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Ye L, Yan K, Tian Z, Xiao ZH, Xie RY, Xie ZY, Tao L. Helicobacter pylori infection is linked to metabolic dysfunction and associated steatotic liver disease: A large cross-sectional study. World J Gastroenterol 2025; 31:102563. [DOI: 10.3748/wjg.v31.i13.102563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 02/19/2025] [Accepted: 03/12/2025] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori), a globally widespread pathogen affecting half of the global population, has been increasingly implicated in metabolic disorders, including obesity, dyslipidemia, and metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is a common condition, impacting nearly one in four adults globally. It also shares significant pathophysiological links with metabolic syndrome. Despite the fact that mechanistic hypotheses (such as oxidative stress and inflammation) have been proposed to explain these relationships, large-scale studies comprehensively assessing multifactorial metabolic associations are lacking. We proposed that H. pylori infection may independently correlate with unfavorable metabolic profiles and the presence of MASLD among adults in a large cohort.
AIM To investigate the associations of H. pylori infection with obesity, glucose, lipids, blood pressure, and MASLD in Chinese adults.
METHODS This study included 28624 adults recruited from the Physical Examination Center at Nanchang University's Second Affiliated Hospital. The 13C-urea breath test was used to identify H. pylori infection, while abdominal ultrasound was employed for MASLD diagnosis. The relationships between H. pylori infection and metabolic factors were analyzed via multivariate logistic regression.
RESULTS The overall H. pylori infection incidence was 26.8%, with higher rates observed in older adults (≥ 70 years: 26.1% vs 18-29 years: 24.6%, P < 0.001) and obese individuals [body mass index (BMI) ≥ 28 kg/m²: 30.0% vs normal BMI: 25.3%, P < 0.001]. H. pylori-positive individuals exhibited elevated blood glucose (5.43 ± 1.55 mmol/L vs 5.27 ± 1.23 mmol/L, P < 0.001), low-density lipoprotein cholesterol (2.97 ± 0.76 mmol/L vs 2.94 ± 0.75 mmol/L, P < 0.001), and blood pressure (systolic: 123.49 ± 19.06 mmHg vs 122.85 ± 18.33 mmHg, P = 0.009; diastolic: 75.48 ± 12.37 vs 74.9 mmHg ± 11.9 mmHg, P < 0.001) levels. Among MASLD patients, infection was associated with increased glucose (5.82 ± 1.95 mmol/L vs 5.60 ± 1.60 mmol/L, P < 0.001), total cholesterol (5.05 ± 1.03 mmol/L vs 5.00 ± 1.00 mmol/L, P = 0.039), BMI (26.23 ± 3.00 kg/m² vs 26.04 ± 2.96 kg/m², P = 0.004), and blood pressure (systolic: 129.5 ± 20.00 mmHg vs 128.49 ± 17.62 mmHg, P = 0.009; diastolic: 79.87 ± 12.07 mmHg vs 79.04 ± 11.76 mmHg, P = 0.002) levels. Multivariate analysis demonstrated elevated glucose [odds ratio (OR) = 1.079, P < 0.001], BMI (OR = 1.016, P = 0.002), and diastolic pressure (OR = 1.003, P = 0.048) levels as independent risk factors, with high-density lipoprotein (HDL) being observed as a protective factor (OR = 0.837, P < 0.001).
CONCLUSION H. pylori infection correlates with older age, obesity, elevated glucose levels, and elevated diastolic blood pressure, whereas HDL protects against H. pylori infection, thus underscoring its role in metabolic disturbances and MASLD.
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Affiliation(s)
- Lin Ye
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang 330008, Jiangxi Province, China
| | - Kai Yan
- Department of Pediatrics, The First Affiliated Hospital of Nanchang University, Nanchang 330008, Jiangxi Province, China
| | - Ze Tian
- Department of Pediatrics, The First Affiliated Hospital of Nanchang University, Nanchang 330008, Jiangxi Province, China
| | - Zhi-Hua Xiao
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang 330008, Jiangxi Province, China
| | - Ru-Yi Xie
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang 330008, Jiangxi Province, China
| | - Zheng-Yuan Xie
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang 330008, Jiangxi Province, China
| | - Li Tao
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang 330008, Jiangxi Province, China
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Shah A, Spannenburg L, Thite P, Morrison M, Fairlie T, Koloski N, Kashyap PC, Pimentel M, Rezaie A, Gores GJ, Jones MP, Holtmann G. Small intestinal bacterial overgrowth in chronic liver disease: an updated systematic review and meta-analysis of case-control studies. EClinicalMedicine 2025; 80:103024. [PMID: 39844931 PMCID: PMC11751576 DOI: 10.1016/j.eclinm.2024.103024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 12/05/2024] [Accepted: 12/12/2024] [Indexed: 01/24/2025] Open
Abstract
Background Small Intestinal Bacterial Overgrowth (SIBO) has been implicated in the pathophysiology of chronic liver disease (CLD). We conducted a systematic review and meta-analysis to assess and compare the prevalence of SIBO among CLD patients (with and without with complications of end stage liver disease) and healthy controls. Methods Electronic databases were searched from inception up to July-2024 for case-control studies reporting SIBO in CLD. Prevalence rates, odds ratios (ORs), and 95% confidence intervals (CIs) of SIBO in patients with CLD and controls were calculated utilizing a random-effects model. The protocol was prospectively registered with PROSPERO (CRD42022379578). Findings The final dataset included 34 case-control studies with 2130 CLD patients and 1222 controls. Overall, the odds for SIBO prevalence in CLD patients compared to controls was 6.7 (95% CI 4.6-9.7, p < 0.001). Although the prevalence of SIBO among patients with CLD with cirrhosis was higher at 42.9% (95% CI: 35.9-50.2) compared to 36.9% (95% CI: 27.4-47.6) in those without cirrhosis, this difference failed statistical significance. However, CLD patients with decompensated cirrhosis had a significantly higher prevalence of SIBO compared to those with compensated cirrhosis, with an OR of 2.6 (95% CI: 1.5-4.5, p < 0.001). Additionally, the prevalence of SIBO was significantly higher in CLD patients with portal hypertension (PHT) than in those without PHT, with an OR of 2.1 (95% CI: 1.4-3.1, p < 0.001). The highest prevalence of SIBO was observed in patients with spontaneous bacterial peritonitis (SBP) (57.7%, 95% CI 38.8-74.5), followed by patients with hepatic encephalopathy (41.0%, 95% CI 16.0-72.3) and patients with variceal bleed (39.5%, 95% CI 12.1-75.6). Interpretation Overall, there is a significantly increased prevalence of SIBO in CLD patients compared to controls. The prevalence is even higher in CLD patients with PHT, especially those with SBP. This meta-analysis suggests that SIBO is associated with complications of CLD and potentially linked to the progression of CLD. Funding National Health and Medical Research Council, Centre for Research Excellence (APP170993).
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Affiliation(s)
- Ayesha Shah
- Faculty of Medicine, University of Queensland, Australia
- Department of Gastroenterology & Hepatology, Princess Alexandra Hospital, Australia
- Translational Research Institute, QLD, Australia
| | - Liam Spannenburg
- Faculty of Medicine, University of Queensland, Australia
- Department of Gastroenterology & Hepatology, Princess Alexandra Hospital, Australia
| | - Parag Thite
- Faculty of Medicine, University of Queensland, Australia
- Department of Gastroenterology & Hepatology, Princess Alexandra Hospital, Australia
| | - Mark Morrison
- Faculty of Medicine, University of Queensland Frazer Institute, Woolloongabba, QLD, Australia
| | - Thomas Fairlie
- Faculty of Medicine, University of Queensland, Australia
- Department of Gastroenterology & Hepatology, Princess Alexandra Hospital, Australia
- Translational Research Institute, QLD, Australia
| | - Natasha Koloski
- Faculty of Medicine, University of Queensland, Australia
- Department of Gastroenterology & Hepatology, Princess Alexandra Hospital, Australia
- Translational Research Institute, QLD, Australia
| | - Purna C. Kashyap
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Mark Pimentel
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Medically Associated Science and Technology Program, Cedars-Sinai, Los Angeles, CA, USA
| | - Ali Rezaie
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Medically Associated Science and Technology Program, Cedars-Sinai, Los Angeles, CA, USA
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Michael P. Jones
- Macquarie University, Department of Psychology, Sydney, NSW, Australia
| | - Gerald Holtmann
- Faculty of Medicine, University of Queensland, Australia
- Department of Gastroenterology & Hepatology, Princess Alexandra Hospital, Australia
- Translational Research Institute, QLD, Australia
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Barbhuiya PA, Ahmed A, Dutta PP, Sen S, Pathak MP. Mitigating Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD): The Role of Bioactive Phytoconstituents in Indian Culinary Spices. Curr Nutr Rep 2025; 14:20. [PMID: 39841356 DOI: 10.1007/s13668-024-00598-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2024] [Indexed: 01/30/2025]
Abstract
PURPOSE OF REVIEW The term metabolic dysfunction-associated steatotic liver disease (MASLD) refers to a group of progressive steatotic liver conditions that include metabolic dysfunction-associated steatohepatitis (MASH), which has varying degrees of liver fibrosis and may advance to cirrhosis, and independent hepatic steatosis. MASLD has a complex underlying mechanism, with patients exhibiting diverse causes and phases of the disease. India has a pool prevalence of MASLD of 38.6% in adults. In 2023, the term NAFLD has been redefined and changed to MASLD. Currently, there are no drugs approved by the FDA for the treatment of MASLD. This study investigates the potential of bioactive phytoconstituents present in spices as a therapeutic approach for MASLD. Moreover, it offers comprehensive data on several pre-clinical studies of bioactive phytoconstituents derived from spices that primarily focus on treating obesity-associated MASLD. RECENT FINDINGS Spices include a high amount of bioactive chemicals and several research have indicated their diverse pharmacological activities. Bioactive phytoconstituents from common Indian spices like cinnamic acid, eugenol, curcumin, allicin, 6-gingerols, capsaicin, piperine, eucalyptol, trigonelline, and linalool have been reported to exhibit anti-MASLD effects both in-vivo and in-vitro. Bioactive phytoconstituents from different culinary species of India have shown promising potential against MASLD in pre-clinical status. Further clinical studies on a large scale would be beneficial for paving the path to the development of a new drug which is the need of time.
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Affiliation(s)
- Pervej Alom Barbhuiya
- Faculty of Pharmaceutical Science, Assam down town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026
- Centre for Research On Ethnomedicine, Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026
| | - Ameena Ahmed
- Faculty of Pharmaceutical Science, Assam down town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026
- Rahman Institute of Pharmaceutical Sciences and Research, Tepesia, Sonapur, Assam, India, PIN - 782402
| | - Partha Pratim Dutta
- Faculty of Pharmaceutical Science, Assam down town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026
- Centre for Research On Ethnomedicine, Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026
| | - Saikat Sen
- Faculty of Pharmaceutical Science, Assam down town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026
- Centre for Research On Ethnomedicine, Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026
| | - Manash Pratim Pathak
- Faculty of Pharmaceutical Science, Assam down town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026.
- Centre for Research On Ethnomedicine, Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026.
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Seidita A, Latteri F, Pistone M, Giuliano A, Bertoncello L, Cavallo G, Chiavetta M, Faraci F, Nigro A, Termini A, Verona L, Ammannato A, Accomando S, Cavataio F, Lospalluti ML, Citrano M, Di Liberto D, Soresi M, Mansueto P, Carroccio A. Celiac Disease and Liver Damage: The Gut-Liver Axis Strikes Back (Again)? A Retrospective Analysis in the Light of a Literature Review. Nutrients 2024; 17:85. [PMID: 39796519 PMCID: PMC11722968 DOI: 10.3390/nu17010085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 12/23/2024] [Accepted: 12/26/2024] [Indexed: 01/13/2025] Open
Abstract
Background/Objectives: An increasing number of studies have reported liver involvement in both children and adults with celiac disease (CD). This often manifests as isolated hypertransaminasemia or hepatic steatosis (HS). The aim of this study was to define the prevalence of hypertransaminasemia and HS in a pediatric population with CD before starting a gluten-free diet (GFD) and to analyze how the introduction of a GFD could modify this condition. We also conducted a state-of-the-art literature review of the association between hypertransaminasemia, metabolic dysfunction-associated steatotic liver disease (MASLD) and CD. Methods: We retrospectively reviewed the clinical charts of pediatric CD patients diagnosed in three different pediatric units of Sicily, analyzing clinical, laboratory, ultrasound, and histology data before and 12 months after the introduction of a GFD. Results: A total of 160 patients (65.0% females, median age 6.4 (0.8-13.2) years) were included; hypertransaminasemia and HS prevalences at diagnosis were 8.1% and 6.1%, respectively. Subjects with hypertransaminasemia were younger (p = 0.01) than those without and had higher frequencies of HS (p = 0.034) and anti-tissue transglutaminase (tTg) immunoglobulin (Ig)G positivity (p = 0.046). Subjects with HS were younger (p = 0.0001) and had a higher frequency of hypertransaminasemia (p = 0.029) compared to non-steatotic ones. After 12 months of a GFD, hypertransaminasemia and HS persisted in 53.8% and 50.0% of patients, respectively. Conclusions: The prevalences of hypertransaminasemia and HS in Sicilian pediatric CD patients seem to be lower than those reported in other geographical areas. A GFD can reverse the trend of liver involvement, although periods of longer than 12 months may be necessary. However, a GFD has been associated with an increased prevalence of HS, and so regular follow-up involving a nutritionist should be recommended to guide physicians in patient management.
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Affiliation(s)
- Aurelio Seidita
- Internal Medicine Unit, “V. Cervello” Hospital, Ospedali Riuniti “Villa Sofia-Cervello”, Via Trabucco, 180, 90146 Palermo, Italy; (A.S.)
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
- Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), 90146 Palermo, Italy
| | - Federica Latteri
- Gastroenterology Unit, “V. Cervello” Hospital, Ospedali Riuniti “Villa Sofia-Cervello”, Via Trabucco, 180, 90146 Palermo, Italy
| | - Mirco Pistone
- Internal Medicine Unit, “V. Cervello” Hospital, Ospedali Riuniti “Villa Sofia-Cervello”, Via Trabucco, 180, 90146 Palermo, Italy; (A.S.)
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Alessandra Giuliano
- Internal Medicine Unit, “V. Cervello” Hospital, Ospedali Riuniti “Villa Sofia-Cervello”, Via Trabucco, 180, 90146 Palermo, Italy; (A.S.)
