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Kuchay MS, Choudhary NS, Ramos-Molina B. Pathophysiological underpinnings of metabolic dysfunction-associated steatotic liver disease. Am J Physiol Cell Physiol 2025; 328:C1637-C1666. [PMID: 40244183 DOI: 10.1152/ajpcell.00951.2024] [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: 01/22/2025] [Revised: 01/31/2025] [Accepted: 03/31/2025] [Indexed: 04/18/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as the leading cause of chronic liver disease worldwide, reflecting the global epidemics of obesity, metabolic syndrome, and type 2 diabetes. Beyond its strong association with excess adiposity, MASLD encompasses a heterogeneous population that includes individuals with normal body weight ("lean MASLD") highlighting the complexity of its pathogenesis. This disease results from a complex interplay between genetic susceptibility, epigenetic modifications, and environmental factors, which converge to disrupt metabolic homeostasis. Adipose tissue dysfunction and insulin resistance trigger an overflow of lipids to the liver, leading to mitochondrial dysfunction, oxidative stress, and hepatocellular injury. These processes promote hepatic inflammation and fibrogenesis, driven by cross talk among hepatocytes, immune cells, and hepatic stellate cells, with key contributions from gut-liver axis perturbations. Recent advances have unraveled pivotal molecular pathways, such as transforming growth factor-β signaling, Notch-induced osteopontin, and sphingosine kinase 1-mediated responses, that orchestrate fibrogenic activation. Understanding these interconnected mechanisms is crucial for developing targeted therapies. This review integrates current knowledge on the pathophysiology of MASLD, emphasizing emerging concepts such as lean metabolic dysfunction-associated steatohepatitis (MASH), epigenetic alterations, hepatic extracellular vesicles, and the relevance of extrahepatic signals. It also discusses novel therapeutic strategies under investigation, aiming to provide a comprehensive and structured overview of the evolving MASLD landscape for both basic scientists and clinicians.
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Affiliation(s)
| | - Narendra Singh Choudhary
- Institute of Digestive and Hepatobiliary Sciences, Medanta-The Medicity Hospital, Gurugram, India
| | - Bruno Ramos-Molina
- Group of Obesity, Diabetes & Metabolism, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
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Koller AM, Săsăran MO, Mărginean CO. Small Intestinal Bacterial Overgrowth and Pediatric Obesity-A Systematic Review. Nutrients 2025; 17:1499. [PMID: 40362809 PMCID: PMC12073544 DOI: 10.3390/nu17091499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/26/2025] [Accepted: 04/26/2025] [Indexed: 05/15/2025] Open
Abstract
Background/Objectives: Childhood obesity is a growing global concern linked to metabolic disorders such as nonalcoholic fatty liver disease (NAFLD). Small intestinal bacterial overgrowth (SIBO) may exacerbate these conditions by promoting systemic inflammation and metabolic dysfunction. This review evaluates the prevalence of SIBO in obese children, its association with inflammatory and metabolic markers, and the efficacy of diagnostic and therapeutic strategies. Methods: A systematic search of PubMed, Scopus, and Web of Science (2010-present) was conducted using Boolean operators: ('small intestinal bacterial overgrowth' OR 'SIBO') AND 'prevalence' AND ('low-grade inflammatory markers' OR 'metabolic status') AND 'gut microbiome' AND 'dysbiosis' AND 'obese children'. Results: The data show that SIBO is frequently observed in obese pediatric populations and is associated with gut dysbiosis, impaired nutrient absorption, and reduced production of short-chain fatty acids. These changes contribute to increased intestinal permeability, endotoxemia, and chronic low-grade inflammation. Several microbial taxa have been proposed as biomarkers and therapeutic targets. Diagnostic inconsistencies persist, but treatments such as probiotics, prebiotics, dietary interventions, and selective antibiotics show potential, pending further validation. Conclusions: Early identification and treatment of SIBO with tailored strategies may help reduce metabolic complications and improve outcomes in children with obesity.
