascular diseases. In this review, we discussed the factors which influence the TMA/TMAO's process of metabolism in the human body. We have also summarized the pathogenic effect of TMA/TMAO in cardiovascular diseases, as well as the limitation of some controversial discoveries.
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Affiliation(s)
- Siyu He
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Hong Jiang
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Caili Zhuo
- The Laboratory of Cardiovascular Diseases, Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Wei Jiang
- The Laboratory of Cardiovascular Diseases, Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
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Barretto SA, Lasserre F, Huillet M, Régnier M, Polizzi A, Lippi Y, Fougerat A, Person E, Bruel S, Bétoulières C, Naylies C, Lukowicz C, Smati S, Guzylack L, Olier M, Théodorou V, Mselli-Lakhal L, Zalko D, Wahli W, Loiseau N, Gamet-Payrastre L, Guillou H, Ellero-Simatos S. The pregnane X receptor drives sexually dimorphic hepatic changes in lipid and xenobiotic metabolism in response to gut microbiota in mice. MICROBIOME 2021; 9:93. [PMID: 33879258 PMCID: PMC8059225 DOI: 10.1186/s40168-021-01050-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/16/2021] [Indexed: 05/10/2023]
Abstract
BACKGROUND The gut microbiota-intestine-liver relationship is emerging as an important factor in multiple hepatic pathologies, but the hepatic sensors and effectors of microbial signals are not well defined. RESULTS By comparing publicly available liver transcriptomics data from conventional vs. germ-free mice, we identified pregnane X receptor (PXR, NR1I2) transcriptional activity as strongly affected by the absence of gut microbes. Microbiota depletion using antibiotics in Pxr+/+ vs Pxr-/- C57BL/6J littermate mice followed by hepatic transcriptomics revealed that most microbiota-sensitive genes were PXR-dependent in the liver in males, but not in females. Pathway enrichment analysis suggested that microbiota-PXR interaction controlled fatty acid and xenobiotic metabolism. We confirmed that antibiotic treatment reduced liver triglyceride content and hampered xenobiotic metabolism in the liver from Pxr+/+ but not Pxr-/- male mice. CONCLUSIONS These findings identify PXR as a hepatic effector of microbiota-derived signals that regulate the host's sexually dimorphic lipid and xenobiotic metabolisms in the liver. Thus, our results reveal a potential new mechanism for unexpected drug-drug or food-drug interactions. Video abstract.
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Affiliation(s)
- Sharon Ann Barretto
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Frederic Lasserre
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Marine Huillet
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Marion Régnier
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Arnaud Polizzi
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Yannick Lippi
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Anne Fougerat
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Elodie Person
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Sandrine Bruel
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Colette Bétoulières
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Claire Naylies
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Céline Lukowicz
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Sarra Smati
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Laurence Guzylack
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Maïwenn Olier
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Vassilia Théodorou
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Laila Mselli-Lakhal
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Daniel Zalko
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Walter Wahli
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, 308232, Singapore
- Center for Integrative Genomics, University of Lausanne, CH-1015, Lausanne, Switzerland
| | - Nicolas Loiseau
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Laurence Gamet-Payrastre
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Hervé Guillou
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Sandrine Ellero-Simatos
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France.
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Raad G, Serra F, Martin L, Derieppe MA, Gilleron J, Costa VL, Pisani DF, Amri EZ, Trabucchi M, Grandjean V. Paternal multigenerational exposure to an obesogenic diet drives epigenetic predisposition to metabolic diseases in mice. eLife 2021; 10:61736. [PMID: 33783350 PMCID: PMC8051948 DOI: 10.7554/elife.61736] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 03/28/2021] [Indexed: 12/25/2022] Open
Abstract
Obesity is a growing societal scourge. Recent studies have uncovered that paternal excessive weight induced by an unbalanced diet affects the metabolic health of offspring. These reports mainly employed single-generation male exposure. However, the consequences of multigenerational unbalanced diet feeding on the metabolic health of progeny remain largely unknown. Here, we show that maintaining paternal Western diet feeding for five consecutive generations in mice induces an enhancement in fat mass and related metabolic diseases over generations. Strikingly, chow-diet-fed progenies from these multigenerational Western-diet-fed males develop a 'healthy' overweight phenotype characterized by normal glucose metabolism and without fatty liver that persists for four subsequent generations. Mechanistically, sperm RNA microinjection experiments into zygotes suggest that sperm RNAs are sufficient for establishment but not for long-term maintenance of epigenetic inheritance of metabolic pathologies. Progressive and permanent metabolic deregulation induced by successive paternal Western-diet-fed generations may contribute to the worldwide epidemic of metabolic diseases.