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Luca Bertoncello
- Internal Medicine Unit, “V. Cervello” Hospital, Ospedali Riuniti “Villa Sofia-Cervello”, Via Trabucco, 180, 90146 Palermo, Italy; (A.S.)
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Giorgia Cavallo
- Internal Medicine Unit, “V. Cervello” Hospital, Ospedali Riuniti “Villa Sofia-Cervello”, Via Trabucco, 180, 90146 Palermo, Italy; (A.S.)
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Marta Chiavetta
- Internal Medicine Unit, “V. Cervello” Hospital, Ospedali Riuniti “Villa Sofia-Cervello”, Via Trabucco, 180, 90146 Palermo, Italy; (A.S.)
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Francesco Faraci
- Internal Medicine Unit, “V. Cervello” Hospital, Ospedali Riuniti “Villa Sofia-Cervello”, Via Trabucco, 180, 90146 Palermo, Italy; (A.S.)
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Alessia Nigro
- Internal Medicine Unit, “V. Cervello” Hospital, Ospedali Riuniti “Villa Sofia-Cervello”, Via Trabucco, 180, 90146 Palermo, Italy; (A.S.)
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Alessandro Termini
- Internal Medicine Unit, “V. Cervello” Hospital, Ospedali Riuniti “Villa Sofia-Cervello”, Via Trabucco, 180, 90146 Palermo, Italy; (A.S.)
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Laura Verona
- Internal Medicine Unit, “V. Cervello” Hospital, Ospedali Riuniti “Villa Sofia-Cervello”, Via Trabucco, 180, 90146 Palermo, Italy; (A.S.)
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Agnese Ammannato
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Salvatore Accomando
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
- Department of Pediatrics, University Hospital of Palermo, 90134 Palermo, Italy
| | - Francesca Cavataio
- Pediatric Gastroenterology Unit, “Di Cristina” Hospital, Palermo, 90134 Palermo, Italy
| | | | - Michele Citrano
- Pediatrics Unit, “V. Cervello” Hospital, Ospedali Riuniti “Villa Sofia-Cervello”, Via Trabucco, 180, 90146 Palermo, Italy
| | - Diana Di Liberto
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Institute of Biochemistry, University of Palermo, 90127 Palermo, Italy
| | - Maurizio Soresi
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Pasquale Mansueto
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Antonio Carroccio
- Internal Medicine Unit, “V. Cervello” Hospital, Ospedali Riuniti “Villa Sofia-Cervello”, Via Trabucco, 180, 90146 Palermo, Italy; (A.S.)
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
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Hermanson JB, Tolba SA, Chrisler EA, Leone VA. Gut microbes, diet, and genetics as drivers of metabolic liver disease: a narrative review outlining implications for precision medicine. J Nutr Biochem 2024; 133:109704. [PMID: 39029595 PMCID: PMC11480923 DOI: 10.1016/j.jnutbio.2024.109704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 07/01/2024] [Accepted: 07/15/2024] [Indexed: 07/21/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing in prevalence, impacting over a third of the global population. The advanced form of MASLD, Metabolic dysfunction-associated steatohepatitis (MASH), is on track to become the number one indication for liver transplant. FDA-approved pharmacological agents are limited for MASH, despite over 400 ongoing clinical trials, with only a single drug (resmetirom) currently on the market. This is likely due to the heterogeneous nature of disease pathophysiology, which involves interactions between highly individualized genetic and environmental factors. To apply precision medicine approaches that overcome interpersonal variability, in-depth insights into interactions between genetics, nutrition, and the gut microbiome are needed, given that each have emerged as dynamic contributors to MASLD and MASH pathogenesis. Here, we discuss the associations and molecular underpinnings of several of these factors individually and outline their interactions in the context of both patient-based studies and preclinical animal model systems. Finally, we highlight gaps in knowledge that will require further investigation to aid in successfully implementing precision medicine to prevent and alleviate MASLD and MASH.
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Affiliation(s)
- Jake B Hermanson
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Samar A Tolba
- Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Evan A Chrisler
- Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Vanessa A Leone
- Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
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Wang X, Wang X, Gao F, Yang S, Zhen Y, Wang X, Zhu G. Polysaccharides from Polygonatum cyrtonema Hua prevent depression-like behaviors in mice with chronic unpredictable mild stress through refining gut microbiota-lipopolysaccharide-paraventricular nucleus signal axis. Heliyon 2024; 10:e38554. [PMID: 39398073 PMCID: PMC11470423 DOI: 10.1016/j.heliyon.2024.e38554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 09/05/2024] [Accepted: 09/25/2024] [Indexed: 10/15/2024] Open
Abstract
As natural polysaccharide cannot directly pass the blood-brain barrier, it is of potential importance to investigate the systemic anti-depression mechanisms of polysaccharides (PSP) from Polygonatum cyrtonema Hua, a well-known herbal medicine with the anti-depressant activity. Here, we explored the underlying mechanisms of effects of PSP on chronic unpredictable mild stress (CUMS)-induced depression-like behavior in mice from the perspective of the microbiota-gut-brain axis. The results demonstrated that PSP intervention for 14 days significantly improved CUMS-induced depressive-like behaviors. Interestingly, PSP treatment increased the relative abundance of Muribaculaceae, Dubosiella and Lactobacillus and decreased the relative abundance of Akkermansia, Helicobacter and Clostridium_methylpentosum in the colon of CUMS mice. Meanwhile, PSP blocked CUMS-induced impairment of intestinal barrier function, inhibited the levels of corticosterone and lipopolysaccharide (LPS), and increased the level of 5-hydroxytryptamine in the serum. Importantly, PSP treatment prevented abnormal neuronal activation and altered local field potential (LFP) in the paraventricular nucleus of CUMS mice, especially the decrease of power spectral density in delta and theta frequency bands. Finally, the results of LFP and c-fos staining after multiple repetitions of LPS injection showed consistencies with CUMS. Taken together, our study indicates that PSP ameliorates depression-like behavior likely via modulating the gut microbiota-lipopolysaccharide-paraventricular nucleus signal axis.
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Affiliation(s)
- Xinya Wang
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, and Key Laboratory of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Xueqing Wang
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, and Key Laboratory of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Feng Gao
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, and Key Laboratory of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Shaojie Yang
- Acupuncture and Moxibustion Clinical Medical Research Center of Anhui Province, The Second Affiliation Hospital of Anhui University of Chinese Medicine, Hefei, 230061, China
| | - Yilan Zhen
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, and Key Laboratory of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Xuncui Wang
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, and Key Laboratory of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Guoqi Zhu
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, and Key Laboratory of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, Hefei, 230012, China
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7
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Kumar AR, Nair B, Kamath AJ, Nath LR, Calina D, Sharifi-Rad J. Impact of gut microbiota on metabolic dysfunction-associated steatohepatitis and hepatocellular carcinoma: pathways, diagnostic opportunities and therapeutic advances. Eur J Med Res 2024; 29:485. [PMID: 39367507 PMCID: PMC11453073 DOI: 10.1186/s40001-024-02072-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 09/22/2024] [Indexed: 10/06/2024] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) and progression to hepatocellular carcinoma (HCC) exhibits distinct molecular and immune characteristics. These traits are influenced by multiple factors, including the gut microbiome, which interacts with the liver through the "gut-liver axis". This bidirectional relationship between the gut and its microbiota and the liver plays a key role in driving various liver diseases, with microbial metabolites and immune responses being central to these processes. Our review consolidates the latest research on how gut microbiota contributes to MASH development and its progression to HCC, emphasizing new diagnostic and therapeutic possibilities. We performed a comprehensive literature review across PubMed/MedLine, Scopus, and Web of Science from January 2000 to August 2024, focusing on both preclinical and clinical studies that investigate the gut microbiota's roles in MASH and HCC. This includes research on pathogenesis, as well as diagnostic and therapeutic advancements related to the gut microbiota. This evidence emphasizes the critical role of the gut microbiome in the pathogenesis of MASH and HCC, highlighting the need for further clinical studies and trials. This is to refine diagnostic techniques and develop targeted therapies that exploit the microbiome's capabilities, aiming to enhance patient care in liver diseases.
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Affiliation(s)
- Ayana R Kumar
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
| | - Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
| | - Adithya Jayaprakash Kamath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health. Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
| | - Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India.
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania.
| | - Javad Sharifi-Rad
- Universidad Espíritu Santo, Samborondón, 092301, Ecuador.
- Centro de Estudios Tecnológicos y Universitarios del Golfo, Veracruz, Mexico.
- Department of Medicine, College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
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8
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Gao Y, Yao Q, Meng L, Wang J, Zheng N. Double-side role of short chain fatty acids on host health via the gut-organ axes. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2024; 18:322-339. [PMID: 39290857 PMCID: PMC11406094 DOI: 10.1016/j.aninu.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 01/29/2024] [Accepted: 05/14/2024] [Indexed: 09/19/2024]
Abstract
Short chain fatty acids (SCFA) exist in dietary foods and are produced by the fermentation of gut microbiota, and are considered an important element for regulating host health. Through blood circulation, SCFA produced in the gut and obtained from foods have an impact on the intestinal health as well as vital organs of the host. It has been recognized that the gut is the "vital organ" in the host. As the gut microbial metabolites, SCFA could create an "axis" connecting the gut and to other organs. Therefore, the "gut-organ axes" have become a focus of research in recent years to analyze organism health. In this review, we summarized the sources, absorption properties, and the function of SCFA in both gut and other peripheral tissues (brain, kidney, liver, lung, bone and cardiovascular) in the way of "gut-organ axes". Short chain fatty acids exert both beneficial and pathological role in gut and other organs in various ways, in which the beneficial effects are more pronounced. In addition, the beneficial effects are reflected in both preventive and therapeutic effects. More importantly, the mechanisms behinds the gut and other tissues provided insight into the function of SCFA, assisting in the development of novel preventive and therapeutic strategies for maintaining the host health.
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Affiliation(s)
- Yanan Gao
- Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Milk and Milk Products Inspection Center of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Qianqian Yao
- Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Milk and Milk Products Inspection Center of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Department of Food Science, Faculty of Veterinary Medicine, University of Liège, Liège 4000, Belgium
| | - Lu Meng
- Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Milk and Milk Products Inspection Center of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Jiaqi Wang
- Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Milk and Milk Products Inspection Center of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Nan Zheng
- Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Milk and Milk Products Inspection Center of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
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9
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Choi YJ, Kim Y, Hwang S. Role of Neutrophils in the Development of Steatotic Liver Disease. Semin Liver Dis 2024; 44:300-318. [PMID: 39117322 DOI: 10.1055/s-0044-1789207] [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] [Indexed: 08/10/2024]
Abstract
This review explores the biological aspects of neutrophils, their contributions to the development of steatotic liver disease, and their potential as therapeutic targets for the disease. Although alcohol-associated and metabolic dysfunction-associated liver diseases originate from distinct etiological factors, the two diseases frequently share excessive lipid accumulation as a common contributor to their pathogenesis, thereby classifying them as types of steatotic liver disease. Dysregulated lipid deposition in the liver induces hepatic injury, triggering the activation of the innate immunity, partially through neutrophil recruitment. Traditionally recognized for their role in microbial clearance, neutrophils have recently garnered attention for their involvement in sterile inflammation, a pivotal component of steatotic liver disease pathogenesis. In conclusion, technological innovations, including single-cell RNA sequencing, have gradually disclosed the existence of various neutrophil subsets; however, how the distinct subsets of neutrophil population contribute differentially to the development of steatotic liver disease remains unclear.
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Affiliation(s)
- You-Jin Choi
- College of Pharmacy, Daegu Catholic University, Gyeongsan, Republic of Korea
| | - Yeonsoo Kim
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Seonghwan Hwang
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
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10
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Huang Y, Wang X, Sun L. The gut-liver axis calibrates PEDF production for ISC homeostasis. BIOPHYSICS REPORTS 2024; 10:175-177. [PMID: 39027319 PMCID: PMC11252237 DOI: 10.52601/bpr.2024.240904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 04/03/2024] [Indexed: 07/20/2024] Open
Affiliation(s)
- Ying Huang
- State Key Laboratory of Female Fertility Promotion, Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
- Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China
| | - Xinran Wang
- State Key Laboratory of Female Fertility Promotion, Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
- Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China
| | - Lulu Sun
- State Key Laboratory of Female Fertility Promotion, Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
- Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China
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11
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Samanta A, Sen Sarma M. Fecal microbiota transplantation in the treatment of hepatic encephalopathy: A perspective. World J Hepatol 2024; 16:678-683. [PMID: 38818298 PMCID: PMC11135264 DOI: 10.4254/wjh.v16.i5.678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/06/2024] [Accepted: 04/16/2024] [Indexed: 05/22/2024] Open
Abstract
Due to its complex pathogenesis, treatment of hepatic encephalopathy (HE) continues to be a therapeutic challenge. Of late, gut microbiome has garnered much attention for its role in the pathogenesis of various gastrointestinal and liver diseases and its potential therapeutic use. New evidence suggests that gut microbiota plays a significant role in cerebral homeostasis. Alteration in the gut microbiota has been documented in patients with HE in a number of clinical and experimental studies. Research on gut dysbiosis in patients with HE has opened newer therapeutic avenues in the form of probiotics, prebiotics and the latest fecal microbiota transplantation (FMT). Recent studies have shown that FMT is safe and could be effective in improving outcomes in advanced liver disease patients presenting with HE. However, questions over the appropriate dose, duration and route of administration for best treatment outcome remains unsettled.
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Affiliation(s)
- Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India.
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12
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Mei EH, Yao C, Chen YN, Nan SX, Qi SC. Multifunctional role of oral bacteria in the progression of non-alcoholic fatty liver disease. World J Hepatol 2024; 16:688-702. [PMID: 38818294 PMCID: PMC11135273 DOI: 10.4254/wjh.v16.i5.688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 02/26/2024] [Accepted: 04/07/2024] [Indexed: 05/22/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders of varying severity, ultimately leading to fibrosis. This spectrum primarily consists of NAFL and non-alcoholic steatohepatitis. The pathogenesis of NAFLD is closely associated with disturbances in the gut microbiota and impairment of the intestinal barrier. Non-gut commensal flora, particularly bacteria, play a pivotal role in the progression of NAFLD. Notably, Porphyromonas gingivalis, a principal bacterium involved in periodontitis, is known to facilitate lipid accumulation, augment immune responses, and induce insulin resistance, thereby exacerbating fibrosis in cases of periodontitis-associated NAFLD. The influence of oral microbiota on NAFLD via the "oral-gut-liver" axis is gaining recognition, offering a novel perspective for NAFLD management through microbial imbalance correction. This review endeavors to encapsulate the intricate roles of oral bacteria in NAFLD and explore underlying mechanisms, emphasizing microbial control strategies as a viable therapeutic avenue for NAFLD.