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Affiliation(s)
- Ana Maria Koller
- Doctoral School, “George Emil Palade” University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Gheorghe Marinescu Street No 38, 540136 Targu Mures, Romania;
| | - Maria Oana Săsăran
- Department of Pediatrics 3, “George Emil Palade” University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Gheorghe Marinescu Street No 38, 540136 Targu Mures, Romania
| | - Cristina Oana Mărginean
- Department of Pediatrics 1, “George Emil Palade” University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Gheorghe Marinescu Street No 38, 540136 Targu Mures, Romania;
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Velimirovic M, Osterman V, Prislan A, Pintar T. Small Intestinal Bacterial Overgrowth in Children with Short Bowel Syndrome: Risk Factors, Clinical Presentation and Management-A Single-Center Experience. CHILDREN (BASEL, SWITZERLAND) 2025; 12:351. [PMID: 40150633 PMCID: PMC11941224 DOI: 10.3390/children12030351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 03/05/2025] [Accepted: 03/10/2025] [Indexed: 03/29/2025]
Abstract
Background: Children with short bowel syndrome (SBS) have abnormal intestinal anatomy, secretion, or motility, which can lead to small intestinal bacterial overgrowth (SIBO). In this paper, we describe our experience with SIBO in children with SBS, focusing on potential risk factors, clinical presentation, and antibiotic treatment. Methods: A single-center retrospective descriptive cohort study of all episodes of clinically suspected SIBO in 16 children with SBS on home parenteral nutrition (HPN) between January 2018 and December 2022 was performed. Results: The mean small bowel remnant was 47 cm (SD = 31.5), with an absent ileocecal valve in 61.5% (8/13). Five children (31.2%) had at least 1 episode of clinically suspected SIBO, with a total of 25 episodes. The most common clinical presentation was diarrhea (76%), followed by meteorism (56%), loss of appetite (48%), flatulence (48%), weight loss (36%), abdominal pain (25%), and vomiting (12%). Fifty-six percent (16/25) of SIBO episodes were treated with one type of antibiotic, 36% (9/25) with two types, and 8% (2/25) with three types. Symptom resolution was achieved in 56% (14/25) of SIBO episodes after one course of antibiotic therapy. Two children (12.5%) had refractory and recurrent SIBO episodes treated with cyclic antibiotic regimens. Conclusions: SIBO can affect the ability of children with SBS to successfully wean off HPN. Diagnostic tests have innate challenges, and early clinical suspicion is paramount. Antibiotic therapy should be individualized considering the child's age, gastrointestinal anatomy, and the risk of SIBO recurrence.
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Affiliation(s)
- Maja Velimirovic
- Department of Pediatric Surgery, Division of Surgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (M.V.); (V.O.); (A.P.)
| | - Veronika Osterman
- Department of Pediatric Surgery, Division of Surgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (M.V.); (V.O.); (A.P.)
- Services for Disease Control and Prevention, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
| | - Ana Prislan
- Department of Pediatric Surgery, Division of Surgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (M.V.); (V.O.); (A.P.)
| | - Tadeja Pintar
- Department of Abdominal Surgery, Division of Surgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
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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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Wang Z, Tan W, Huang J, Li Q, Wang J, Su H, Guo C, Liu H. Small intestinal bacterial overgrowth and metabolic dysfunction-associated steatotic liver disease. Front Nutr 2024; 11:1502151. [PMID: 39742106 PMCID: PMC11685094 DOI: 10.3389/fnut.2024.1502151] [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: 09/26/2024] [Accepted: 12/03/2024] [Indexed: 01/03/2025] Open
Abstract
Small intestinal bacterial overgrowth (SIBO), characterized by alterations in both the type and quantity of bacteria in the small intestine, leads to impaired intestinal digestion and absorption that can cause a range of clinical symptoms. Recent studies have identified significant changes in the composition of the small intestinal microbiota and metabolomic profiles of patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study systematically reviewed and synthesized the available data to explore the association between SIBO and MASLD. Comprehensive literature searches of the Embase, PubMed, Web of Science, Ovid, and Cochrane databases were conducted. Article quality screening was performed using the Newcastle-Ottawa Quality Assessment Scale. Cross-sectional, cohort, and case-control studies were included. A total of 7,200 articles were initially screened, of which 14 were ultimately included for analysis. Individuals with SIBO in both the MASLD and non-MASLD groups were extracted and a chi-square test was performed to calculate the odds ratio (OR) and 95% confidence interval (CI). The I2 index was used to measure heterogeneity. For heterogeneity >50%, a random effects model was used. There was a clear association between SIBO and MASLD (OR = 3.09; 95% CI 2.09-4.59, I 2 = 66%, p < 0.0001). Subgroup analyses by MASLD stage showed that the probability of SIBO positivity increased with MASLD lesion severity. After stratifying by the diagnostic methods for SIBO and MASLD, the meta-analysis results suggest a reduction in inter-group heterogeneity. For the MASLD subgroup diagnosed via liver biopsy, the OR was 4.89. A subgroup analysis of four studies that included intestinal permeability testing revealed an OR of 3.86 (95% CI: 1.80-8.28, I 2 = 9%, p = 0.0005). A meta-regression analyses revealed that both race and regional development level significantly influenced the relationship between SIBO and MASLD (p = 0.010, p = 0.047). In conclusion, this meta-analyses provides strong evidence that SIBO may contribute to the development and progression of MASLD. The strongest associations were observed between lactulose breath testing, gut microbiota culture, liver biopsy diagnosis of MASLD, and SIBO detected through intestinal permeability testing. The primary sources of heterogeneity are race and developed regions. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=427040.