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Affiliation(s)
- Georges Raad
- Université Côte d'Azur, Inserm, C3M, TeamControl of Gene Expression (10), Nice, France.,Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France
| | - Fabrizio Serra
- Université Côte d'Azur, Inserm, C3M, TeamControl of Gene Expression (10), Nice, France
| | - Luc Martin
- Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France
| | | | - Jérôme Gilleron
- Université Côte d'Azur, Inserm, C3M, Team Cellular and Molecular Pathophysiology of Obesity and Diabetes (7), Nice, France
| | - Vera L Costa
- Université Côte d'Azur, Inserm, C3M, TeamControl of Gene Expression (10), Nice, France
| | | | | | - Michele Trabucchi
- Université Côte d'Azur, Inserm, C3M, TeamControl of Gene Expression (10), Nice, France
| | - Valerie Grandjean
- Université Côte d'Azur, Inserm, C3M, TeamControl of Gene Expression (10), Nice, France
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Associations between untargeted plasma metabolomic signatures and gut microbiota composition in the Milieu Intérieur population of healthy adults. Br J Nutr 2020; 126:982-992. [PMID: 33298217 DOI: 10.1017/s0007114520004870] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Host-microbial co-metabolism products are being increasingly recognised to play important roles in physiological processes. However, studies undertaking a comprehensive approach to consider host-microbial metabolic relationships remain scarce. Metabolomic analysis yielding detailed information regarding metabolites found in a given biological compartment holds promise for such an approach. This work aimed to explore the associations between host plasma metabolomic signatures and gut microbiota composition in healthy adults of the Milieu Intérieur study. For 846 subjects, gut microbiota composition was profiled through sequencing of the 16S rRNA gene in stools. Metabolomic signatures were generated through proton NMR analysis of plasma. The associations between metabolomic variables and α- and β-diversity indexes and relative taxa abundances were tested using multi-adjusted partial Spearman correlations, permutational ANOVA and multivariate associations with linear models, respectively. A multiple testing correction was applied (Benjamini-Hochberg, 10 % false discovery rate). Microbial richness was negatively associated with lipid-related signals and positively associated with amino acids, choline, creatinine, glucose and citrate (-0·133 ≤ Spearman's ρ ≤ 0·126). Specific associations between metabolomic signals and abundances of taxa were detected (twenty-five at the genus level and nineteen at the species level): notably, numerous associations were observed for creatinine (positively associated with eleven species and negatively associated with Faecalibacterium prausnitzii). This large-scale population-based study highlights metabolites associated with gut microbial features and provides new insights into the understanding of complex host-gut microbiota metabolic relationships. In particular, our results support the implication of a 'gut-kidney axis'. More studies providing a detailed exploration of these complex interactions and their implications for host health are needed.
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40
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Šket R, Deutsch L, Prevoršek Z, Mekjavić IB, Plavec J, Rittweger J, Debevec T, Eiken O, Stres B. Systems View of Deconditioning During Spaceflight Simulation in the PlanHab Project: The Departure of Urine 1 H-NMR Metabolomes From Healthy State in Young Males Subjected to Bedrest Inactivity and Hypoxia. Front Physiol 2020; 11:532271. [PMID: 33364971 PMCID: PMC7750454 DOI: 10.3389/fphys.2020.532271] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 11/04/2020] [Indexed: 12/27/2022] Open
Abstract
We explored the metabolic makeup of urine in prescreened healthy male participants within the PlanHab experiment. The run-in (5 day) and the following three 21-day interventions [normoxic bedrest (NBR), hypoxic bedrest (HBR), and hypoxic ambulation (HAmb)] were executed in a crossover manner within a controlled laboratory setup (medical oversight, fluid and dietary intakes, microbial bioburden, circadian rhythm, and oxygen level). The inspired O2 (FiO2) fraction next to inspired O2 (PiO2) partial pressure were 0.209 and 133.1 ± 0.3 mmHg for the NBR variant in contrast to 0.141 ± 0.004 and 90.0 ± 0.4 mmHg (approx. 4,000 m of simulated altitude) for HBR and HAmb interventions, respectively. 1H-NMR metabolomes were processed using standard quantitative approaches. A consensus of ensemble of multivariate analyses showed that the metabolic makeup at the start of the experiment and at HAmb endpoint differed significantly from the NBR and HBR endpoints. Inactivity alone or combined with hypoxia resulted in a significant reduction of metabolic diversity and increasing number of affected metabolic pathways. Sliding window analysis (3 + 1) unraveled that metabolic changes in the NBR lagged behind those observed in the HBR. These results show that the negative effects of cessation of activity on systemic metabolism are further aggravated by additional hypoxia. The PlanHab HAmb variant that enabled ambulation, maintained vertical posture, and controlled but limited activity levels apparently prevented the development of negative physiological symptoms such as insulin resistance, low-level systemic inflammation, constipation, and depression. This indicates that exercise apparently prevented the negative spiral between the host's metabolism, intestinal environment, microbiome physiology, and proinflammatory immune activities in the host.