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Affiliation(s)
- En-Hua Mei
- Shanghai Medical College, Fudan University, Shanghai 200000, China
- Department of Prothodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200000, China
- Shanghai Key Laboratory of Craniomaxiofacial Development and Diseases, Fudan University, Shanghai 200000, China
| | - Chao Yao
- Department of Prothodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200000, China
- Shanghai Key Laboratory of Craniomaxiofacial Development and Diseases, Fudan University, Shanghai 200000, China
| | - Yi-Nan Chen
- Shanghai Medical College, Fudan University, Shanghai 200000, China
| | - Shun-Xue Nan
- Shanghai Medical College, Fudan University, Shanghai 200000, China
| | - Sheng-Cai Qi
- Department of Prothodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200000, China
- Shanghai Key Laboratory of Craniomaxiofacial Development and Diseases, Fudan University, Shanghai 200000, China.
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13
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Cienkowski K, Cienkowska A, Kupczynska K, Bielecka-Dabrowa A. The Role of Gut Microbiota and Its Metabolites in Patients with Heart Failure. Biomedicines 2024; 12:894. [PMID: 38672248 PMCID: PMC11048107 DOI: 10.3390/biomedicines12040894] [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: 02/29/2024] [Revised: 04/14/2024] [Accepted: 04/15/2024] [Indexed: 04/28/2024] Open
Abstract
Heart failure (HF) is a significant health concern; early detection and prevention are crucial. Recent studies suggest that the gut microbiota and its metabolites may influence HF development and risk factors. We explored this relationship by examining changes in gut microbiota composition and metabolite levels in HF patients. HF patients often exhibit decreased alpha and beta diversity compared to controls, suggesting lower bacterial richness and community variation. Changes in specific bacterial phyla were observed, with decreases in Firmicutes (e.g., Ruminococcus) and Bacteroidetes (e.g., Prevotella) and increases in Proteobacteria (e.g., Escherichia, Shigella, and Klebsiella) and Actinobacteria. Gut-microbiota-related metabolites have been identified, potentially affecting various body systems, including the cardiovascular system. Among these are short-chain fatty acids (SCFAs), betaine, trimethylamine N-oxide (TMAO), phenylalanine, tryptophan-kynurenine, and phenylacetylgutamine (PAGIn). Although SCFAs positively affect our organisms, patients with HF have been observed to experience a decline in bacteria responsible for producing these chemical compounds. There have been indications of possible links between betaine, TMAO, phenylalanine, tryptophan-kynurenine, PAGIn, and heart failure. TMAO and phenylalanine, in particular, show promise as potential prognostic factors. However, their clinical significance has not yet been thoroughly evaluated and requires further investigation.
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Affiliation(s)
- Krzysztof Cienkowski
- Faculty of Medicine, Medical University of Lodz (MUL), al. Tadeusza Kosciuszki 4, 90419 Lodz, Poland
| | - Alicja Cienkowska
- Faculty of Biology and Environmental Protection, University of Lodz, ul. Gabriela Narutowicza 68, 90136 Lodz, Poland
| | - Karolina Kupczynska
- Department of Cardiology and Adult Congenital Heart Diseases, Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Rzgowska 281/289, 93338 Lodz, Poland; (K.K.)
| | - Agata Bielecka-Dabrowa
- Department of Cardiology and Adult Congenital Heart Diseases, Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Rzgowska 281/289, 93338 Lodz, Poland; (K.K.)
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Rzgowska 281/289, 93338 Lodz, Poland
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14
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Alghamdi W, Mosli M, Alqahtani SA. Gut microbiota in MAFLD: therapeutic and diagnostic implications. Ther Adv Endocrinol Metab 2024; 15:20420188241242937. [PMID: 38628492 PMCID: PMC11020731 DOI: 10.1177/20420188241242937] [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] [Received: 09/13/2023] [Accepted: 02/22/2024] [Indexed: 04/19/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease, is becoming a significant contributor to chronic liver disease globally, surpassing other etiologies, such as viral hepatitis. Prevention and early treatment strategies to curb its growing prevalence are urgently required. Recent evidence suggests that targeting the gut microbiota may help treat and alleviate disease progression in patients with MAFLD. This review aims to explore the complex relationship between MAFLD and the gut microbiota in relation to disease pathogenesis. Additionally, it delves into the therapeutic strategies targeting the gut microbiota, such as diet, exercise, antibiotics, probiotics, synbiotics, glucagon-like peptide-1 receptor agonists, and fecal microbiota transplantation, and discusses novel biomarkers, such as microbiota-derived testing and liquid biopsy, for their diagnostic and staging potential. Overall, the review emphasizes the urgent need for preventive and therapeutic strategies to address the devastating consequences of MAFLD at both individual and societal levels and recognizes that further exploration of the gut microbiota may open avenues for managing MAFLD effectively in the future.
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Affiliation(s)
- Waleed Alghamdi
- Division of Gastroenterology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mahmoud Mosli
- Division of Gastroenterology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Saleh A. Alqahtani
- Organ Transplant Center of Excellence, King Faisal Specialist Hospital & Research Center, Riyadh 11211, Saudi Arabia
- Division of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
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15
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Cai W, Qiu T, Hu W, Fang T. Changes in the intestinal microbiota of individuals with non-alcoholic fatty liver disease based on sequencing: An updated systematic review and meta-analysis. PLoS One 2024; 19:e0299946. [PMID: 38547205 PMCID: PMC10977702 DOI: 10.1371/journal.pone.0299946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 02/20/2024] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND Alterations in the composition and abundance of the intestinal microbiota occur in non-alcoholic fatty liver disease (NAFLD). However, the results are inconsistent because of differences in the study design, subject area, and sequencing methodology. In this study, we compared the diversity and abundance of the intestinal microbiota of patients with NAFLD and healthy individuals through a systematic review and meta-analysis. METHODS Three databases (PubMed, EMBASE, and Cochrane Library) were searched from their inception to March 20, 2023. A meta-analysis was performed using Stata software to analyze variations in the richness and abundance of the intestinal microbiota in patients with NAFLD. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used for quality assessment. RESULTS A total of 28 articles were included. Shannon diversity was reduced in patients with NAFLD (SMD = -0.24 (95% CI -0.43-0.05, I2 = 71.7%). The relative abundance of Ruminococcus, Faecalibacterium, and Coprococcus all decreased, with total SMDs of -0.96 (95% CI -1.29 to -0.63, I2 = 4.8%), -1.13 (95% CI -2.07 to -0.19, I2 = 80.5%), and -1.66 (95% CI -3.04 to -0.28, I2 = 91.5%). Escherichia was increased in individuals with NAFLD (SMD = 1.78, 95% CI 0.12 to 3.45, I2 = 94.4%). CONCLUSION Increasing the species diversity and altering the abundance of specific gut microbiota, including Coprococcus, Faecalibacterium, Ruminococcus, and Escherichia, may be beneficial for improving NAFLD.
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Affiliation(s)
- Wenpin Cai
- Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Ting Qiu
- Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Weitao Hu
- Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Taiyong Fang
- Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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16
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Zhang J, Zhou J, He Z, Li H. Bacteroides and NAFLD: pathophysiology and therapy. Front Microbiol 2024; 15:1288856. [PMID: 38572244 PMCID: PMC10988783 DOI: 10.3389/fmicb.2024.1288856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 03/07/2024] [Indexed: 04/05/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition observed globally, with the potential to progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and even hepatocellular carcinoma. Currently, the US Food and Drug Administration (FDA) has not approved any drugs for the treatment of NAFLD. NAFLD is characterized by histopathological abnormalities in the liver, such as lipid accumulation, steatosis, hepatic balloon degeneration, and inflammation. Dysbiosis of the gut microbiota and its metabolites significantly contribute to the initiation and advancement of NAFLD. Bacteroides, a potential probiotic, has shown strong potential in preventing the onset and progression of NAFLD. However, the precise mechanism by which Bacteroides treats NAFLD remains uncertain. In this review, we explore the current understanding of the role of Bacteroides and its metabolites in the treatment of NAFLD, focusing on their ability to reduce liver inflammation, mitigate hepatic steatosis, and enhance intestinal barrier function. Additionally, we summarize how Bacteroides alleviates pathological changes by restoring the metabolism, improving insulin resistance, regulating cytokines, and promoting tight-junctions. A deeper comprehension of the mechanisms through which Bacteroides is involved in the pathogenesis of NAFLD should aid the development of innovative drugs targeting NAFLD.
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Affiliation(s)
- Jun Zhang
- Liver Disease Department of Integrative Medicine, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
- Cixi Biomedical Research Institute, Wenzhou Medical University, Ningbo, Zhejiang, China
| | - Jing Zhou
- Liver Disease Department of Integrative Medicine, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Zheyun He
- Liver Diseases Institute, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo, Zhejiang, China
| | - Hongshan Li
- Liver Disease Department of Integrative Medicine, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo, Zhejiang, China
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17
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Violi F, Pastori D, Pignatelli P, Cammisotto V. Endotoxemia and Platelets: 2 Players of Intrahepatic Microthrombosis in NAFLD. JACC Basic Transl Sci 2024; 9:404-413. [PMID: 38559621 PMCID: PMC10978333 DOI: 10.1016/j.jacbts.2023.07.003] [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] [Received: 03/22/2023] [Revised: 05/31/2023] [Accepted: 07/05/2023] [Indexed: 04/04/2024]
Abstract
Gut dysbiosis-related intestinal barrier dysfunction with increased translocation of bacterial products such as lipopolysaccharide (LPS) into systemic circulation is emerging as pathogenic factor of nonalcoholic fatty liver disease (NAFLD). Experimental and clinical studies suggested a potential role of LPS as a trigger eliciting in situ liver inflammation upon interaction with its receptor toll-like receptor 4. Also, LPS has been reported to prime platelets to respond to the common agonists indicating that it behaves as a prothrombotic molecule. Of note, recent studies suggested platelet-related intrahepatic thrombosis triggered by LPS as a mechanism implicated in the process of liver inflammation. This review describes: 1) the impact of gut barrier dysfunction and endotoxemia in the process of NAFLD; 2) the relationship between endotoxemia and platelet activation in NAFLD; 3) clinical evidence for the use of antiplatelet drugs in NAFLD/nonalcoholic steatohepatitis patients; and 4) the potential therapeutic approach to modulate endotoxemia and eventually platelet activation.
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Affiliation(s)
| | - Daniele Pastori
- Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Pasquale Pignatelli
- Mediterranea Cardiocentro-Napoli, Naples, Italy
- Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Vittoria Cammisotto
- Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
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Su C, Wang J, Luo H, Chen J, Lin F, Mo J, Xiong F, Zha L. Gut Microbiota Plays Essential Roles in Soyasaponin's Preventive Bioactivities against Steatohepatitis in the Methionine and Choline Deficient (MCD) Diet-Induced Non-Alcoholic Steatohepatitis (NASH) Mice. Mol Nutr Food Res 2024; 68:e2300561. [PMID: 38234006 DOI: 10.1002/mnfr.202300561] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 11/24/2023] [Indexed: 01/19/2024]
Abstract
SCOPE Gut microbiota (GM) is involved in nonalcoholic steatohepatitis (NASH) development. Phytochemicals soyasaponins can prevent NASH possibly by modulating GM. This study aims to investigate the preventive bioactivities of soyasaponin monomers (SS-A1 and SS-Bb) against NASH and explores the mechanisms by targeting GM. METHODS AND RESULTS Male C57BL/6 mice are fed with methionine and choline deficient (MCD) diet containing SS-A1 , SS-Bb, or not for 16 weeks. Antibiotics-treated pseudo germ-free (PGF) mice are fed with MCD diet containing SS-A1 , SS-Bb, or not for 8 weeks. GM is determined by 16S rRNA amplicon sequencing. Bile acids (BAs) are measured by UPLC-MS/MS. In NASH mice, SS-A1 and SS-Bb alleviate steatohepatitis and fibrosis, reduce ALT, AST, and LPS in serum, decrease TNF-α, IL-6, α-SMA, triglycerides, and cholesterol in liver. SS-A1 and SS-Bb decrease Firmicutes, Erysipelotrichaceae, unidentified-Clostridiales, Eggerthellaceae, Atopobiaceae, Aerococcus, Jeotgalicoccus, Gemella, Rikenella, increase Proteobacteria, Verrucomicrobia, Akkermansiaceae, Romboutsia, and Roseburia. SS-A1 and SS-Bb alter BAs composition in liver, serum, and feces, activate farnesoid X receptor (FXR) in liver and ileum, increase occludin and ZO-1 in intestine. However, GM clearance abrogates the preventive bioactivities of SS-A1 and SS-Bb against NASH. CONCLUSION GM plays essential roles in soyasaponin's preventive bioactivities against steatohepatitis in MCD diet-induced NASH mice.