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Affiliation(s)
- Ziteng Wang
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wentao Tan
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Jiali Huang
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Qian Li
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Jing Wang
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Hui Su
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Chunmei Guo
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Hong Liu
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
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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] [Download PDF] [Figures] [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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Rotaru M, Singeap AM, Ciobica A, Huiban L, Stanciu C, Romila L, Burlui V, Mavroudis I, Trifan A. Oral Health and "Modern" Digestive Diseases: Pathophysiologic and Etiologic Factors. Biomedicines 2024; 12:1854. [PMID: 39200318 PMCID: PMC11351600 DOI: 10.3390/biomedicines12081854] [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: 06/03/2024] [Revised: 08/02/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
In the contemporary era of medicine, exploring the complexity of the human body and its intricate interactions has become a central concern for health researchers. The main purpose of this article is to summarize the current understanding of relevant pathophysiological factors such as chronic inflammation, dysbiosis (microbial imbalance), and metabolic disorders, as well as etiological factors including dietary habits, lifestyle choices, obesity, metabolic syndrome, and genetic predispositions, as well as to emphasize potential avenues for upcoming studies and their medical significance. Additionally, this article aims to assess the potential impact of integrated treatment approaches on patient outcomes, emphasizing the need for interdisciplinary collaboration between gastroenterologists, dentists, and other healthcare professionals to develop comprehensive care plans that address both oral and digestive health issues simultaneously. Among the branches with a significant impact on general well-being are oral cavity health and digestive diseases, which have been the subject of intensive research in recent decades. In this context, analysis of the current state of knowledge on oral cavity disorders in relation to "modern" digestive diseases such as non-alcoholic fatty liver disease (NAFLD), small intestinal bacterial overgrowth (SIBO), inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS) becomes essential for a deeper understanding of the interconnections between oral and digestive health. The temporal overlap or succession, whether preceding or following, of oral manifestations and digestive disorders should be taken seriously by both gastroenterologists and dentists to facilitate early diagnosis and explain to patients the correlation between these two body systems. In summary, this article underscores the importance of understanding the intricate relationship between oral and digestive health, advocating for interdisciplinary approaches to improve patient outcomes and guide future research.
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Affiliation(s)
- Mihaela Rotaru
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iasi, Bd. Carol I No. 20A, 700505 Iasi, Romania; (M.R.); (A.C.)
| | - Ana-Maria Singeap
- Department of Gastroenterology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Universitatii Street No. 16, 700115 Iasi, Romania; (L.H.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Emergency County Hospital, Bd. Independentei No. 1, 700111 Iasi, Romania
- CENEMED Platform for Interdisciplinary Research, “Grigore T. Popa” University of Medicine and Pharmacy, Universitatii Street No. 16, 700115 Iasi, Romania
| | - Alin Ciobica
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iasi, Bd. Carol I No. 20A, 700505 Iasi, Romania; (M.R.); (A.C.)