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Affiliation(s)
- Robert Šket
- Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Leon Deutsch
- Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Zala Prevoršek
- Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Igor B. Mekjavić
- Department of Automation, Biocybernetics and Robotics, Jožef Stefan Institute, Ljubljana, Slovenia
| | - Janez Plavec
- National Institute of Chemistry, NMR Center, Ljubljana, Slovenia
| | - Joern Rittweger
- German Aerospace Center, Institute of Aerospace Medicine, Muscle and Bone Metabolism, Köln, Germany
| | - Tadej Debevec
- Department of Automation, Biocybernetics and Robotics, Jožef Stefan Institute, Ljubljana, Slovenia
- Faculty of Sports, University of Ljubljana, Ljubljana, Slovenia
| | - Ola Eiken
- Department of Environmental Physiology, Swedish Aerospace Physiology Centre, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Blaz Stres
- Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
- Department of Automation, Biocybernetics and Robotics, Jožef Stefan Institute, Ljubljana, Slovenia
- Faculty of Civil and Geodetic Engineering, Institute of Sanitary Engineering, University of Ljubljana, Ljubljana, Slovenia
- Laboratory for Clinical Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Microbiology, University of Innsbruck, Innsbruck, Austria
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Penney N, Barton W, Posma JM, Darzi A, Frost G, Cotter PD, Holmes E, Shanahan F, O'Sullivan O, Garcia-Perez I. Investigating the Role of Diet and Exercise in Gut Microbe-Host Cometabolism. mSystems 2020; 5:e00677-20. [PMID: 33262239 PMCID: PMC7716389 DOI: 10.1128/msystems.00677-20] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 11/04/2020] [Indexed: 12/22/2022] Open
Abstract
We investigated the individual and combined effects of diet and physical exercise on metabolism and the gut microbiome to establish how these lifestyle factors influence host-microbiome cometabolism. Urinary and fecal samples were collected from athletes and less active controls. Individuals were further classified according to an objective dietary assessment score of adherence to healthy dietary habits according to WHO guidelines, calculated from their proton nuclear magnetic resonance (1H-NMR) urinary profiles. Subsequent models were generated comparing extremes of dietary habits, exercise, and the combined effect of both. Differences in metabolic phenotypes and gut microbiome profiles between the two groups were assessed. Each of the models pertaining to diet healthiness, physical exercise, or a combination of both displayed a metabolic and functional microbial signature, with a significant proportion of the metabolites identified as discriminating between the various pairwise comparisons resulting from gut microbe-host cometabolism. Microbial diversity was associated with a combination of high adherence to healthy dietary habits and exercise and was correlated with a distinct array of microbially derived metabolites, including markers of proteolytic activity. Improved control of dietary confounders, through the use of an objective dietary assessment score, has uncovered further insights into the complex, multifactorial relationship between diet, exercise, the gut microbiome, and metabolism. Furthermore, the observation of higher proteolytic activity associated with higher microbial diversity indicates that increased microbial diversity may confer deleterious as well as beneficial effects on the host.IMPORTANCE Improved control of dietary confounders, through the use of an objective dietary assessment score, has uncovered further insights into the complex, multifactorial relationship between diet, exercise, the gut microbiome, and metabolism. Each of the models pertaining to diet healthiness, physical exercise, or a combination of both, displayed a distinct metabolic and functional microbial signature. A significant proportion of the metabolites identified as discriminating between the various pairwise comparisons result from gut microbe-host cometabolism, and the identified interactions have expanded current knowledge in this area. Furthermore, although increased microbial diversity has previously been linked with health, our observation of higher microbial diversity being associated with increased proteolytic activity indicates that it may confer deleterious as well as beneficial effects on the host.