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Affiliation(s)
- Chuhong Su
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA), Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Jiexian Wang
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA), Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Huiyu Luo
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA), Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Junbin Chen
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA), Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Fengjuan Lin
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA), Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Jiaqi Mo
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA), Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Fei Xiong
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA), Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
- Department of Clinical Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510280, P. R. China
| | - Longying Zha
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA), Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
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19
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Bourinet M, Anty R, Gual P, Luci C. Roles of innate lymphoid cells in metabolic and alcohol-associated liver diseases. JHEP Rep 2024; 6:100962. [PMID: 38304237 PMCID: PMC10831956 DOI: 10.1016/j.jhepr.2023.100962] [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] [Received: 07/24/2023] [Revised: 10/09/2023] [Accepted: 10/25/2023] [Indexed: 02/03/2024] Open
Abstract
Innate lymphoid cells (ILCs) have been identified as potent regulators of inflammation, cell death and wound healing, which are the main biological processes involved in the progression of chronic liver disease. Obesity and chronic alcohol consumption are the leading contributors to chronic liver diseases in developed countries, due to inappropriate lifestyles. In particular, inflammation is a key factor in these liver abnormalities and promotes the development of more severe lesions such as fibrosis, cirrhosis and hepatocellular carcinoma. Opposite roles of ILC subsets have been described in the development of chronic liver disease, depending on the stage and aetiology of the disease. The heterogeneous family of ILCs encompasses cytotoxic natural killer cells, the cytokine-producing type 1, 2 and 3 ILCs and lymphoid tissue inducer cells. Dysfunction of these immune cells provokes uncontrolled inflammation and tissue damage, which are the basis for tumour development. In this review, we provide an overview of the recent and putative roles of ILC subsets in obesity and alcohol-associated liver diseases, which are currently the major contributors to end-stage liver complications such as fibrosis/cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Manon Bourinet
- Université Côte d’Azur, INSERM, U1065, C3M, Nice, France
| | - Rodolphe Anty
- Université Côte d’Azur, CHU, INSERM, U1065, C3M, Nice, France
| | - Philippe Gual
- Université Côte d’Azur, INSERM, U1065, C3M, Nice, France
| | - Carmelo Luci
- Université Côte d’Azur, INSERM, U1065, C3M, Nice, France
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20
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Kuraji R, Ye C, Zhao C, Gao L, Martinez A, Miyashita Y, Radaic A, Kamarajan P, Le C, Zhan L, Range H, Sunohara M, Numabe Y, Kapila YL. Nisin lantibiotic prevents NAFLD liver steatosis and mitochondrial oxidative stress following periodontal disease by abrogating oral, gut and liver dysbiosis. NPJ Biofilms Microbiomes 2024; 10:3. [PMID: 38233485 PMCID: PMC10794237 DOI: 10.1038/s41522-024-00476-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 01/02/2024] [Indexed: 01/19/2024] Open
Abstract
Oral microbiome dysbiosis mediates chronic periodontal disease, gut microbial dysbiosis, and mucosal barrier disfunction that leads to steatohepatitis via the enterohepatic circulation. Improving this dysbiosis towards health may improve liver disease. Treatment with antibiotics and probiotics have been used to modulate the microbial, immunological, and clinical landscape of periodontal disease with some success. The aim of the present investigation was to evaluate the potential for nisin, an antimicrobial peptide produced by Lactococcus lactis, to counteract the periodontitis-associated gut dysbiosis and to modulate the glycolipid-metabolism and inflammation in the liver. Periodontal pathogens, namely Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia and Fusobacterium nucleatum, were administrated topically onto the oral cavity to establish polymicrobial periodontal disease in mice. In the context of disease, nisin treatment significantly shifted the microbiome towards a new composition, commensurate with health while preventing the harmful inflammation in the small intestine concomitant with decreased villi structural integrity, and heightened hepatic exposure to bacteria and lipid and malondialdehyde accumulation in the liver. Validation with RNA Seq analyses, confirmed the significant infection-related alteration of several genes involved in mitochondrial dysregulation, oxidative phosphorylation, and metal/iron binding and their restitution following nisin treatment. In support of these in vivo findings indicating that periodontopathogens induce gastrointestinal and liver distant organ lesions, human autopsy specimens demonstrated a correlation between tooth loss and severity of liver disease. Nisin's ability to shift the gut and liver microbiome towards a new state commensurate with health while mitigating enteritis, represents a novel approach to treating NAFLD-steatohepatitis-associated periodontal disease.
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Affiliation(s)
- Ryutaro Kuraji
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Changchang Ye
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Periodontology, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Chuanjiang Zhao
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Department of Periodontology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Li Gao
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Department of Periodontology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - April Martinez
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
| | - Yukihiro Miyashita
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Allan Radaic
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Sections of Biosystems and Function and Periodontics, School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA
| | - Pachiyappan Kamarajan
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Sections of Biosystems and Function and Periodontics, School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA
| | - Charles Le
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
| | - Ling Zhan
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
| | - Helene Range
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Department of Periodontology, University of Rennes, UFR of Odontology; Service d'Odontologie, CHU de Rennes, Rennes, France
- INSERM CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer); CIC 1414, Rennes, France
| | - Masataka Sunohara
- Department of Anatomy, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Yukihiro Numabe
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Yvonne L Kapila
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA.
- Sections of Biosystems and Function and Periodontics, School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA.
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21
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Forlano R, Martinez-Gili L, Takis P, Miguens-Blanco J, Liu T, Triantafyllou E, Skinner C, Loomba R, Thursz M, Marchesi JR, Mullish B, Manousou P. Disruption of gut barrier integrity and host-microbiome interactions underlie MASLD severity in patients with type-2 diabetes mellitus. Gut Microbes 2024; 16:2304157. [PMID: 38235661 PMCID: PMC10798360 DOI: 10.1080/19490976.2024.2304157] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 01/08/2024] [Indexed: 01/19/2024] Open
Abstract
Aberration of the "gut-liver axis" contributes to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we use multi-omics to analyze the gut microbiota composition and metabolic profile of patients with type-2 diabetes mellitus (T2DM). T2DM patients were screened for liver disease by blood tests, ultrasound, and liver stiffness measurements. Stool microbiota was analyzed by 16S rRNA gene sequencing; metabolomic profiling by Nuclear Magnetic Resonance spectroscopy and Ultra-High Performance-Mass Spectrometry. Microbiome and metabolic signatures were analyzed in the whole cohort and in matched subsets to identify signatures specific for steatosis (MASLD±) or fibrosis (Fibrosis±). Gut permeability was assessed in-vitro using monolayers of MDCK cells and trans-epithelial electric resistance (TEER). Cytokine profile was assessed in serum and stools.Overall, 285 patients were enrolled: 255 serum, 252 urine and 97 stool samples were analyzed. Anaeroplasma and Escherichia/Shigella ASVs were higher, while Butyricicoccus ASVs were lower in those with normal liver. In MASLD±, Butyricicoccus ASV was significantly higher in those with steatosis. In the Fibrosis±, Butyricicoccus ASV was significantly lower in those with fibrosis. Glycochenodeoxycholic acid-3-sulfate (G-UDCA-3S) appeared to be higher in MASLD with fibrosis. Fecal water from patients with MASLD and fibrosis caused the greatest drop in the TEER vs those with normal liver; this was reversed with protease inhibitors. Finally, fecal IL-13 was lower in MASLD with fibrosis. We identified microbiome signatures which were specific for steatosis and fibrosis and independent of other metabolic risk factors. Moreover, we conclude that protease-related gut permeability plays a role in those MASLD patients with fibrosis, and that disease progression is linked to a gut-liver axis which is at least partially independent of T2DM.
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Affiliation(s)
- R. Forlano
- Liver unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - L. Martinez-Gili
- Liver unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
- Section of Bioinformatics, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - P. Takis
- National Phenome Centre, Imperial College London, London, UK
| | - J. Miguens-Blanco
- Liver unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - T. Liu
- Liver unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - E. Triantafyllou
- Liver unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - C. Skinner
- Liver unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - R Loomba
- NAFLD Research Center, Division of Gastroenterology. University of California at San Diego, La Jolla, CA, USA
| | - M. Thursz
- Liver unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - J. R. Marchesi
- Liver unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - B.H. Mullish
- Liver unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - P. Manousou
- Liver unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
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22
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Guariglia M, Saba F, Rosso C, Bugianesi E. Molecular Mechanisms of Curcumin in the Pathogenesis of Metabolic Dysfunction Associated Steatotic Liver Disease. Nutrients 2023; 15:5053. [PMID: 38140312 PMCID: PMC10745597 DOI: 10.3390/nu15245053] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/23/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial condition characterized by insulin resistance, oxidative stress, chronic low-grade inflammation, and sometimes fibrosis. To date, no effective pharmacological therapy has been approved for the treatment of metabolic-associated steatohepatitis (MASH), the progressive form of MASLD. Recently, numerous in vitro and in vivo studies have described the efficacy of nutraceutical compounds in the diet has been tested. Among them, curcumin is the most widely used polyphenol in the diet showing potent anti-inflammatory and antifibrotic activities. This review aims to summarize the most important basic studies (in vitro and animal models studies), describing the molecular mechanisms by which curcumin acts in the context of MASLD, providing the rationale for its effective translational use in humans.
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Affiliation(s)
| | | | - Chiara Rosso
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (M.G.); (F.S.)
| | - Elisabetta Bugianesi
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (M.G.); (F.S.)
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23
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Chen X, Peng R, Peng D, Xiao J, Liu D, Li R. An update: is there a relationship between H. pylori infection and nonalcoholic fatty liver disease? why is this subject of interest? Front Cell Infect Microbiol 2023; 13:1282956. [PMID: 38145041 PMCID: PMC10739327 DOI: 10.3389/fcimb.2023.1282956] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 11/21/2023] [Indexed: 12/26/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection is thought to impact various extragastric diseases, including nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease. Meanwhile, the pathogenesis of NAFLD needs further research, and effective treatment for this disease remains elusive. In this mini-review, we enumerate and ponder on the evidence demonstrating an association between H. pylori infection and NAFLD. Primarily, we delve into high-quality meta-analyses and clinical randomized controlled trials focusing on the association studies between the two. We also discuss clinical studies that present opposite conclusions. In addition, we propose a mechanism through which H. pylori infection aggravates NAFLD: inflammatory cytokines and adipocytokines, insulin resistance, lipid metabolism, intestinal barrier and microbiota, H. pylori outer membrane vesicles and H. pylori-infected cell-extracellular vesicles. This mini-review aims to further explore NAFLD pathogenesis and extragastric disease mechanisms caused by H. pylori infection.
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Affiliation(s)
- Xingcen Chen
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, Hunan, China
- Clinical Research Center, Digestive Diseases of Hunan Province, Changsha, Hunan, China
| | - Ruyi Peng
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, Hunan, China
- Clinical Research Center, Digestive Diseases of Hunan Province, Changsha, Hunan, China
| | - Dongzi Peng
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, Hunan, China
- Clinical Research Center, Digestive Diseases of Hunan Province, Changsha, Hunan, China
| | - Jia Xiao
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, Hunan, China
- Clinical Research Center, Digestive Diseases of Hunan Province, Changsha, Hunan, China
| | - Deliang Liu
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, Hunan, China
- Clinical Research Center, Digestive Diseases of Hunan Province, Changsha, Hunan, China
| | - Rong Li
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, Hunan, China
- Clinical Research Center, Digestive Diseases of Hunan Province, Changsha, Hunan, China
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24
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Pourteymour S, Drevon CA, Dalen KT, Norheim FA. Mechanisms Behind NAFLD: a System Genetics Perspective. Curr Atheroscler Rep 2023; 25:869-878. [PMID: 37812367 DOI: 10.1007/s11883-023-01158-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/19/2023] [Indexed: 10/10/2023]
Abstract
PURPOSE OF REVIEW To summarize the key factors contributing to the onset and progress of nonalcoholic fatty liver disease (NAFLD) and put them in a system genetics context. We particularly focus on how genetic regulation of hepatic lipids contributes to NAFLD. RECENT FINDINGS NAFLD is characterized by excessive accumulation of fat in the liver. This can progress to steatohepatitis (inflammation and hepatocyte injury) and eventually, cirrhosis. The severity of NAFLD is determined by a combination of factors including obesity, insulin resistance, and lipotoxic lipids, along with genetic susceptibility. Numerous studies have been conducted on large human cohorts and mouse panels, to identify key determinants in the genome, transcriptome, proteome, lipidome, microbiome and different environmental conditions contributing to NAFLD. We review common factors contributing to NAFLD and put them in a systems genetics context. In particular, we describe how genetic regulation of liver lipids contributes to NAFLD. The combination of an unhealthy lifestyle and genetic predisposition increases the likelihood of accumulating lipotoxic specie lipids that may be one of the driving forces behind developing severe forms of NAFLD.
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Affiliation(s)
- Shirin Pourteymour
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Blindern, PO Box 1046, 0317, Oslo, Norway
| | - Christian A Drevon
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Blindern, PO Box 1046, 0317, Oslo, Norway
- Vitas Ltd. Oslo Science Park, Oslo, Norway
| | - Knut Tomas Dalen
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Blindern, PO Box 1046, 0317, Oslo, Norway
| | - Frode A Norheim
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Blindern, PO Box 1046, 0317, Oslo, Norway.
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25
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Kister B, Viehof A, Rolle-Kampczyk U, Schwentker A, Treichel NS, Jennings SA, Wirtz TH, Blank LM, Hornef MW, von Bergen M, Clavel T, Kuepfer L. A physiologically based model of bile acid metabolism in mice. iScience 2023; 26:107922. [PMID: 37817939 PMCID: PMC10561051 DOI: 10.1016/j.isci.2023.107922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 07/04/2023] [Accepted: 09/12/2023] [Indexed: 10/12/2023] Open
Abstract
Bile acid (BA) metabolism is a complex system that includes a wide variety of primary and secondary, as well as conjugated and unconjugated BAs that undergo continuous enterohepatic circulation (EHC). Alterations in both composition and dynamics of BAs have been associated with various diseases. However, a mechanistic understanding of the relationship between altered BA metabolism and related diseases is lacking. Computational modeling may support functional analyses of the physiological processes involved in the EHC of BAs along the gut-liver axis. In this study, we developed a physiologically based model of murine BA metabolism describing synthesis, hepatic and microbial transformations, systemic distribution, excretion, and EHC of BAs at the whole-body level. For model development, BA metabolism of specific pathogen-free (SPF) mice was characterized in vivo by measuring BA levels and composition in various organs, expression of transporters along the gut, and cecal microbiota composition. We found significantly different BA levels between male and female mice that could only be explained by adjusted expression of the hepatic enzymes and transporters in the model. Of note, this finding was in agreement with experimental observations. The model for SPF mice could also describe equivalent experimental data in germ-free mice by specifically switching off microbial activity in the intestine. The here presented model can therefore facilitate and guide functional analyses of BA metabolism in mice, e.g., the effect of pathophysiological alterations on BA metabolism and translation of results from mouse studies to a clinically relevant context through cross-species extrapolation.