- CENEMED Platform for Interdisciplinary Research, “Grigore T. Popa” University of Medicine and Pharmacy, Universitatii Street No. 16, 700115 Iasi, Romania
- Centre of Biomedical Research, Romanian Academy, Bd. Carol I No. 8, 700506 Iasi, Romania
- Academy of Romanian Scientists, Splaiul Independentei Street No. 54, 050094 Bucharest, Romania
| | - Laura Huiban
- Department of Gastroenterology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Universitatii Street No. 16, 700115 Iasi, Romania; (L.H.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Emergency County Hospital, Bd. Independentei No. 1, 700111 Iasi, Romania
| | - Carol Stanciu
- Department of Gastroenterology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Universitatii Street No. 16, 700115 Iasi, Romania; (L.H.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Emergency County Hospital, Bd. Independentei No. 1, 700111 Iasi, Romania
- Centre of Biomedical Research, Romanian Academy, Bd. Carol I No. 8, 700506 Iasi, Romania
- Academy of Romanian Scientists, Splaiul Independentei Street No. 54, 050094 Bucharest, Romania
| | - Laura Romila
- “Ioan Haulica” Institute, Apollonia University, Pacurari Street No. 11, 700511 Iasi, Romania;
| | - Vasile Burlui
- “Ioan Haulica” Institute, Apollonia University, Pacurari Street No. 11, 700511 Iasi, Romania;
| | - Ioannis Mavroudis
- Department of Neuroscience, Leeds Teaching Hospitals, NHS Trust, Leeds LS2 9JT, UK;
- Third Department of Neurology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Anca Trifan
- Department of Gastroenterology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Universitatii Street No. 16, 700115 Iasi, Romania; (L.H.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Emergency County Hospital, Bd. Independentei No. 1, 700111 Iasi, Romania
- CENEMED Platform for Interdisciplinary Research, “Grigore T. Popa” University of Medicine and Pharmacy, Universitatii Street No. 16, 700115 Iasi, Romania
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Stachowska E, Gudan A, Mańkowska-Wierzbicka D, Liebe R, Krawczyk M. Dysbiosis and nutrition in steatotic liver disease: addressing the unrecognized small intestinal bacterial overgrowth (SIBO) challenge. Intern Emerg Med 2024; 19:1229-1234. [PMID: 38499938 DOI: 10.1007/s11739-024-03533-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 01/09/2024] [Indexed: 03/20/2024]
Abstract
Steatotic liver disease (SLD) is characterized by hepatic fat accumulation, potentially causing major consequences such as liver decompensation. Currently, we lack medications for the treatment of SLD. Therapeutic recommendations for patients include a hypocaloric diet, weight loss, and physical activity. In particular, the Mediterranean diet is frequently recommended. However, this diet might exacerbate intestinal problems in a subset of patients with coexisting small intestinal bacterial overgrowth (SIBO). Previous studies have reported that SIBO is more predominant in patients with fatty liver than in healthy individuals. Both our research and the findings of others have highlighted a challenge related to nutritional therapy in patients with fatty liver who also suffer from SIBO inasmuch as SIBO induces several phenomena (like bloating or abdominal pain) that can adversely affect patients' quality of life and might be exacerbated by the Mediterranean diet. This may lower their adherence to the intervention. As a solution, we suggest introducing additional diagnostics (e.g., breath test) in patients with SLD who complain of SIBO-like symptoms. The next step is to modify their diets temporarily starting with several weeks of "elimination and sanitation." This would involve restricting products rich in fermentable sugars and polyols, while simultaneously treating the bacterial overgrowth. In summary, while the hypocaloric Mediterranean diet is beneficial for patients with fatty liver, those with coexisting SIBO may experience exacerbated symptoms. It is vital to consider additional diagnostics and dietary modifications for this subset of patients to address both liver and intestinal health concurrently.
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Affiliation(s)
- Ewa Stachowska
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University, Broniewskiego 24, 71-460, Szczecin, Poland.