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Affiliation(s)
- N Penney
- Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - W Barton
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland
- Teagasc Food Research Centre, Moorepark, Co. Cork, Ireland
- Department of Medicine, University College Cork, National University of Ireland, Cork, Ireland
| | - J M Posma
- Section of Bioinformatics, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
- Health Data Research UK, London, United Kingdom
| | - A Darzi
- Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - G Frost
- Section for Nutrition Research, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - P D Cotter
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland
- Teagasc Food Research Centre, Moorepark, Co. Cork, Ireland
| | - E Holmes
- Section for Nutrition Research, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - F Shanahan
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland
- Department of Medicine, University College Cork, National University of Ireland, Cork, Ireland
| | - O O'Sullivan
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland
- Teagasc Food Research Centre, Moorepark, Co. Cork, Ireland
| | - I Garcia-Perez
- Section for Nutrition Research, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
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42
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Smith L, Klément W, Dopavogui L, de Bock F, Lasserre F, Barretto S, Lukowicz C, Fougerat A, Polizzi A, Schaal B, Patris B, Denis C, Feuillet G, Canlet C, Jamin EL, Debrauwer L, Mselli-Lakhal L, Loiseau N, Guillou H, Marchi N, Ellero-Simatos S, Gamet-Payrastre L. Perinatal exposure to a dietary pesticide cocktail does not increase susceptibility to high-fat diet-induced metabolic perturbations at adulthood but modifies urinary and fecal metabolic fingerprints in C57Bl6/J mice. ENVIRONMENT INTERNATIONAL 2020; 144:106010. [PMID: 32745781 DOI: 10.1016/j.envint.2020.106010] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/21/2020] [Accepted: 07/22/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND We recently demonstrated that chronic dietary exposure to a mixture of pesticides at low-doses induced sexually dimorphic obesogenic and diabetogenic effects in adult mice. Perinatal pesticide exposure may also be a factor in metabolic disease etiology. However, the long-term consequences of perinatal pesticide exposure remain controversial and largely unexplored. OBJECTIVES Here we assessed how perinatal exposure to the same low-dose pesticide cocktail impacted metabolic homeostasis in adult mice. METHODS Six pesticides (boscalid, captan, chlopyrifos, thiachloprid, thiophanate, and ziram) were incorporated in food pellets. During the gestation and lactation periods, female (F0) mice were fed either a pesticide-free or a pesticide-enriched diet at doses exposing them to the tolerable daily intake (TDI) level for each compound, using a 1:1 body weight scaling from humans to mice. All male and female offsprings (F1) were then fed the pesticide-free diet until 18 weeks of age, followed by challenge with a pesticide-free high-fat diet (HFD) for 6 weeks. Metabolic parameters, including body weight, food and water consumption, glucose tolerance, and urinary and fecal metabolomes, were assessed over time. At the end of the experiment, we evaluated energetic metabolism and microbiota activity using biochemical assays, gene expression profiling, and 1H NMR-based metabolomics in the liver, urine, and feces. RESULTS Perinatal pesticide exposure did not affect body weight or energy homeostasis in 6- and 14-week-old mice. As expected, HFD increased body weight and induced metabolic disorders as compared to a low-fat diet. However, HFD-induced metabolic perturbations were similar between mice with and without perinatal pesticide exposure. Interestingly, perinatal pesticide exposure induced time-specific and sex-specific alterations in the urinary and fecal metabolomes of adult mice, suggesting long-lasting changes in gut microbiota. CONCLUSIONS Perinatal pesticide exposure induced sustained sexually dimorphic perturbations of the urinary and fecal metabolic fingerprints, but did not significantly influence the development of HFD-induced metabolic diseases.
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Affiliation(s)
- Lorraine Smith
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France
| | - Wendy Klément
- IGF Cerebrovascular and Glia Research, Dept. Neuroscience, Institute of Functional Genomics, University of Montpellier, UMR 5203 CNRS, U1191 INSERM, France
| | - Léonie Dopavogui
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France
| | - Frédéric de Bock
- IGF Cerebrovascular and Glia Research, Dept. Neuroscience, Institute of Functional Genomics, University of Montpellier, UMR 5203 CNRS, U1191 INSERM, France
| | - Frédéric Lasserre
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France
| | - Sharon Barretto
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France
| | - Céline Lukowicz
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France
| | - Anne Fougerat
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France
| | - Arnaud Polizzi
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France
| | - Benoist Schaal
- Developmental Ethology Laboratory, Centre for Taste, Smell and Feeding Behavior Science, CNRS-UBFC-INRAE-ASD, 21000 Dijon, France
| | - Bruno Patris
- Developmental Ethology Laboratory, Centre for Taste, Smell and Feeding Behavior Science, CNRS-UBFC-INRAE-ASD, 21000 Dijon, France
| | - Colette Denis
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France, Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Guylène Feuillet
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France, Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Cécile Canlet
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France
| | - Emilien L Jamin
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France
| | - Laurent Debrauwer
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France
| | - Laila Mselli-Lakhal
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France
| | - Nicolas Loiseau
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France
| | - Hervé Guillou
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France
| | - Nicola Marchi
- IGF Cerebrovascular and Glia Research, Dept. Neuroscience, Institute of Functional Genomics, University of Montpellier, UMR 5203 CNRS, U1191 INSERM, France
| | - Sandrine Ellero-Simatos
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France
| | - Laurence Gamet-Payrastre
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France.