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Affiliation(s)
- Bastian Kister
- Institute for Systems Medicine with Focus on Organ Interaction, University Hospital RWTH Aachen, Aachen, Germany
- Institute of Applied Microbiology - iAMB, Aachen Biology and Biotechnology - ABBt, RWTH Aachen University, Aachen, Germany
| | - Alina Viehof
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Ulrike Rolle-Kampczyk
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany
| | - Annika Schwentker
- Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Nicole Simone Treichel
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Susan A.V. Jennings
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Theresa H. Wirtz
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Lars M. Blank
- Institute of Applied Microbiology - iAMB, Aachen Biology and Biotechnology - ABBt, RWTH Aachen University, Aachen, Germany
| | - Mathias W. Hornef
- Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Martin von Bergen
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany
- German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany
- Faculty of Life Sciences, Institute of Biochemistry, University of Leipzig, Leipzig, Germany
| | - Thomas Clavel
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Lars Kuepfer
- Institute for Systems Medicine with Focus on Organ Interaction, University Hospital RWTH Aachen, Aachen, Germany
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26
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Soppert J, Brandt EF, Heussen NM, Barzakova E, Blank LM, Kuepfer L, Hornef MW, Trebicka J, Jankowski J, Berres ML, Noels H. Blood Endotoxin Levels as Biomarker of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2023; 21:2746-2758. [PMID: 36470528 DOI: 10.1016/j.cgh.2022.11.030] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/19/2022] [Accepted: 11/22/2022] [Indexed: 01/02/2023]
Abstract
BACKGROUND & AIMS Growing evidence supports a role of gut-derived metabolites in nonalcoholic fatty liver disease (NAFLD), but the relation of endotoxin levels with gut permeability and NAFLD stage remains unclear. This systematic review with meta-analysis aims to provide further insights. METHODS PubMed, Embase, and Cochrane Library were searched for studies published until January 2022 assessing blood endotoxins in patients with NAFLD. Meta-analyses and univariate/multivariate meta-regression, as well as correlation analyses, were performed for endotoxin values and potential relationships to disease stage, age, sex, parameters of systemic inflammation, and metabolic syndrome, as well as liver function and histology. RESULTS Forty-three studies were included, of which 34 were used for meta-analyses. Blood endotoxin levels were higher in patients with simple steatosis vs liver-healthy controls (standardized mean difference, 0.86; 95% confidence interval, 0.62-1.11) as well as in patients with nonalcoholic steatohepatitis vs patients with nonalcoholic fatty liver/non-nonalcoholic steatohepatitis (standardized mean difference, 0.81; 95% confidence interval, 0.27-1.35; P = .0078). Consistently, higher endotoxin levels were observed in patients with more advanced histopathological gradings of liver steatosis and fibrosis. An increase of blood endotoxin levels was partially attributed to a body mass index rise in patients with NAFLD compared with controls. Nevertheless, significant increases of blood endotoxin levels in NAFLD retained after compensation for differences in body mass index, metabolic condition, or liver enzymes. Increases in blood endotoxin levels were associated with increases in C-reactive protein concentrations, and in most cases, paralleled a rise in markers for intestinal permeability. CONCLUSION Our results support blood endotoxin levels as relevant diagnostic biomarker for NAFLD, both for disease detection as well as staging during disease progression, and might serve as surrogate marker of enhanced intestinal permeability in NAFLD. Registration number in Prospero: CRD42022311166.
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Affiliation(s)
- Josefin Soppert
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany; Department of Anesthesiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Elisa Fabiana Brandt
- Department of Internal Medicine III, University Hospital of Aachen, Aachen, Germany
| | - Nicole Maria Heussen
- Department of Medical Statistics, RWTH Aachen University, Aachen, Germany; Center of Biostatistics and Epidemiology, Medical School, Sigmund Freud University, Vienna, Austria
| | - Emona Barzakova
- Department of Diagnostic and Interventional Radiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Lars Mathias Blank
- Institute of Applied Microbiology - iAMB, Aachen Biology and Biotechnology - ABBt, RWTH Aachen University, Aachen, Germany
| | - Lars Kuepfer
- Institute for Systems Medicine, University Hospital RWTH Aachen, Aachen, Germany
| | | | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Münster, Germany
| | - Joachim Jankowski
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
| | - Marie-Luise Berres
- Department of Internal Medicine III, University Hospital of Aachen, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Site Aachen, Germany
| | - Heidi Noels
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
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27
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Shang Y, Widman L, Ebrahimi F, Ludvigsson JF, Hagström H, Wester A. Risk of infections in non-alcoholic fatty liver disease: A nationwide population-based cohort study. Liver Int 2023; 43:2142-2152. [PMID: 37475642 DOI: 10.1111/liv.15680] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/07/2023] [Accepted: 07/09/2023] [Indexed: 07/22/2023]
Abstract
BACKGROUND AND AIMS Previous literature suggests an association between non-alcoholic fatty liver disease (NAFLD) and infections. We aimed to determine the rate and risk of severe infections in NAFLD compared to the general population. METHODS In this population-based cohort study, we used national registers to identify all patients with a hospital-based diagnosis of NAFLD in Sweden 1987-2020 (n = 14 869). The patients were matched with ≤10 comparators from the general population for age, sex, municipality, and calendar year (n = 137 145). Cox regression was used to estimate hazard ratios (HR) for infections in patients with NAFLD compared to comparators. Cumulative incidences were calculated while accounting for competing risks (non-infection death and liver transplantation). RESULTS Severe infections leading to death or hospitalization occurred in 1990 (13.4%) patients with NAFLD and 9899 (7.2%) comparators during a median of 4.5 and 6.1 years of follow-up, respectively. The rate of severe infections per 1000 person-years was higher in patients with NAFLD (21.0) than comparators (9.1) independently of components related to the metabolic syndrome (adjusted HR 1.9, 95% CI = 1.8-2.0). Infection-related mortality was also higher in NAFLD compared to comparators (adjusted HR 1.8, 95% CI = 1.6-2.2). The 10-year cumulative incidence of severe infections was 16.6% (95% CI = 15.8-17.4) in NAFLD and 8.0% (95% CI = 7.8-8.2) in comparators. CONCLUSION NAFLD was associated with severe infections and infection-related mortality, independently of components associated with the metabolic syndrome. Increased clinical vigilance of severe infections in NAFLD may diminish the risk of premature death.
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Affiliation(s)
- Ying Shang
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Linnea Widman
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Fahim Ebrahimi
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Gastroenterology and Hepatology, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Hannes Hagström
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
- Division of Hepatology, Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden
| | - Axel Wester
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
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Bernabeu M, Gharibzahedi SMT, Ganaie AA, Macha MA, Dar BN, Castagnini JM, Garcia-Bonillo C, Meléndez-Martínez AJ, Altintas Z, Barba FJ. The potential modulation of gut microbiota and oxidative stress by dietary carotenoid pigments. Crit Rev Food Sci Nutr 2023; 64:12555-12573. [PMID: 37691412 DOI: 10.1080/10408398.2023.2254383] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Gut microbiota plays a crucial role in regulating the response to immune checkpoint therapy, therefore modulation of the microbiome with bioactive molecules like carotenoids might be a very effective strategy to reduce the risk of chronic diseases. This review highlights the bio-functional effect of carotenoids on Gut Microbiota modulation based on a bibliographic search of the different databases. The methodology given in the preferred reporting items for systematic reviews and meta-analyses (PRISMA) has been employed for developing this review using papers published over two decades considering keywords related to carotenoids and gut microbiota. Moreover, studies related to the health-promoting properties of carotenoids and their utilization in the modulation of gut microbiota have been presented. Results showed that there can be quantitative changes in intestinal bacteria as a function of the type of carotenoid. Due to the dependency on several factors, gut microbiota continues to be a broad and complex study subject. Carotenoids are promising in the modulation of Gut Microbiota, which favored the appearance of beneficial bacteria, resulting in the protection of villi and intestinal permeability. In conclusion, it can be stated that carotenoids may help to protect the integrity of the intestinal epithelium from pathogens and activate immune cells.
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Affiliation(s)
- Manuel Bernabeu
- Research Group in Innovative Technologies for Sustainable Food (ALISOST), Preventive Medicine and Public Health, Food Science, Toxicology and Forensic Medicine Department, Faculty of Pharmacy, Universitat de València, Avda, Burjassot, Burjassot, València, Spain
- Vicerectorat de Recerca, Universitat de Barcelona (UB), Barcelona, Spain
| | - Seyed Mohammad Taghi Gharibzahedi
- Faculty of Natural Sciences and Maths, Institute of Chemistry, Technical University of Berlin, Berlin, Germany
- Faculty of Engineering, Institute of Materials Science, Kiel University, Kiel, Germany
| | - Arsheed A Ganaie
- Watson Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Kashmir, India
| | - Muzafar A Macha
- Watson Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Kashmir, India
| | - Basharat N Dar
- Department of Food Technology, Islamic University of Science and Technology, Kashmir, India
| | - Juan M Castagnini
- Research Group in Innovative Technologies for Sustainable Food (ALISOST), Preventive Medicine and Public Health, Food Science, Toxicology and Forensic Medicine Department, Faculty of Pharmacy, Universitat de València, Avda, Burjassot, Burjassot, València, Spain
| | | | | | - Zeynep Altintas
- Faculty of Natural Sciences and Maths, Institute of Chemistry, Technical University of Berlin, Berlin, Germany
- Faculty of Engineering, Institute of Materials Science, Kiel University, Kiel, Germany
| | - Francisco J Barba
- Research Group in Innovative Technologies for Sustainable Food (ALISOST), Preventive Medicine and Public Health, Food Science, Toxicology and Forensic Medicine Department, Faculty of Pharmacy, Universitat de València, Avda, Burjassot, Burjassot, València, Spain
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Park HJ, Choi J, Kim H, Yang DY, An TH, Lee EW, Han BS, Lee SC, Kim WK, Bae KH, Oh KJ. Cellular heterogeneity and plasticity during NAFLD progression. Front Mol Biosci 2023; 10:1221669. [PMID: 37635938 PMCID: PMC10450943 DOI: 10.3389/fmolb.2023.1221669] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 07/18/2023] [Indexed: 08/29/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease that can progress to nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis, and hepatocellular carcinoma (HCC). NAFLD ranges from simple steatosis (or nonalcoholic fatty liver [NAFL]) to NASH as a progressive form of NAFL, which is characterized by steatosis, lobular inflammation, and hepatocellular ballooning with or without fibrosis. Because of the complex pathophysiological mechanism and the heterogeneity of NAFLD, including its wide spectrum of clinical and histological characteristics, no specific therapeutic drugs have been approved for NAFLD. The heterogeneity of NAFLD is closely associated with cellular plasticity, which describes the ability of cells to acquire new identities or change their phenotypes in response to environmental stimuli. The liver consists of parenchymal cells including hepatocytes and cholangiocytes and nonparenchymal cells including Kupffer cells, hepatic stellate cells, and endothelial cells, all of which have specialized functions. This heterogeneous cell population has cellular plasticity to adapt to environmental changes. During NAFLD progression, these cells can exert diverse and complex responses at multiple levels following exposure to a variety of stimuli, including fatty acids, inflammation, and oxidative stress. Therefore, this review provides insights into NAFLD heterogeneity by addressing the cellular plasticity and metabolic adaptation of hepatocytes, cholangiocytes, hepatic stellate cells, and Kupffer cells during NAFLD progression.
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Affiliation(s)
- Hyun-Ju Park
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Juyong Choi
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Hyunmi Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Da-Yeon Yang
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Tae Hyeon An
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Eun-Woo Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Baek-Soo Han
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
- Biodefense Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Sang Chul Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Won Kon Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Kwang-Hee Bae
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Kyoung-Jin Oh
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
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Zhao Y, Li C, Luan Z, Chen J, Wang C, Jing Y, Qi S, Zhao Z, Zhang H, Wu J, Chen Y, Li Z, Zhao B, Wang S, Yang Y, Sun G. Lactobacillus oris improves non-alcoholic fatty liver in mice and inhibits endogenous cholesterol biosynthesis. Sci Rep 2023; 13:12946. [PMID: 37558739 PMCID: PMC10412569 DOI: 10.1038/s41598-023-38530-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 07/10/2023] [Indexed: 08/11/2023] Open
Abstract
We previously confirmed that a strain of Lactobacillus oris isolated from the fecal samples of healthy Hainan centenarian having potent lipid-lowering ability in HepG2 cells; and this study was to investigate the effect of the stain on non-alcoholic fatty liver in mice in vivio. The Lactobacillus oris strain isolated from Hainan centenarian fecal samples were frozen stored in our laboratory. Thirty ob/ob mice (10 in each group) were orally gavaged with Lactobacillus oris (Lactobacillus, 5 × 109 cfu), mixed probiotics (Mixed, 5 × 109 cfu, a mixture with known lipid-lowering ability), or culture medium (Control) respectively. Lactobacillus oris isolated from fecal samples of Hainan centenarians showed significantly in vivo lipid lowering ability compared with the controls, and the ability was comparable with mixed probiotics strains in mice The possible mechanisms of lipid-lowering of probiotics and Lactobacillus oris may be associated with HMGR inhibition to suppress the synthesis of endogenous cholesterol; bile acids reabsorption, and intestinal FXR-FGF15 signaling pathways promoting the cholesterol conversion into bile acids secretion.
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Affiliation(s)
- Yiming Zhao
- Department of Gastroenterology and Hepatology, Hainan Hospital of PLA General Hospital, Sanya, 572013, China
| | - Congyong Li
- Sixth Health Care Department, Second Medical Center of PLA General Hospital, Beijing, 100853, China
| | - Zhe Luan
- Department of Gastroenterology and Hepatology, First Medical Center of PLA General Hospital, Beijing, 100853, China
| | - Jun Chen
- Unit 91917, Beijing, 102401, China
| | - Cong Wang
- Emergency Department, Tianjin First Central Hospital, Tianjin, 300192, China
| | - Yujia Jing
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China
| | - Shirui Qi
- Emergency Department, Tianjin First Central Hospital, Tianjin, 300192, China
| | - Zhizhuang Zhao
- Department of Gastroenterology and Hepatology, Hainan Hospital of PLA General Hospital, Sanya, 572013, China
| | - Hanwen Zhang
- Department of Gastroenterology and Hepatology, First Medical Center of PLA General Hospital, Beijing, 100853, China
| | - Junling Wu
- Department of Gastroenterology and Hepatology, First Medical Center of PLA General Hospital, Beijing, 100853, China
| | - Yi Chen
- Department of Gastroenterology and Hepatology, First Medical Center of PLA General Hospital, Beijing, 100853, China
| | - Zhuanyu Li
- Beijing QuantiHealth Technology Co., Ltd., Beijing, 100070, China
| | - Bowen Zhao
- Beijing QuantiHealth Technology Co., Ltd., Beijing, 100070, China
| | - Shufang Wang
- Department of Gastroenterology and Hepatology, First Medical Center of PLA General Hospital, Beijing, 100853, China.
| | - Yunsheng Yang
- Department of Gastroenterology and Hepatology, First Medical Center of PLA General Hospital, Beijing, 100853, China.
| | - Gang Sun
- Department of Gastroenterology and Hepatology, First Medical Center of PLA General Hospital, Beijing, 100853, China.