| | - Anna Gudan
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University, Broniewskiego 24, 71-460, Szczecin, Poland
| | - Dorota Mańkowska-Wierzbicka
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Roman Liebe
- Clinic of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University, Magdeburg, Germany
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
- Laboratory of Metabolic Liver Diseases, Center for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
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9
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Román-Sagüillo S, Quiñones Castro R, Juárez-Fernández M, Soluyanova P, Stephens C, Robles-Díaz M, Jorquera Plaza F, González-Gallego J, Martínez-Flórez S, García-Mediavilla MV, Nistal E, Jover R, Sánchez-Campos S. Idiosyncratic Drug-Induced Liver Injury and Amoxicillin-Clavulanate: Spotlight on Gut Microbiota, Fecal Metabolome and Bile Acid Profile in Patients. Int J Mol Sci 2024; 25:6863. [PMID: 38999973 PMCID: PMC11241776 DOI: 10.3390/ijms25136863] [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: 05/20/2024] [Revised: 06/18/2024] [Accepted: 06/20/2024] [Indexed: 07/14/2024] Open
Abstract
Several hepatic disorders are influenced by gut microbiota, but its role in idiosyncratic drug-induced liver injury (iDILI), whose main causative agent is amoxicillin-clavulanate, remains unknown. This pioneering study aims to unravel particular patterns of gut microbiota composition and associated metabolites in iDILI and iDILI patients by amoxicillin-clavulanate (iDILI-AC). Thus, serum and fecal samples from 46 patients were divided into three study groups: healthy controls (n = 10), non-iDILI acute hepatitis (n = 12) and iDILI patients (n = 24). To evaluate the amoxicillin-clavulanate effect, iDILI patients were separated into two subgroups: iDILI non-caused by amoxicillin-clavulanate (iDILI-nonAC) (n = 18) and iDILI-AC patients (n = 6). Gut microbiota composition and fecal metabolome plus serum and fecal bile acid (BA) analyses were performed, along with correlation analyses. iDILI patients presented a particular microbiome profile associated with reduced fecal secondary BAs and fecal metabolites linked to lower inflammation, such as dodecanedioic acid and pyridoxamine. Moreover, certain taxa like Barnesiella, Clostridia UCG-014 and Eubacterium spp. correlated with significant metabolites and BAs. Additionally, comparisons between iDILI-nonAC and iDILI-AC groups unraveled unique features associated with iDILI when caused by amoxicillin-clavulanate. In conclusion, specific gut microbiota profiles in iDILI and iDILI-AC patients were associated with particular metabolic and BA status, which could affect disease onset and progression.
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Affiliation(s)
- Sara Román-Sagüillo
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
| | - Raisa Quiñones Castro
- Servicio de Aparato Digestivo, Complejo Asistencial Universitario de León, 24008 León, Spain
| | - María Juárez-Fernández
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Polina Soluyanova
- Unidad Mixta de Investigación en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain
- Departamento de Bioquímica y Biología Molecular, Universidad de Valencia, 46010 Valencia, Spain
| | - Camilla Stephens
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Unidad de Gestión Clínica de Aparato Digestivo y Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA Plataforma BIONAND, Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Universidad de Málaga, 29010 Málaga, Spain
| | - Mercedes Robles-Díaz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Unidad de Gestión Clínica de Aparato Digestivo y Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA Plataforma BIONAND, Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Universidad de Málaga, 29010 Málaga, Spain
| | - Francisco Jorquera Plaza
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
- Servicio de Aparato Digestivo, Complejo Asistencial Universitario de León, 24008 León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Javier González-Gallego
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Susana Martínez-Flórez
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
| | - María Victoria García-Mediavilla
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Esther Nistal
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Ramiro Jover
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Unidad Mixta de Investigación en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain
- Departamento de Bioquímica y Biología Molecular, Universidad de Valencia, 46010 Valencia, Spain
| | - Sonia Sánchez-Campos
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
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10
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Kitaghenda FK, Hong J, Shao Y, Yao L, Zhu X. The Prevalence of Small Intestinal Bacterial Overgrowth After Roux-en-Y Gastric Bypass (RYGB): a Systematic Review and Meta-analysis. Obes Surg 2024; 34:250-257. [PMID: 38062344 DOI: 10.1007/s11695-023-06974-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/15/2023] [Accepted: 11/26/2023] [Indexed: 01/11/2024]
Abstract
We reviewed the literature on the prevalence of small intestinal bacterial overgrowth (SIBO) after Roux-en-Y gastric bypass (RYGB). Eight studies examining 893 patients were included. The mean age of the patients was 48.11 ± 4.89 years. The mean BMI before surgery and at the time of SIBO diagnosis was 44.57 ± 2.89 kg/m2 and 31.53 ± 2.29 kg/m2, respectively. Moreover, the results showed a 29% and 53% prevalence of SIBO at < 3-year and > 3-year follow-up after RYGB, respectively. Symptoms included abdominal pain, diarrhea, bloating, nausea, vomiting, constipation, soft stool, frequent defecation, flatulence, rumpling, dumping syndrome, and irritable bowel syndrome. SIBO is prevalent after RYGB; digestive symptoms should prompt the consideration of SIBO as a potential etiology. Antibiotic therapy has proven to be therapeutic.