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Leyrolle Q, Cserjesi R, Mulders MDGH, Zamariola G, Hiel S, Gianfrancesco MA, Rodriguez J, Portheault D, Amadieu C, Leclercq S, Bindels LB, Neyrinck AM, Cani PD, Karkkainen O, Hanhineva K, Lanthier N, Trefois P, Paquot N, Cnop M, Thissen JP, Klein O, Luminet O, Delzenne NM. Specific gut microbial, biological, and psychiatric profiling related to binge eating disorders: A cross-sectional study in obese patients. Clin Nutr 2020; 40:2035-2044. [PMID: 33023763 DOI: 10.1016/j.clnu.2020.09.025] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Binge eating disorder (BED) is a frequent eating disorder associated with obesity and co-morbidities including psychiatric pathologies, which represent a big health burden on the society. The biological processes related to BED remain unknown. Based on psychological testing, anthropometry, clinical biology, gut microbiota analysis and metabolomic assessment, we aimed to examine the complex biological and psychiatric profile of obese patients with and without BED. METHODS Psychological and biological characteristics (anthropometry, plasma biology, gut microbiota, blood pressure) of 101 obese subjects from the Food4Gut cohort were analysed to decipher the differences between BED and Non BED patients, classified based on the Questionnaire for Eating Disorder Diagnosis (Q-EDD). Microbial 16S rDNA sequencing and plasma non-targeted metabolomics (liquid chromatography-mass spectrometry) were performed in a subcohort of 91 and 39 patients respectively. RESULTS BED subjects exhibited an impaired affect balance, deficits in inhibition and self-regulation together with marked alterations of eating behaviour (increased emotional and external eating). BED subjects displayed a lower blood pressure and hip circumference. A decrease in Akkermansia and Intestimonas as well as an increase in Bifidobacterium and Anaerostipes characterized BED subjects. Interestingly, metabolomics analysis revealed that BED subjects displayed a higher level of one food contaminants, Bisphenol A bis(2,3-dihydroxypropyl) ether (BADGE.2H(2)O) and a food derived-metabolite the Isovalerylcarnitine. CONCLUSIONS Non-targeted omics approaches allow to select specific microbial genera and two plasma metabolites that characterize BED obese patients. Further studies are needed to confirm their potential role as drivers or biomarkers of binge eating disorder. Food4gut, clinicaltrial.gov:NCT03852069, https://clinicaltrials.gov/ct2/show/NCT03852069.
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Affiliation(s)
- Quentin Leyrolle
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
| | - Renata Cserjesi
- Center for Social and Cultural Psychology, Université libre de Bruxelles, Belgium
| | - Maria D G H Mulders
- Center for Social and Cultural Psychology, Université libre de Bruxelles, Belgium
| | - Giorgia Zamariola
- Research Institute for Psychological Sciences, UCLouvain, Louvain-La-Neuve, Belgium
| | - Sophie Hiel
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
| | - Marco A Gianfrancesco
- Laboratory of Immunometabolism and Nutrition, GIGA-Inflammation, Infection & Immunity, University of Liège, Liège, Belgium
| | - Julie Rodriguez
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
| | - Daphnée Portheault
- ULB Center for Diabetes Research, Université Libre de Bruxelles, and Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Camille Amadieu
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium; Institute of Neuroscience, UClouvain, Brussels, Belgium
| | - Sophie Leclercq
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium; Institute of Neuroscience, UClouvain, Brussels, Belgium
| | - Laure B Bindels
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
| | - Audrey M Neyrinck
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
| | - Patrice D Cani
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium; WELBIO- Walloon Excellence in Life Sciences and BIOtechnology, UCLouvain, Brussels, Belgium
| | - Olli Karkkainen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Kati Hanhineva
- Food Chemistry and Food Development Unit, Department of Biochemistry, University of Turku, Turku, Finland; Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Nicolas Lanthier
- Laboratory of Hepatogastroenterology, Institut de recherche expérimentale et Clinique, UCLouvain, Brussels, Belgium; Service d'Hépato-Gastroentérologie, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Pierre Trefois
- Medical Imaging Department, Cliniques Universitaires St-Luc, Brussels, Belgium
| | - Nicolas Paquot
- Laboratory of Immunometabolism and Nutrition, GIGA-Inflammation, Infection & Immunity, University of Liège, Liège, Belgium
| | - Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles, and Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Jean-Paul Thissen
- Pole of Endocrinology, Diabetes and Nutrition, Institut de Recherche Expérimentale et Clinique IREC, UCLouvain, Brussels, Belgium
| | - Olivier Klein
- Center for Social and Cultural Psychology, Université libre de Bruxelles, Belgium
| | - Olivier Luminet
- Research Institute for Psychological Sciences, UCLouvain, Louvain-La-Neuve, Belgium
| | - Nathalie M Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium.