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Miao X, Luo P, Liu J, Wang J, Chen Y. Dihydromyricetin ameliorated nonalcoholic steatohepatitis in mice by regulating the composition of serous lipids, bile acids and ileal microflora. Lipids Health Dis 2023; 22:112. [PMID: 37533083 PMCID: PMC10394885 DOI: 10.1186/s12944-023-01871-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 07/07/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND Dihydromyricetin (DMY) is a natural flavonoid with anti-nonalcoholic steatohepatitis (NASH) activity. However, the effects of DMY on the composition of lipids and bile acids (BAs) in serum, and gut microbiota (GM) in ileum of mice with NASH are not clear. METHODS After male C57BL/6 mice was fed with methionine and choline deficiency (MCD) diet and simultaneously administered with DMY (300 mg/kg/day) by gavage for 8 weeks, the pathological changes of liver tissue were observed by Oil Red O, hematoxylin eosin and Masson staining, the levels of serum alaninea minotransferase, aspartate aminotransferase and liver triglyceride, malonic dialdehyde were detected by the detection kits, the composition and contents of serum lipids and BAs were detected by Liquid Chromatograph-Mass Spectrometry, the mRNA levels of hepatic BAs homeostasis-related genes were detected by RT-qPCR, and microbiological diversity in ileum was analyzed by 16S rDNA sequencing. RESULTS The results showed that the significant changes including 29 lipids, 4 BAs (23-nor-deoxycholic acid, ursodeoxycholic acid, 7-ketodeoxycholic acid and cholic acid), 2 BA transporters (Mrp2 and Oatp1b2) and 8 GMs between MCD and DMY groups. Among them, DMY treatment significantly down-regulated 21 lipids, 4 BAs mentioned above, the ratio of Firmicutes/Bacteroidota and the abundance of Erysipelotrichaceae, Faecalibacuium, significantly up-regulated 8 lipids and 5 GMs (Verrucomicrobiota, Bacteroidota, Actinobacteria, Akkermansiaceae and Akkermansia). CONCLUSIONS The results suggested that DMY may alleviate MCD diet-induced NASH through decreasing the serum levels of toxic BAs which regulated by liver Oatp1b2 and Mrp2, regulating the metabolism of related lipids, and up-regulating intestinal probiotics (Actinobacteria and Verrucomicrobiota at the phylum level; Akkermansiaceae at the family level; Akkermansiaat at the genus level) and inhibiting intestinal harmful bacteria (Firmicutes at the phylum level; Erysipelotrichaceae at the family level; Faecalibaculum at the genus level).
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Affiliation(s)
- Xiaolei Miao
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, 430062, China
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China
| | - Ping Luo
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China
| | - Jiao Liu
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, 430062, China
| | - Junjun Wang
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, 430062, China.
| | - Yong Chen
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, 430062, China.
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Ma K, Hu X, Nambu K, Ueda D, Ichimaru N, Fujino M, Li XK. Coral calcium carried hydrogen ameliorates the severity of non-alcoholic steatohepatitis induced by a choline deficient high carbohydrate fat-free diet in elderly rats. Sci Rep 2023; 13:11646. [PMID: 37468618 DOI: 10.1038/s41598-023-38856-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 07/16/2023] [Indexed: 07/21/2023] Open
Abstract
Hydrogen has been reported to act as an antioxidant, anti-apoptosis and anti-inflammatory agent. Coral calcium carried hydrogen (G2-SUISO) is a safer and more convenient form of hydrogen agent than others. The mechanism underlying the hepatoprotective effects of G2-SUISO using an elderly non-alcoholic steatohepatitis (NASH) rat model was investigated. Two days after fasting, six-month-old elderly male F344/NSlc rats were given a choline deficient high carbohydrate fat-free (CDHCFF) diet from day 0 to day 3 as CDHCFF control group, and then switched to a normal diet from days 4 to 7 with or without 300 mg/kg G2-SUISO. Rats in each group were finally being sacrificed on day 3 or day 7. In the CDHCFF diet group, G2-SUISO decreased the liver weight-to-body weight ratio, the serum AST, ALT, total cholesterol levels, inflammatory infiltration, pro-inflammatory cytokine expression and lipid droplets with inhibiting lipogenic pathways by reducing sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase and fatty acid synthase gene expression compared with the CDHCFF diet alone. G2-SUISO had beneficial effects of anti-apoptosis as well the down-regulation of pro-apoptotic molecules including NF-κB, caspase-3, caspase-9 and Bax. These findings suggest that G2-SUISO treatment exerts a significant hepatoprotective effect against steatosis, inflammation and apoptosis in elderly NASH rats.
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Affiliation(s)
- Kuai Ma
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan
| | - Xin Hu
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan
| | | | - Daisuke Ueda
- Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | | | - Masayuki Fujino
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
- Management Department of Biosafety, Laboratory Animal, and Pathogen Bank, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.
| | - Xiao-Kang Li
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
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Narciso-Schiavon JL, Schiavon LL. Fatty liver and celiac disease: Why worry? World J Hepatol 2023; 15:666-674. [PMID: 37305374 PMCID: PMC10251279 DOI: 10.4254/wjh.v15.i5.666] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/27/2023] [Accepted: 04/18/2023] [Indexed: 05/24/2023] Open
Abstract
Celiac disease (CD) is a chronic inflammatory intestinal disorder mediated by the ingestion of gluten in genetically susceptible individuals. Liver involvement in CD has been widely described, and active screening for CD is recommended in patients with liver diseases, particularly in those with autoimmune disorders, fatty liver in the absence of metabolic syndrome, noncirrhotic intrahepatic portal hypertension, cryptogenic cirrhosis, and in the context of liver transplantation. Non-alcoholic fatty liver disease is estimated to affect approximately 25% of the world’s adult population and is the world’s leading cause of chronic liver disease. In view of both diseases’ global significance, and to their correlation, this study reviews the available literature on fatty liver and CD and verifies particularities of the clinical setting.
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Affiliation(s)
- Janaina Luz Narciso-Schiavon
- Department of Internal Medicine, Gastroenterology Division, Federal University of Santa Catarina, Florianópolis 88040-900, Santa Catarina, Brazil
| | - Leonardo Lucca Schiavon
- Department of Internal Medicine, Gastroenterology Division, Federal University of Santa Catarina, Florianópolis 88040-900, Santa Catarina, Brazil
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Ahrodia T, Kandiyal B, Das B. Microbiota and epigenetics: Health impact. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 198:93-117. [PMID: 37225326 DOI: 10.1016/bs.pmbts.2023.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Epigenetic changes associated with disease development and progressions are of increasing importance because of their potential diagnostic and therapeutic applications. Several epigenetic changes associated with chronic metabolic disorders have been studied in various diseases. Epigenetic changes are mostly modulated by environmental factors, including the human microbiota living in different parts of our bodies. The microbial structural components and the microbially derived metabolites directly interact with host cells, thereby maintaining homeostasis. Microbiome dysbiosis, on the other hand, is known to produce elevated levels of disease-linked metabolites, which may directly affect a host metabolic pathway or induce epigenetic changes that can lead to disease development. Despite their important role in host physiology and signal transduction, there has been little research into the mechanics and pathways associated with epigenetic modifications. This chapter focuses on the relationship between microbes and their epigenetic effects in diseased pathology, as well as on the regulation and metabolism of the dietary options available to the microbes. Furthermore, this chapter also provides a prospective link between these two important phenomena, termed "Microbiome and Epigenetics."
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Affiliation(s)
- Taruna Ahrodia
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
| | - Bharti Kandiyal
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
| | - Bhabatosh Das
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India.
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Qiu YY, Zhang J, Zeng FY, Zhu YZ. Roles of the peroxisome proliferator-activated receptors (PPARs) in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Pharmacol Res 2023; 192:106786. [PMID: 37146924 DOI: 10.1016/j.phrs.2023.106786] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 04/28/2023] [Accepted: 05/02/2023] [Indexed: 05/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease phenotypes which start with simple steatosis and lipid accumulation in the hepatocytes - a typical histological lesions characteristic. It may progress to non-alcoholic steatohepatitis (NASH) that is characterized by hepatic inflammation and/or fibrosis and subsequent onset of NAFLD-related cirrhosis and hepatocellular carcinoma (HCC). Due to the central role of the liver in metabolism, NAFLD is regarded as a result of and contribution to the metabolic abnormalities seen in the metabolic syndrome. Peroxisome proliferator-activated receptors (PPARs) has three subtypes, which govern the expression of genes responsible for energy metabolism, cellular development, inflammation, and differentiation. The agonists of PPARα, such as fenofibrate and clofibrate, have been used as lipid-lowering drugs in clinical practice. Thiazolidinediones (TZDs) - ligands of PPARγ, such as rosiglitazone and pioglitazone, are also used in the treatment of type 2 diabetes (T2D) with insulin resistance (IR). Increasing evidence suggests that PPARβ/δ agonists have potential therapeutic effects in improving insulin sensitivity and lipid metabolism disorders. In addition, PPARs ligands have been considered as potential therapeutic drugs for hypertension, atherosclerosis (AS) or diabetic nephropathy. Their crucial biological roles dictate the significance of PPARs-targeting in medical research and drug discovery. Here, it reviews the biological activities, ligand selectivity and biological functions of the PPARs family, and discusses the relationship between PPARs and the pathogenesis of NAFLD and metabolic syndrome. This will open new possibilities for PPARs application in medicine, and provide a new idea for the treatment of fatty liver and related diseases.
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Affiliation(s)
- Yuan-Ye Qiu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, 999078, Macau, China; Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, 999078, Macau, China.
| | - Jing Zhang
- University International College, Macau University of Science and Technology, Avenida Wai Long, Taipa, 999078, Macau, China.
| | - Fan-Yi Zeng
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, 999078, Macau, China; School of Pharmacy, Macau University of Science and Technology, Avenida Wai Long, Taipa, 999078, Macau, China; Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai Jiao Tong University, 24/1400 West Beijing Road, Shanghai, 200040, China.
| | - Yi Zhun Zhu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, 999078, Macau, China; Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, 999078, Macau, China; School of Pharmacy, Macau University of Science and Technology, Avenida Wai Long, Taipa, 999078, Macau, China.
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Horowitz A, Chanez-Paredes SD, Haest X, Turner JR. Paracellular permeability and tight junction regulation in gut health and disease. Nat Rev Gastroenterol Hepatol 2023:10.1038/s41575-023-00766-3. [PMID: 37186118 PMCID: PMC10127193 DOI: 10.1038/s41575-023-00766-3] [Citation(s) in RCA: 225] [Impact Index Per Article: 112.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/03/2023] [Indexed: 05/17/2023]
Abstract
Epithelial tight junctions define the paracellular permeability of the intestinal barrier. Molecules can cross the tight junctions via two distinct size-selective and charge-selective paracellular pathways: the pore pathway and the leak pathway. These can be distinguished by their selectivities and differential regulation by immune cells. However, permeability increases measured in most studies are secondary to epithelial damage, which allows non-selective flux via the unrestricted pathway. Restoration of increased unrestricted pathway permeability requires mucosal healing. By contrast, tight junction barrier loss can be reversed by targeted interventions. Specific approaches are needed to restore pore pathway or leak pathway permeability increases. Recent studies have used preclinical disease models to demonstrate the potential of pore pathway or leak pathway barrier restoration in disease. In this Review, we focus on the two paracellular flux pathways that are dependent on the tight junction. We discuss the latest evidence that highlights tight junction components, structures and regulatory mechanisms, their impact on gut health and disease, and opportunities for therapeutic intervention.
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Affiliation(s)
- Arie Horowitz
- UNIROUEN, INSERM U1245, Normandy Centre for Genomic and Personalized Medicine, Normandie University, Rouen, France
| | - Sandra D Chanez-Paredes
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Xenia Haest
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jerrold R Turner
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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Elghannam MT, Hassanien MH, Ameen YA, Turky EA, Elattar GM, ElRay AA, Eltalkawy MD. Oral microbiota and liver diseases. Clin Nutr ESPEN 2023; 54:68-72. [PMID: 36963900 DOI: 10.1016/j.clnesp.2022.12.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 12/25/2022] [Accepted: 12/30/2022] [Indexed: 01/07/2023]
Abstract
Gut microbiota plays a crucial role in our health and particularly liver diseases, including NAFLD, cirrhosis, and HCC. Oral microbiome and its role in health and disease represent an active field of research. Several lines of evidence have suggested that oral microbiota dysbiosis represents a major factor contributing to the occurrence and progression of many liver diseases. The human microbiome is valuable to the diagnosis of cancer and provides a novel strategy for targeted therapy of HCC. The most studied liver disease in relation to oral-gut-liver axis dysbiosis includes MAFLD; however, other diseases include Precancerous liver disease as viral liver diseases, liver cirrhosis, AIH and liver carcinoma (HCC). It seems that restoring populations of beneficial organisms and correcting dysbiosis appears to improve outcomes in liver disorders. We discuss the possible role of oral microbiota in these diseases.
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Affiliation(s)
- Maged Tharwat Elghannam
- TBRI, Warak ALHadar, P.O. Box 30 Imbaba, Cairo, Egypt; Hepatogastroenterology Department, Theodor Bilharz Research Institute, Giza, Egypt.
| | | | | | | | | | - Ahmed Aly ElRay
- Hepatogastroenterology Department, Theodor Bilharz Research Institute, Giza, Egypt.