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Affiliation(s)
- Fidele Kakule Kitaghenda
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People's Republic of China
| | - Jian Hong
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People's Republic of China
| | - Yong Shao
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People's Republic of China
| | - Libin Yao
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People's Republic of China.
| | - Xiaocheng Zhu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People's Republic of China.
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11
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Romeo M, Dallio M, Scognamiglio F, Ventriglia L, Cipullo M, Coppola A, Tammaro C, Scafuro G, Iodice P, Federico A. Role of Non-Coding RNAs in Hepatocellular Carcinoma Progression: From Classic to Novel Clinicopathogenetic Implications. Cancers (Basel) 2023; 15:5178. [PMID: 37958352 PMCID: PMC10647270 DOI: 10.3390/cancers15215178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a predominant malignancy with increasing incidences and mortalities worldwide. In Western countries, the progressive affirmation of Non-alcoholic Fatty Liver Disease (NAFLD) as the main chronic liver disorder in which HCC occurrence is appreciable even in non-cirrhotic stages, constitutes a real health emergency. In light of this, a further comprehension of molecular pathways supporting HCC onset and progression represents a current research challenge to achieve more tailored prognostic models and appropriate therapeutic approaches. RNA non-coding transcripts (ncRNAs) are involved in the regulation of several cancer-related processes, including HCC. When dysregulated, these molecules, conventionally classified as "small ncRNAs" (sncRNAs) and "long ncRNAs" (lncRNAs) have been reported to markedly influence HCC-related progression mechanisms. In this review, we describe the main dysregulated ncRNAs and the relative molecular pathways involved in HCC progression, analyzing their implications in certain etiologically related contexts, and their applicability in clinical practice as novel diagnostic, prognostic, and therapeutic tools. Finally, given the growing evidence supporting the immune system response, the oxidative stress-regulated mechanisms, and the gut microbiota composition as relevant emerging elements mutually influencing liver-cancerogenesis processes, we investigate the relationship of ncRNAs with this triad, shedding light on novel pathogenetic frontiers of HCC progression.
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Affiliation(s)
- Mario Romeo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Marcello Dallio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Flavia Scognamiglio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Lorenzo Ventriglia
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Marina Cipullo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Annachiara Coppola
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Chiara Tammaro
- Biochemistry Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (C.T.); (G.S.)
| | - Giuseppe Scafuro
- Biochemistry Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (C.T.); (G.S.)
| | - Patrizia Iodice
- Division of Medical Oncology, AORN Azienda dei Colli, Monaldi Hospital, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Alessandro Federico
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
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12
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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: 20] [Impact Index Per Article: 10.0] [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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13
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Ng JJJ, Loo WM, Siah KTH. Associations between irritable bowel syndrome and non-alcoholic fatty liver disease: A systematic review. World J Hepatol 2023; 15:925-938. [PMID: 37547029 PMCID: PMC10401413 DOI: 10.4254/wjh.v15.i7.925] [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: 03/26/2023] [Revised: 06/12/2023] [Accepted: 07/03/2023] [Indexed: 07/21/2023] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is associated with obesity and metabolic syndrome. IBS and non-alcoholic fatty liver disease (NAFLD) are highly prevalent entities worldwide and may share similar mechanisms including gut dysbiosis, impaired intestinal mucosal barrier and immune system activation.
AIM To systematically review their association according to the Preferred Reporting Items for Systemic Review and Meta-analyses guidelines.
METHODS PubMed, EMBASE and Cochrane Database of Systematic Reviews were searched for relevant papers. Manual searches were also performed.
RESULTS Six studies were included. Both IBS and NAFLD subjects had significantly more metabolic risk factors like hypertension, obesity, dyslipidaemia and diabetes. Our review showed that 23.2% to 29.4% of NAFLD patients had IBS. IBS was significantly higher in NAFLD patients compared with patients without NAFLD (23.2% vs 12.5%, P < 0.01). A higher proportion of IBS patients had NAFLD (65.8% to 74.0%). IBS patients were three times more likely to have NAFLD compared with non-IBS patients (P < 0.001). Two studies showed a significant correlation between the severity of IBS and NAFLD. The proportion of NAFLD subjects with IBS increased with NAFLD severity.
CONCLUSION Further prospective studies are warranted to evaluate the relationship and shared pathways between IBS and NAFLD, potentially leading to the development of future therapeutics.