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Huang L, Ren P, Ouyang Z, Wei T, Kong X, Li T, Yin Y, He S, Yang C, He Q. Effect of fermented feed on growth performance, holistic metabolism and fecal microbiota in weanling piglets. Anim Feed Sci Technol 2020. [DOI: 10.1016/j.anifeedsci.2020.114505] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Impact of Protein Intake in Older Adults with Sarcopenia and Obesity: A Gut Microbiota Perspective. Nutrients 2020; 12:nu12082285. [PMID: 32751533 PMCID: PMC7468805 DOI: 10.3390/nu12082285] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 07/27/2020] [Accepted: 07/28/2020] [Indexed: 02/07/2023] Open
Abstract
The continuous population increase of older adults with metabolic diseases may contribute to increased prevalence of sarcopenia and obesity and requires advocacy of optimal nutrition treatments to combat their deleterious outcomes. Sarcopenic obesity, characterized by age-induced skeletal-muscle atrophy and increased adiposity, may accelerate functional decline and increase the risk of disability and mortality. In this review, we explore the influence of dietary protein on the gut microbiome and its impact on sarcopenia and obesity. Given the associations between red meat proteins and altered gut microbiota, a combination of plant and animal-based proteins are deemed favorable for gut microbiota eubiosis and muscle-protein synthesis. Additionally, high-protein diets with elevated essential amino-acid concentrations, alongside increased dietary fiber intake, may promote gut microbiota eubiosis, given the metabolic effects derived from short-chain fatty-acid and branched-chain fatty-acid production. In conclusion, a greater abundance of specific gut bacteria associated with increased satiation, protein synthesis, and overall metabolic health may be driven by protein and fiber consumption. This could counteract the development of sarcopenia and obesity and, therefore, represent a novel approach for dietary recommendations based on the gut microbiota profile. However, more human trials utilizing advanced metabolomic techniques to investigate the microbiome and its relationship with macronutrient intake, especially protein, are warranted.
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Rodriguez-Martinez A, Ayala R, Posma JM, Harvey N, Jiménez B, Sonomura K, Sato TA, Matsuda F, Zalloua P, Gauguier D, Nicholson JK, Dumas ME. pJRES Binning Algorithm (JBA): a new method to facilitate the recovery of metabolic information from pJRES 1H NMR spectra. Bioinformatics 2020; 35:1916-1922. [PMID: 30351417 PMCID: PMC6546129 DOI: 10.1093/bioinformatics/bty837] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 08/24/2018] [Accepted: 10/22/2018] [Indexed: 01/21/2023] Open
Abstract
Motivation Data processing is a key bottleneck for 1H NMR-based metabolic profiling of complex biological mixtures, such as biofluids. These spectra typically contain several thousands of signals, corresponding to possibly few hundreds of metabolites. A number of binning-based methods have been proposed to reduce the dimensionality of 1 D 1H NMR datasets, including statistical recoupling of variables (SRV). Here, we introduce a new binning method, named JBA (“pJRES Binning Algorithm”), which aims to extend the applicability of SRV to pJRES spectra. Results The performance of JBA is comprehensively evaluated using 617 plasma 1H NMR spectra from the FGENTCARD cohort. The results presented here show that JBA exhibits higher sensitivity than SRV to detect peaks from low-abundance metabolites. In addition, JBA allows a more efficient removal of spectral variables corresponding to pure electronic noise, and this has a positive impact on multivariate model building Availability and implementation The algorithm is implemented using the MWASTools R/Bioconductor package. Supplementary information Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Andrea Rodriguez-Martinez
- Division of Integrative Systems Medicine and Digestive Diseases, Department of Surgery and Cancer, Imperial College London, London, UK.,Department of Epidemiology and Biostatistics School of Public Health, Imperial College London, London, UK
| | - Rafael Ayala
- Section of Structural Biology, Department of Medicine, Shimadzu Corporation, Kyoto, Japan
| | - Joram M Posma
- Division of Integrative Systems Medicine and Digestive Diseases, Department of Surgery and Cancer, Imperial College London, London, UK.,Department of Epidemiology and Biostatistics School of Public Health, Imperial College London, London, UK
| | - Nikita Harvey
- Division of Integrative Systems Medicine and Digestive Diseases, Department of Surgery and Cancer, Imperial College London, London, UK
| | - Beatriz Jiménez
- Division of Integrative Systems Medicine and Digestive Diseases, Department of Surgery and Cancer, Imperial College London, London, UK
| | - Kazuhiro Sonomura
- Life Science Research Center, Technology Research Laboratory, Shimadzu Corporation, Kyoto, Japan.,Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Taka-Aki Sato
- Life Science Research Center, Technology Research Laboratory, Shimadzu Corporation, Kyoto, Japan.,Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Fumihiko Matsuda
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Pierre Zalloua
- School of Medicine, Lebanese American University, Beirut, Lebanon
| | - Dominique Gauguier
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Cordeliers Research Centre, INSERM UMR_S, Paris, France
| | - Jeremy K Nicholson