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Zhu L, Li D, Yang X. Gut metabolomics and 16S rRNA sequencing analysis of the effects of arecoline on non-alcoholic fatty liver disease in rats. Front Pharmacol 2023; 14:1132026. [PMID: 37050898 PMCID: PMC10083296 DOI: 10.3389/fphar.2023.1132026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 02/28/2023] [Indexed: 03/29/2023] Open
Abstract
Introduction: Non-alcoholic fatty liver disease (NAFLD) has gradually become the primary cause of fatty liver disease. Betel nuts have been used to treat gastrointestinal diseases.Methods: In the present study, we analyzed the pathology, serology, gut flora, and metabolites in a rat model of NAFLD, with and without betel nut alkaloid treatment, using an integrated approach involving pathology, serological testing, 16S rRNA gene sequencing, and ultra-performance liquid chromatography-mass spectrometry metabolomics.Results: Two rats were used for model validation. Thirty SD rats were included and divided into the normal group (C group), NAFLD model group (M group), low-dose group, medium-dose group (T group), and high-dose group with intraperitoneal injection of arecoline. The expression of blood lipids was significantly downregulated at all three arecoline concentrations (p < 0.05). Alpha-diversity analysis of the intestinal flora showed significant differences among the three groups, with a significant reduction in population diversity in the M group and a recovery of population diversity after arecoline treatment. At the phylum level, the relative abundance of Firmicutes was significantly higher in the T group and Proteobacteria in the M group. The KEGG metabolic pathways included polyketide sugar unit biosynthesis and hypertrophic cardiomyopathy. Thirty-three significantly different metabolites were identified among the groups. Significantly different metabolites between groups T and M included indolepyruvate, 2-deoxystreptamine, sakuranetin, glycyl-leucine, and riboflavin. The KEGG metabolic pathway suggested a potential role for arachidonic acid metabolism, serotonergic synapses, neuroactive ligand-receptor interactions, tyrosine metabolism, and regiomelanin. Vitamin digestion and absorption, as well as regulation of lipolysis in adipocytes, were the main metabolic pathways that distinguished the T vs. M groups. PGE2 is involved in several metabolic pathways. Correlation analysis showed that 29 bacterial species were significantly associated with PGE2 levels in the M and T groups. Vagococcus, Lawsonia, Christensenella, unidentified Erysipelotrichaceae, unidentified Coriobacteriaceae, and five other bacterial groups are unique in the PGE2 metabolic pathway regulated by arecoline.Discussion: Arecoline has lipid-lowering effects and may exert therapeutic effects in NAFLD through intestinal metabolites and intestinal flora, as well as through the Butyricicoccus/Christensenella/Coriobacteriaceae-COX2/PGE2 pathway. Thus, arecoline may represent a potential drug or target for NAFLD treatment.
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Affiliation(s)
- Lingping Zhu
- Department of General Practice, Hengyang Medical School, The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, China
- Hunan Provincial Clinical Research Center for Metabolic Associated Fatty Liver Disease, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Duo Li
- Department of General Practice, Hengyang Medical School, The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, China
| | - Xuefeng Yang
- Department of General Practice, Hengyang Medical School, The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, China
- Hunan Provincial Clinical Research Center for Metabolic Associated Fatty Liver Disease, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- *Correspondence: Xuefeng Yang,
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Small Intestinal Bacterial Overgrowth and Non-Alcoholic Fatty Liver Disease: What Do We Know in 2023? Nutrients 2023; 15:nu15061323. [PMID: 36986052 PMCID: PMC10052062 DOI: 10.3390/nu15061323] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 02/27/2023] [Accepted: 03/03/2023] [Indexed: 03/11/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with the pathological accumulation of lipids inside hepatocytes. Untreated NAFL can progress to non-alcoholic hepatitis (NASH), followed by fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The common denominator of the above-mentioned metabolic disorders seems to be insulin resistance, which occurs in NAFLD patients. Obesity is the greatest risk factor for lipid accumulation inside hepatocytes, but a part of the NAFLD patient population has a normal body weight according to the BMI index. Obese people with or without NAFLD have a higher incidence of small intestinal bacterial overgrowth (SIBO), and those suffering from NAFLD show increased intestinal permeability, including a more frequent presence of bacterial overgrowth in the small intestine (SIBO). The health consequences of SIBO are primarily malabsorption disorders (vitamin B12, iron, choline, fats, carbohydrates and proteins) and bile salt deconjugation. Undetected and untreated SIBO may lead to nutrient and/or energy malnutrition, thus directly impairing liver function (e.g., folic acid and choline deficiency). However, whether SIBO contributes to liver dysfunction, decreased intestinal barrier integrity, increased inflammation, endotoxemia and bacterial translocation is not yet clear. In this review, we focus on gut–liver axis and discuss critical points, novel insights and the role of nutrition, lifestyle, pre- and probiotics, medication and supplements in the therapy and prevention of both SIBO and NAFLD.
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Yahoo N, Dudek M, Knolle P, Heikenwälder M. Role of immune responses for development of NAFLD-associated liver cancer and prospects for therapeutic modulation. J Hepatol 2023:S0168-8278(23)00165-4. [PMID: 36893854 DOI: 10.1016/j.jhep.2023.02.033] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 02/04/2023] [Accepted: 02/14/2023] [Indexed: 03/11/2023]
Abstract
The liver is the central metabolic organ of the body regulating energy and lipid metabolism and at the same time has potent immunological functions. Overwhelming the metabolic capacity of the liver by obesity and sedentary lifestyle leads to hepatic lipid accumulation, chronic necro-inflammation, enhanced mitochondrial/ER-stress and development of non-alcoholic fatty liver disease (NAFLD), with its pathologic form nonalcoholic steatohepatitis (NASH). Based on knowledge on pathophysiological mechanisms, specifically targeting metabolic diseases to prevent or slow down progression of NAFLD to liver cancer will become possible. Genetic/environmental factors contribute to development of NASH and liver cancer progression. The complex pathophysiology of NAFLD-NASH is reflected by environmental factors, particularly the gut microbiome and its metabolic products. NAFLD-associated HCC occurs in most of the cases in the context of a chronically inflamed liver and cirrhosis. Recognition of environmental alarmins or metabolites derived from the gut microbiota and the metabolically injured liver create a strong inflammatory milieu supported by innate and adaptive immunity. Several recent studies indicate that the chronic hepatic microenvironment of steatosis induces auto-aggressive CD8+CXCR6+PD1+ T cells secreting TNF and upregulating FasL to eliminate parenchymal and non-parenchymal cells in an antigen independent manner. This promotes chronic liver damage and a pro-tumorigenic environment. CD8+CXCR6+PD1+ T cells possess an exhausted, hyperactivated, resident phenotype and trigger NASH to HCC transition, and might be responsible for a less efficient treatment response to immune-check-point inhibitors - in particular atezolizumab/bevacizumab. Here, we provide an overview of NASH-related inflammation/pathogenesis focusing on new discoveries on the role of T cells in NASH-immunopathology and therapy response. This review discusses preventive measures to halt disease progression to liver cancer and therapeutic strategies to manage NASH-HCC patients.
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Affiliation(s)
- Neda Yahoo
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
| | - Michael Dudek
- Institute of Molecular Immunology and Experimental Oncology, School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Percy Knolle
- Institute of Molecular Immunology and Experimental Oncology, School of Medicine, Technical University of Munich (TUM), Munich, Germany.
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany; Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany; The M3 Research Institute, Karl Eberhards Universitaet Tübingen, Medizinische Fakultät, Otfried-Müller-Straße 37, 72076 Tübingen.
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Ehtezazi T, Rahman K, Davies R, Leach AG. The Pathological Effects of Circulating Hydrophobic Bile Acids in Alzheimer's Disease. J Alzheimers Dis Rep 2023; 7:173-211. [PMID: 36994114 PMCID: PMC10041467 DOI: 10.3233/adr-220071] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/19/2023] Open
Abstract
Recent clinical studies have revealed that the serum levels of toxic hydrophobic bile acids (deoxy cholic acid, lithocholic acid [LCA], and glycoursodeoxycholic acid) are significantly higher in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) when compared to control subjects. The elevated serum bile acids may be the result of hepatic peroxisomal dysfunction. Circulating hydrophobic bile acids are able to disrupt the blood-brain barrier and promote the formation of amyloid-β plaques through enhancing the oxidation of docosahexaenoic acid. Hydrophobic bile acid may find their ways into the neurons via the apical sodium-dependent bile acid transporter. It has been shown that hydrophobic bile acids impose their pathological effects by activating farnesoid X receptor and suppressing bile acid synthesis in the brain, blocking NMDA receptors, lowering brain oxysterol levels, and interfering with 17β-estradiol actions such as LCA by binding to E2 receptors (molecular modelling data exclusive to this paper). Hydrophobic bile acids may interfere with the sonic hedgehog signaling through alteration of cell membrane rafts and reducing brain 24(S)-hydroxycholesterol. This article will 1) analyze the pathological roles of circulating hydrophobic bile acids in the brain, 2) propose therapeutic approaches, and 3) conclude that consideration be given to reducing/monitoring toxic bile acid levels in patients with AD or aMCI, prior/in combination with other treatments.
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Affiliation(s)
- Touraj Ehtezazi
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
| | - Khalid Rahman
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
| | - Rhys Davies
- The Walton Centre, NHS Foundation Trust, Liverpool, UK
| | - Andrew G Leach
- School of Pharmacy, University of Manchester, Manchester, UK
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Ji J, Wu L, Wei J, Wu J, Guo C. The Gut Microbiome and Ferroptosis in MAFLD. J Clin Transl Hepatol 2023; 11:174-187. [PMID: 36406312 PMCID: PMC9647110 DOI: 10.14218/jcth.2022.00136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/22/2022] [Accepted: 06/12/2022] [Indexed: 12/04/2022] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a new disease definition, and is proposed to replace the previous name, nonalcoholic fatty liver disease (NAFLD). Globally, MAFLD/NAFLD is the most common liver disease, with an incidence rate ranging from 6% to 35% in adult populations. The pathogenesis of MAFLD/NAFLD is closely related to insulin resistance (IR), and the genetic susceptibility to acquired metabolic stress-associated liver injury. Similarly, the gut microbiota in MAFLD/NAFLD is being revaluated by scientists, as the gut and liver influence each other via the gut-liver axis. Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation. Emerging evidence suggests that ferroptosis has a key role in the pathological progression of MAFLD/NAFLD, and inhibition of ferroptosis may become a novel therapeutic strategy for the treatment of NAFLD. This review focuses on the main mechanisms behind the promotion of MAFLD/NAFLD occurrence and development by the intestinal microbiota and ferroptosis. It outlines new strategies to target the intestinal microbiota and ferroptosis to facilitate future MAFLD/NAFLD therapies.
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Affiliation(s)
- Jie Ji
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University, Shanghai, China
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Liwei Wu
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University, Shanghai, China
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jue Wei
- Department of Gastroenterology Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jianye Wu
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University, Shanghai, China
- Correspondence to: Chuanyong Guo, Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, NO. 301, Middle Yanchang Road, Jing’an District, Shanghai 200072, China. ORCID: https://orcid.org/0000-0002-6527-4673. E-mail: ; Jianye Wu: Department of Gastroenterology, Putuo People’s Hospital, NO. 1291, Jiangning road, Putuo, Shanghai 200060, China. ORCID: https://orcid.org/0000-0003-2675-4241. E-mail:
| | - Chuanyong Guo
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University, Shanghai, China
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Correspondence to: Chuanyong Guo, Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, NO. 301, Middle Yanchang Road, Jing’an District, Shanghai 200072, China. ORCID: https://orcid.org/0000-0002-6527-4673. E-mail: ; Jianye Wu: Department of Gastroenterology, Putuo People’s Hospital, NO. 1291, Jiangning road, Putuo, Shanghai 200060, China. ORCID: https://orcid.org/0000-0003-2675-4241. E-mail:
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Kanezawa S, Moriyama M, Kanda T, Fukushima A, Masuzaki R, Sasaki-Tanaka R, Tsunemi A, Ueno T, Fukuda N, Kogure H. Gut-Microbiota Dysbiosis in Stroke-Prone Spontaneously Hypertensive Rats with Diet-Induced Steatohepatitis. Int J Mol Sci 2023; 24:ijms24054603. [PMID: 36902037 PMCID: PMC10002594 DOI: 10.3390/ijms24054603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 02/14/2023] [Accepted: 02/23/2023] [Indexed: 03/03/2023] Open
Abstract
Metabolic-dysfunction-associated fatty-liver disease (MAFLD) is the principal worldwide cause of liver disease. Individuals with nonalcoholic steatohepatitis (NASH) have a higher prevalence of small-intestinal bacterial overgrowth (SIBO). We examined gut-microbiota isolated from 12-week-old stroke-prone spontaneously hypertensive-5 rats (SHRSP5) fed on a normal diet (ND) or a high-fat- and high-cholesterol-containing diet (HFCD) and clarified the differences between their gut-microbiota. We observed that the Firmicute/Bacteroidetes (F/B) ratio in both the small intestines and the feces of the SHRSP5 rats fed HFCD increased compared to that of the SHRSP5 rats fed ND. Notably, the quantities of the 16S rRNA genes in small intestines of the SHRSP5 rats fed HFCD were significantly lower than those of the SHRSP5 rats fed ND. As in SIBO syndrome, the SHRSP5 rats fed HFCD presented with diarrhea and body-weight loss with abnormal types of bacteria in the small intestine, although the number of bacteria in the small intestine did not increase. The microbiota of the feces in the SHRSP5 rats fed HFCD was different from those in the SHRP5 rats fed ND. In conclusion, there is an association between MAFLD and gut-microbiota alteration. Gut-microbiota alteration may be a therapeutic target for MAFLD.
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Affiliation(s)
- Shini Kanezawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
- Correspondence: (M.M.); (T.K.); Tel.: +81-3-3972-8111 (M.M. & T.K.)
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
- Correspondence: (M.M.); (T.K.); Tel.: +81-3-3972-8111 (M.M. & T.K.)
| | - Akiko Fukushima
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Ryota Masuzaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Akiko Tsunemi
- Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Takahiro Ueno
- Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Noboru Fukuda
- Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hirofumi Kogure
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
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Kuraji R, Shiba T, Dong TS, Numabe Y, Kapila YL. Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis. World J Gastroenterol 2023; 29:967-996. [PMID: 36844143 PMCID: PMC9950865 DOI: 10.3748/wjg.v29.i6.967] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 11/14/2022] [Accepted: 01/30/2023] [Indexed: 02/10/2023] Open
Abstract
A growing body of evidence from multiple areas proposes that periodontal disease, accompanied by oral inflammation and pathological changes in the microbiome, induces gut dysbiosis and is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A subgroup of NAFLD patients have a severely progressive form, namely nonalcoholic steatohepatitis (NASH), which is characterized by histological findings that include inflammatory cell infiltration and fibrosis. NASH has a high risk of further progression to cirrhosis and hepatocellular carcinoma. The oral microbiota may serve as an endogenous reservoir for gut microbiota, and transport of oral bacteria through the gastro-intestinal tract can set up a gut microbiome dysbiosis. Gut dysbiosis increases the production of potential hepatotoxins, including lipopolysaccharide, ethanol, and other volatile organic compounds such as acetone, phenol and cyclopentane. Moreover, gut dysbiosis increases intestinal permeability by disrupting tight junctions in the intestinal wall, leading to enhanced translocation of these hepatotoxins and enteric bacteria into the liver through the portal circulation. In particular, many animal studies support that oral administration of Porphyromonas gingivalis, a typical periodontopathic bacterium, induces disturbances in glycolipid metabolism and inflammation in the liver with gut dysbiosis. NAFLD, also known as the hepatic phenotype of metabolic syndrome, is strongly associated with metabolic complications, such as obesity and diabetes. Periodontal disease also has a bidirectional relationship with metabolic syndrome, and both diseases may induce oral and gut microbiome dysbiosis with insulin resistance and systemic chronic inflammation cooperatively. In this review, we will describe the link between periodontal disease and NAFLD with a focus on basic, epidemiological, and clinical studies, and discuss potential mechanisms linking the two diseases and possible therapeutic approaches focused on the microbiome. In conclusion, it is presumed that the pathogenesis of NAFLD involves a complex crosstalk between periodontal disease, gut microbiota, and metabolic syndrome. Thus, the conventional periodontal treatment and novel microbiome-targeted therapies that include probiotics, prebiotics and bacteriocins would hold great promise for preventing the onset and progression of NAFLD and subsequent complications in patients with periodontal disease.