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Affiliation(s)
- Jareth Jun Jie Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Wai Mun Loo
- AliveoMedical, Mount Alvernia and Mount Elizabeth Hospitals, Singapore 574623, Singapore
| | - Kewin Tien Ho Siah
- Division of Gastroenterology and Hepatology, National University Hospital, Singapore 119228, Singapore
- Department of Medicine, National University Hospital, Singapore 119228, Singapore
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14
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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] [MESH Headings] [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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15
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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: 18] [Impact Index Per Article: 6.0] [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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16
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Gudan A, Jamioł-Milc D, Hawryłkowicz V, Skonieczna-Żydecka K, Stachowska E. The Prevalence of Small Intestinal Bacterial Overgrowth in Patients with Non-Alcoholic Liver Diseases: NAFLD, NASH, Fibrosis, Cirrhosis-A Systematic Review, Meta-Analysis and Meta-Regression. Nutrients 2022; 14:nu14245261. [PMID: 36558421 PMCID: PMC9783356 DOI: 10.3390/nu14245261] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/27/2022] [Accepted: 11/30/2022] [Indexed: 12/14/2022] Open
Abstract
Bacterial overgrowth in the small intestine (SIBO) is a pathological growth of the intestinal microbiota in the small intestine that causes clinical symptoms and can lead to digestive and absorption disorders. There is increasing evidence that people with NAFLD have a distinct gut microflora profile as well metabolome changes compared to people without NAFLD. Thorough analysis of observational and RCT studies in the current databases (EMBASE, Web of Science, PubMed, Cinahl, Clinical Trials) was conducted from 3 November 2021 to 21 June 2022. The following inclusion criteria were applied: confirmed NAFLD, NASH, LIVER FIBROSIS, CIRRHOSIS due to steatosis; diagnostic methods of liver diseases—biopsy, elastography, transabdominal ultrasound; nonalcoholic fatty liver disease activity score; confirmed SIBO; diagnostic methods of SIBO−breath tests (hydrogen test; methane test and mix test; duodenal and jejunal aspiration before any type of intervention; adults above 18yo; number of participants ≥20; full articles. We excluded review articles, populations with HBV/HCV infection and alcohol etiology and interventions that may affect NAFLD or SIBO treatment. The quality of each study methodology was classified by means of the Cochrane Collaboration’s tool (RCT) and Newcastle—Ottawa Quality Assessment Scale adapted for cross-sectional, cohort and case-control studies. The random effects meta-analysis of outcomes for which ≥2 studies contributed data was conducted. The I2 index to measure heterogeneity and the χ2 test of homogeneity (statistically significant heterogeneity p < 0.05) were applied. For categorical outcome, the pooled event rate (effect size) was calculated. This systematic review was reported according to PRISMA reporting guidelines. We initially identified 6643 studies, from which 18 studies were included in final meta-analysis. The total number of patients was 1263. Accepted SIBO diagnostic methods were both available breath tests (n-total = 15) and aspirate culture (n-total = 3). We found that among patients with non-alcoholic liver diseases, the random overall event rate of SIBO was 0.350 (95% CI, 0.244−0.472), p = 0.017. The subgroup analysis regarding a type of diagnosis revealed that the lowest ER was among patients who developed simultaneously NAFLD, NASH and fibrosis: 0.197 (95% CI, 0.054−0.510) as compared to other annotated subgroups. The highest prevalence of SIBO was observed in the NASH subgroup: 0.411 (95% CI, 0.219−0.634). There were no statistically significant differences in the prevalence of SIBO in different subgroups (p = 0.854). Statistically significant heterogeneity between studies was estimated (I2 = 86.17%, p = 0.00). Egger’s test did not indicate a publication bias (df = 16, p = 0.885). A meta-regression using a random-effects model revealed that higher percentage of males in the population with liver diseases is a predisposing factor toward SIBO (Q = 4.11, df = 1, p = 0.0426 with coefficient = 0.0195, SE = 0.0096, Z = 2.03). We showed that the prevalence of SIBO in patients with chronic non-alcoholic liver diseases can be as high as 35%, and it increases with the percentage of men in the population. The prevalence of SIBO does not differ significantly depending on the type of chronic liver disease. Despite the high heterogeneity and moderate and low quality of included studies, our meta-analysis suggests the existence of a problem of SIBO in the population of patients with non-alcoholic liver diseases, and the presence of SIBO, in turn, determines the therapeutic treatment of such type of patients, which indicates the need for further research in this area. The study protocol was registered with the international Prospective Register of Systematic Reviews (PROSPERO ID: CRD42022341473).