- Division of Integrative Systems Medicine and Digestive Diseases, Department of Surgery and Cancer, Imperial College London, London, UK
| | - Marc-Emmanuel Dumas
- Division of Integrative Systems Medicine and Digestive Diseases, Department of Surgery and Cancer, Imperial College London, London, UK
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Gutiérrez-Repiso C, Moreno-Indias I, Martín-Núñez GM, Ho-Plágaro A, Rodríguez-Cañete A, Gonzalo M, García-Fuentes E, Tinahones FJ. Mucosa-associated microbiota in the jejunum of patients with morbid obesity: alterations in states of insulin resistance and metformin treatment. Surg Obes Relat Dis 2020; 16:1575-1585. [PMID: 32475753 DOI: 10.1016/j.soard.2020.04.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 03/26/2020] [Accepted: 04/04/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Stool samples have been widely used to evaluate gut microbiota; however, little is known about the composition of human small intestinal microbiota and the alterations provoked by insulin resistance. OBJECTIVE To describe the composition of jejunal microbiota in morbidly obese patients, as well as its link with insulin resistance and metformin treatment. SETTING Virgen de la Victoria University Hospital and Regional University Hospital, Málaga, Spain. METHODS Jejunal biopsies from 46 morbidly obese patients were analyzed by next-generation sequencing method. Patients were classified in the following 3 groups: low homeostasis model assessment of insulin resistance index (HOMA-IR) value, high HOMA-IR value, and metformin-treated type 2 diabetes patients (T2D-metf). RESULTS Richness (q = .011) together with Proteobacteria (W = 2), Fusobacteria (W = 2), and Bacteroidetes (W = 1) phyla were significantly higher in high HOMA-IR compared with low HOMA-IR group. At family level, several differences were found between low HOMA-IR and T2D-metf group, being the most important the higher abundance of Halomonadacea in T2D-metf group (W = 22). PICRUSt analysis showed that predicted genes involved in trimethylamine-N-oxide biosynthesis pathway could be increased in jejunal microbiota of T2D-metf group compared with the low HOMA-IR group, while indole biosynthesis pathway could be increased in the low HOMA-IR group compared with the high HOMA-IR group. CONCLUSION An increase in richness and an enrichment in Proteobacteria, Fusobacteria, and Bacteroidetes was observed in jejunal from morbidly obese patients with high insulin resistance. Halomonadaceae family was significantly increased in metformin-treated patients. Functional analysis of predicted metagenome suggests that trimethylamine-N-oxide biosynthesis pathway could be increased in the jejunal microbiota of T2D-meft group, while indole biosynthesis pathway could be increased in low HOMA-IR group. These results contribute to the increase in the scarce knowledge about the mucosal microbiota of the hardly accessible small intestine.
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Affiliation(s)
- Carolina Gutiérrez-Repiso
- Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Madrid, Spain
| | - Isabel Moreno-Indias
- Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Madrid, Spain
| | - Gracia M Martín-Núñez
- Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Madrid, Spain
| | - Ailec Ho-Plágaro
- Unidad de Gestión Clínica de Aparato Digestivo del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - Alberto Rodríguez-Cañete
- Unidad de Gestión Clínica de Cirugía General, Digestiva y Trasplantes, Hospital Regional Universitario de Málaga, Málaga, Spain; Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Universidad de Málaga, Málaga, Spain
| | - Monserrat Gonzalo
- Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga, Málaga, Spain
| | - Eduardo García-Fuentes
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Madrid, Spain; Unidad de Gestión Clínica de Aparato Digestivo del Hospital Virgen de la Victoria. Instituto de Investigación Biomédica de Málaga, Málaga, Spain.
| | - Francisco J Tinahones
- Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Madrid, Spain.
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A Role for Gut Microbiome Fermentative Pathways in Fatty Liver Disease Progression. J Clin Med 2020; 9:jcm9051369. [PMID: 32392712 PMCID: PMC7291163 DOI: 10.3390/jcm9051369] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/24/2020] [Accepted: 05/03/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease in which environmental and genetic factors are involved. Although the molecular mechanisms involved in NAFLD onset and progression are not completely understood, the gut microbiome (GM) is thought to play a key role in the process, influencing multiple physiological functions. GM alterations in diversity and composition directly impact disease states with an inflammatory course, such as non-alcoholic steatohepatitis (NASH). However, how the GM influences liver disease susceptibility is largely unknown. Similarly, the impact of strategies targeting the GM for the treatment of NASH remains to be evaluated. This review provides a broad insight into the role of gut microbiota in NASH pathogenesis, as a diagnostic tool, and as a therapeutic target in this liver disease. We highlight the idea that the balance in metabolic fermentations can be key in maintaining liver homeostasis. We propose that an overabundance of alcohol-fermentation pathways in the GM may outcompete healthier, acid-producing members of the microbiota. In this way, GM ecology may precipitate a self-sustaining vicious cycle, boosting liver disease progression.