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Affiliation(s)
- Ryutaro Kuraji
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo 102-0071, Japan
- Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94143, United States
| | - Takahiko Shiba
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, United States
- Department of Periodontology, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
| | - Tien S Dong
- The Vatche and Tamar Manoukian Division of Digestive Diseases, University of California Los Angeles, Department of Medicine, University of California David Geffen School of Medicine, Los Angeles, CA 90095, United States
| | - Yukihiro Numabe
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo 102-8159, Japan
| | - Yvonne L Kapila
- Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94143, United States
- Sections of Biosystems and Function and Periodontics, Professor and Associate Dean of Research, Felix and Mildred Yip Endowed Chair in Dentistry, University of California Los Angeles, Los Angeles, CA 90095, United States
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Understanding NAFLD: From Case Identification to Interventions, Outcomes, and Future Perspectives. Nutrients 2023; 15:nu15030687. [PMID: 36771394 PMCID: PMC9921401 DOI: 10.3390/nu15030687] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 01/25/2023] [Accepted: 01/28/2023] [Indexed: 02/01/2023] Open
Abstract
While non-alcoholic fatty liver disease (NAFLD) is a prevalent and frequent cause of liver-related morbidity and mortality, it is also strongly associated with cardiovascular disease-related morbidity and mortality, likely driven by its associations with insulin resistance and other manifestations of metabolic dysregulation. However, few satisfactory pharmacological treatments are available for NAFLD due in part to its complex pathophysiology, and challenges remain in stratifying individual patient's risk for liver and cardiovascular disease related outcomes. In this review, we describe the development and progression of NAFLD, including its pathophysiology and outcomes. We also describe different tools for identifying patients with NAFLD who are most at risk of liver-related and cardiovascular-related complications, as well as current and emerging treatment options, and future directions for research.
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De Munck TJI, Verhaegh P, Spooren C, Mujagic Z, Wienhold T, Jonkers D, Masclee AAM, Koek GH, Verbeek J. Colonic permeability is increased in non-cirrhotic patients with nonalcoholic fatty liver disease. Dig Liver Dis 2023; 55:614-621. [PMID: 36710170 DOI: 10.1016/j.dld.2022.12.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 11/21/2022] [Accepted: 12/26/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND AND AIM Intestinal permeability (IP) plays an important role in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). We assessed site-specific (gastroduodenum, small intestine, colon and whole gut) IP in NAFLD patients and healthy controls (HC) and its association with the degree of hepatic steatosis, hepatic fibrosis and dietary composition in these NAFLD patients. METHODS In vivo site-specific IP was analysed with a validated multi-sugar test in NAFLD patients and HC. Furthermore, in NAFLD patients, hepatic steatosis (chemical shift MRI), hepatic fibrosis (transient elastography) and dietary composition (food frequency questionnaire) were assessed. RESULTS Fifty-two NAFLD patients and forty-six HC were included in this study. Small intestinal (P <0.001), colonic (P = 0.004) and whole gut (P <0.001) permeability were increased in NAFLD patients compared to HC. Furthermore, colonic permeability (P = 0.029) was significantly higher in NAFLD patients with clinically significant fibrosis compared to those without. Colonic permeability remained positively associated with the presence of clinically significant fibrosis (P = 0.017) after adjustment for age, sex and BMI. CONCLUSION Colonic permeability is increased in at least a subset of NAFLD patients compared to HC and is independently associated with clinically significant NAFLD fibrosis.
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Affiliation(s)
- Toon J I De Munck
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands; School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands.
| | - Pauline Verhaegh
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands; School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Corinne Spooren
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands; School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Zlatan Mujagic
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands; School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Tobias Wienhold
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Daisy Jonkers
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands; School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Ad A M Masclee
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands; School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Ger H Koek
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands; School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Jef Verbeek
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands; School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands; Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium
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47
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Santacroce G, Gentile A, Soriano S, Novelli A, Lenti MV, Di Sabatino A. Glutathione: Pharmacological aspects and implications for clinical use in non-alcoholic fatty liver disease. Front Med (Lausanne) 2023; 10:1124275. [PMID: 37035339 PMCID: PMC10075255 DOI: 10.3389/fmed.2023.1124275] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/27/2023] [Indexed: 04/11/2023] Open
Abstract
Glutathione is a tripeptide synthesized at cytosolic level, that exists in cells in a reduced form (thiol-reduced-GSH-) and in an oxidized form (disulfide-oxidized). The antioxidant function of GSH has led to speculation about its therapeutic role in numerous chronic diseases characterized by altered redox balance and reduced GSH levels, including, for instance, neurodegenerative disorders, cancer, and chronic liver diseases. Among these latter, non-alcoholic fatty liver disease (NAFLD), characterized by lipid accumulation in hepatocytes, in the absence of alcohol abuse or other steatogenic factors, is one of the most prevalent. The umbrella term NAFLD includes the pure liver fat accumulation, the so-called hepatic steatosis or non-alcoholic fatty liver, and the progressive form with inflammation, also known as non-alcoholic steatohepatitis, which is related to the increase in oxidative stress and reactive oxygen species, eventually leading to liver fibrosis. Although the pathogenetic role of oxidative stress in these diseases is well established, there is still limited evidence on the therapeutic role of GSH in such conditions. Hence, the aim of this review is to depict the current molecular and pharmacological knowledge on glutathione, focusing on the available studies related to its therapeutic activity in NAFLD.
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Affiliation(s)
- Giovanni Santacroce
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy
- First Department of Internal Medicine, San Matteo Hospital Foundation, Pavia, Italy
| | - Antonella Gentile
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy
- First Department of Internal Medicine, San Matteo Hospital Foundation, Pavia, Italy
| | - Simone Soriano
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy
- First Department of Internal Medicine, San Matteo Hospital Foundation, Pavia, Italy
| | - Andrea Novelli
- Department of Health Sciences, Clinical Pharmacology and Oncology Section, Università Degli Studi di Firenze, Firenze, Italy
| | - Marco Vincenzo Lenti
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy
- First Department of Internal Medicine, San Matteo Hospital Foundation, Pavia, Italy
| | - Antonio Di Sabatino
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy
- First Department of Internal Medicine, San Matteo Hospital Foundation, Pavia, Italy
- *Correspondence: Antonio Di Sabatino,
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48
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Pipitone RM, Ciccioli C, Infantino G, La Mantia C, Parisi S, Tulone A, Pennisi G, Grimaudo S, Petta S. MAFLD: a multisystem disease. Ther Adv Endocrinol Metab 2023; 14:20420188221145549. [PMID: 36726391 PMCID: PMC9885036 DOI: 10.1177/20420188221145549] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/26/2022] [Indexed: 01/29/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), affecting about 25% of general population and more than 50% of dysmetabolic patients, is an emerging cause of chronic liver disease and its complications. Recently, an international consensus of experts proposed to rename this disease as 'Metabolic dysfunction-Associated Fatty Liver Disease' (MAFLD) to focus on the bidirectional interplay between fatty liver and metabolic alterations and to stress the need of assessing fatty liver independently from alcohol consumption and other coexisting causes of liver disease. The peculiarity of NAFLD/MAFLD lies in the presence of a higher risk of not only - as expected - liver-related events but also of extrahepatic events, mostly cardiovascular and cancers. Available evidence suggests that these associations are not only the expression of sharing the same risk factors but shed light about the ability of NAFLD/MAFLD and particularly of its progressive form - nonalcoholic/metabolic dysfunction-associated steatohepatitis - to act as an independent risk factor via promotion of atherogenic dyslipidemia and a proinflammatory, profibrogenic, and procoagulant systemic environment. The present review summarizes available epidemiological and clinical evidence supporting the concept of NAFLD/MAFLD as a multisystemic disease, and highlights potential explanatory mechanisms underlying the association between NAFLD/MAFLD and extrahepatic disorders.
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Affiliation(s)
- Rosaria Maria Pipitone
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
| | - Carlo Ciccioli
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
| | - Giuseppe Infantino
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
| | - Claudia La Mantia
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
| | - Stefanie Parisi
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
| | - Adele Tulone
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
| | - Grazia Pennisi
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
| | - Stefania Grimaudo
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
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Bamba S, Imai T, Sasaki M, Ohno M, Yoshida S, Nishida A, Takahashi K, Inatomi O, Andoh A. Altered gut microbiota in patients with small intestinal bacterial overgrowth. J Gastroenterol Hepatol 2023; 38:61-69. [PMID: 36180941 DOI: 10.1111/jgh.16013] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 06/06/2022] [Accepted: 09/26/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIM Small intestinal bacterial overgrowth (SIBO) is diagnosed by using quantitative culture of duodenal aspirates and/or a hydrogen breath test. However, few studies have analyzed bacterial microbiota in Japanese patients with SIBO. METHODS Twenty-four patients with any abdominal symptoms and suspected SIBO were enrolled. Quantitative culture of duodenal aspirates and a glucose hydrogen breath test were performed on the same day. SIBO was diagnosed based on a bacterial count ≥ 103 CFU/mL or a rise in the hydrogen breath level of ≥ 20 ppm. The composition of the duodenal microbiota was analyzed by 16S rRNA gene sequencing. RESULTS Small intestinal bacterial overgrowth was diagnosed in 17 of the 24 patients (71%). The positive rates for the hydrogen breath test and quantitative culture of duodenal aspirates were 50% and 62%, respectively. Patients with SIBO showed significantly reduced α-diversity compared with non-SIBO patients, and analysis of β-diversity revealed significantly different distributions between SIBO and non-SIBO patients. In addition, the intestinal microbiome in SIBO patients was characterized by increased relative abundance of Streptococcus and decreased relative abundance of Bacteroides compared with non-SIBO patients. CONCLUSIONS Duodenal dysbiosis was identified in patients with SIBO and may play a role in the pathophysiology of SIBO.
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Affiliation(s)
- Shigeki Bamba
- Division of Digestive Endoscopy, Shiga University of Medical Science, Otsu, Japan
| | - Takayuki Imai
- Division of Digestive Endoscopy, Shiga University of Medical Science, Otsu, Japan
| | - Masaya Sasaki
- Division of Clinical Nutrition, Shiga University of Medical Science, Otsu, Japan
| | - Masashi Ohno
- Division of Gastroenterology, Shiga University of Medical Science, Otsu, Japan
| | - Shinya Yoshida
- Division of Gastroenterology, Shiga University of Medical Science, Otsu, Japan
| | - Atsushi Nishida
- Division of Gastroenterology, Shiga University of Medical Science, Otsu, Japan
| | - Kenichiro Takahashi
- Division of Gastroenterology, Shiga University of Medical Science, Otsu, Japan
| | - Osamu Inatomi
- Division of Gastroenterology, Shiga University of Medical Science, Otsu, Japan
| | - Akira Andoh
- Division of Gastroenterology, Shiga University of Medical Science, Otsu, Japan
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50
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Sroka N, Rydzewska-Rosołowska A, Kakareko K, Rosołowski M, Głowińska I, Hryszko T. Show Me What You Have Inside-The Complex Interplay between SIBO and Multiple Medical Conditions-A Systematic Review. Nutrients 2022; 15:nu15010090. [PMID: 36615748 PMCID: PMC9824151 DOI: 10.3390/nu15010090] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/18/2022] [Accepted: 12/20/2022] [Indexed: 12/28/2022] Open
Abstract
The microbiota, as a complex of microorganisms in a particular ecosystem, is part of the wider term-microbiome, which is defined as the set of all genetic content in the microbial community. Imbalanced gut microbiota has a great impact on the homeostasis of the organism. Dysbiosis, as a disturbance in bacterial balance, might trigger or exacerbate the course of different pathologies. Small intestinal bacterial overgrowth (SIBO) is a disorder characterized by differences in quantity, quality, and location of the small intestine microbiota. SIBO underlies symptoms associated with functional gastrointestinal disorders (FGD) as well as may alter the presentation of chronic diseases such as heart failure, diabetes, etc. In recent years there has been growing interest in the influence of SIBO and its impact on the whole human body as well as individual systems. Therefore, we aimed to investigate the co-existence of SIBO with different medical conditions. The PubMed database was searched up to July 2022 and we found 580 original studies; inclusion and exclusion criteria let us identify 112 eligible articles, which are quoted in this paper. The present SIBO diagnostic methods could be divided into two groups-invasive, the gold standard-small intestine aspirate culture, and non-invasive, breath tests (BT). Over the years scientists have explored SIBO and its associations with other diseases. Its role has been confirmed not only in gastroenterology but also in cardiology, endocrinology, neurology, rheumatology, and nephrology. Antibiotic therapy could reduce SIBO occurrence resulting not only in the relief of FGD symptoms but also manifestations of comorbid diseases. Although more research is needed, the link between SIBO and other diseases is an important pathway for scientists to follow.
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Affiliation(s)
- Natalia Sroka
- 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Białystok, 15-276 Białystok, Poland
- Correspondence:
| | - Alicja Rydzewska-Rosołowska
- 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Białystok, 15-276 Białystok, Poland
| | - Katarzyna Kakareko
- 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Białystok, 15-276 Białystok, Poland
| | - Mariusz Rosołowski
- Department of Internal Medicine and Hypertension, Medical University of Białystok, 15-540 Białystok, Poland
| | - Irena Głowińska
- 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Białystok, 15-276 Białystok, Poland
| | - Tomasz Hryszko
- 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Białystok, 15-276 Białystok, Poland
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