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Isaiah S, Loots DT, Solomons R, van der Kuip M, Tutu Van Furth AM, Mason S. Overview of Brain-to-Gut Axis Exposed to Chronic CNS Bacterial Infection(s) and a Predictive Urinary Metabolic Profile of a Brain Infected by Mycobacterium tuberculosis. Front Neurosci 2020; 14:296. [PMID: 32372900 PMCID: PMC7186443 DOI: 10.3389/fnins.2020.00296] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 03/16/2020] [Indexed: 12/12/2022] Open
Abstract
A new paradigm in neuroscience has recently emerged - the brain-gut axis (BGA). The contemporary focus in this paradigm has been gut → brain ("bottom-up"), in which the gut-microbiome, and its perturbations, affects one's psychological state-of-mind and behavior, and is pivotal in neurodegenerative disorders. The emerging brain → gut ("top-down") concept, the subject of this review, proposes that dysfunctional brain health can alter the gut-microbiome. Feedback of this alternative bidirectional highway subsequently aggravates the neurological pathology. This paradigm shift, however, focuses upon non-communicable neurological diseases (progressive neuroinflammation). What of infectious diseases, in which pathogenic bacteria penetrate the blood-brain barrier and interact with the brain, and what is this effect on the BGA in bacterial infection(s) that cause chronic neuroinflammation? Persistent immune activity in the CNS due to chronic neuroinflammation can lead to irreversible neurodegeneration and neuronal death. The properties of cerebrospinal fluid (CSF), such as immunological markers, are used to diagnose brain disorders. But what of metabolic markers for such purposes? If a BGA exists, then chronic CNS bacterial infection(s) should theoretically be reflected in the urine. The premise here is that chronic CNS bacterial infection(s) will affect the gut-microbiome and that perturbed metabolism in both the CNS and gut will release metabolites into the blood that are filtered (kidneys) and excreted in the urine. Here we assess the literature on the effects of chronic neuroinflammatory diseases on the gut-microbiome caused by bacterial infection(s) of the CNS, in the context of information attained via metabolomics-based studies of urine. Furthermore, we take a severe chronic neuroinflammatory infectious disease - tuberculous meningitis (TBM), caused by Mycobacterium tuberculosis, and examine three previously validated CSF immunological biomarkers - vascular endothelial growth factor, interferon-gamma and myeloperoxidase - in terms of the expected changes in normal brain metabolism. We then model the downstream metabolic effects expected, predicting pivotal altered metabolic pathways that would be reflected in the urinary profiles of TBM subjects. Our cascading metabolic model should be adjustable to account for other types of CNS bacterial infection(s) associated with chronic neuroinflammation, typically prevalent, and difficult to distinguish from TBM, in the resource-constrained settings of poor communities.
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Affiliation(s)
- Simon Isaiah
- Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa
| | - Du Toit Loots
- Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa
| | - Regan Solomons
- Department of Pediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
| | - Martijn van der Kuip
- Pediatric Infectious Diseases and Immunology, Amsterdam University Medical Center, Academic Medical Center, Emma Children’s Hospital, Amsterdam, Netherlands
| | - A. Marceline Tutu Van Furth
- Pediatric Infectious Diseases and Immunology, Amsterdam University Medical Center, Academic Medical Center, Emma Children’s Hospital, Amsterdam, Netherlands
| | - Shayne Mason
- Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa
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Archaea, specific genetic traits, and development of improved bacterial live biotherapeutic products: another face of next-generation probiotics. Appl Microbiol Biotechnol 2020; 104:4705-4716. [PMID: 32281023 DOI: 10.1007/s00253-020-10599-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/25/2020] [Accepted: 03/31/2020] [Indexed: 02/07/2023]
Abstract
Trimethylamine (TMA) and its oxide TMAO are important biomolecules involved in disease-associated processes in humans (e.g., trimethylaminuria and cardiovascular diseases). TMAO in plasma (pTMAO) stems from intestinal TMA, which is formed from various components of the diet in a complex interplay between diet, gut microbiota, and the human host. Most approaches to prevent the occurrence of such deleterious molecules focus on actions to interfere with gut microbiota metabolism to limit the synthesis of TMA. Some human gut archaea however use TMA as terminal electron acceptor for producing methane, thus indicating that intestinal TMA does not accumulate in some human subjects. Therefore, a rational alternative approach is to eliminate neo-synthesized intestinal TMA. This can be achieved through bioremediation of TMA by these peculiar methanogenic archaea, either by stimulating or providing them, leading to a novel kind of next-generation probiotics referred to as archaebiotics. Finally, specific components which are involved in this archaeal metabolism could also be used as intestinal TMA sequesters, facilitating TMA excretion along with stool. Referring to a standard pharmacological approach, these TMA traps could be synthesized ex vivo and then delivered into the human gut. Another approach is the engineering of known probiotic strain in order to metabolize TMA, i.e., live engineered biotherapeutic products. These alternatives would require, however, to take into account the necessity of synthesizing the 22nd amino acid pyrrolysine, i.e., some specificities of the genetics of TMA-consuming archaea. Here, we present an overview of these different strategies and recent advances in the field that will sustain such biotechnological developments. KEY POINTS: • Some autochthonous human archaea can use TMA for their essential metabolism, a methyl-dependent hydrogenotrophic methanogenesis. • They could therefore be used as next-generation probiotics for preventing some human diseases, especially cardiovascular diseases and trimethylaminuria. • Their genetic capacities can also be used to design live recombinant biotherapeutic products. • Encoding of the 22nd amino acid pyrrolysine is necessary for such alternative developments.
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