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Affiliation(s)
- Anna Gudan
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, ul. Władysława Broniewskiego 24, 71-460 Szczecin, Poland
| | - Dominika Jamioł-Milc
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, ul. Władysława Broniewskiego 24, 71-460 Szczecin, Poland
- Correspondence: (D.J.-M.); (K.S.-Ż.); Tel.: +48-91-441-48-06 (D.J.-M. & K.S.-Ż.); Fax: +48-91-441-48-07 (D.J.-M. & K.S.-Ż.)
| | - Victoria Hawryłkowicz
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, ul. Władysława Broniewskiego 24, 71-460 Szczecin, Poland
| | - Karolina Skonieczna-Żydecka
- Department of Biochemical Sciences, Pomeranian Medical University in Szczecin, ul. Władysława Broniewskiego 24, 71-460 Szczecin, Poland
- Correspondence: (D.J.-M.); (K.S.-Ż.); Tel.: +48-91-441-48-06 (D.J.-M. & K.S.-Ż.); Fax: +48-91-441-48-07 (D.J.-M. & K.S.-Ż.)
| | - Ewa Stachowska
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, ul. Władysława Broniewskiego 24, 71-460 Szczecin, Poland
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Kamiya A, Ida K. Liver Injury and Cell Survival in Non-Alcoholic Steatohepatitis Regulated by Sex-Based Difference through B Cell Lymphoma 6. Cells 2022; 11:cells11233751. [PMID: 36497010 PMCID: PMC9737870 DOI: 10.3390/cells11233751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/14/2022] [Accepted: 11/20/2022] [Indexed: 11/25/2022] Open
Abstract
The liver is a crucial organ for maintaining homeostasis in living organisms and is the center of various metabolic functions. Therefore, abnormal metabolic activity, as in metabolic syndrome, leads to pathological conditions, such as abnormal accumulation of lipids in the liver. Inflammation and cell death are induced by several stresses in the fatty liver, namely steatohepatitis. In recent years, an increase in non-alcoholic steatohepatitis (NASH), which is not dependent on excessive alcohol intake, has become an issue as a major cause of liver cirrhosis and liver cancer. There are several recent findings on functional sex-based differences, NASH, and cell stress and death in the liver. In particular, NASH-induced liver injury and tumorigeneses were suppressed by B cell lymphoma 6, the transcriptional factor regulating sex-based liver functional gene expression. In this review, we discuss cell response to stress and lipotoxicity in NASH and its regulatory mechanisms.
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Affiliation(s)
- Akihide Kamiya
- Correspondence: ; Tel.: +81-463-93-1121 (ext. 2783); Fax: +81-463-95-3522
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Hao Y, Xu Y, Ban Y, Li J, Wu B, Ouyang Q, Sun Z, Zhang M, Cai Y, Wang M, Wang W. Efficacy evaluation of probiotics combined with prebiotics in patients with clinical hypothyroidism complicated with small intestinal bacterial overgrowth during the second trimester of pregnancy. Front Cell Infect Microbiol 2022; 12:983027. [PMID: 36275023 PMCID: PMC9583945 DOI: 10.3389/fcimb.2022.983027] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/20/2022] [Indexed: 11/18/2022] Open
Abstract
Objective To explore the effect of probiotics combined with prebiotics on clinical hypothyroidism during pregnancy combined with small intestinal bacterial overgrowth. Methods (1) In total, 441 pregnant women were included in this study. A total of 231 patients with clinical hypothyroidism during the second trimester of pregnancy and 210 normal pregnant women were enrolled in the lactulose methane-hydrogen breath test. The positive rate of intestinal bacterial overgrowth (SIBO), gastrointestinal symptoms, thyroid function and inflammatory factors were compared between the two groups by chi-square test and two independent sample t-test. (2) SIBO-positive patients in the clinical hypothyroidism group during pregnancy (n=112) were treated with probiotics combined with prebiotics based on conventional levothyroxine sodium tablets treatment. The changes in the methane-hydrogen breath test, gastrointestinal symptoms, thyroid function and inflammatory factors were compared before treatment (G0) and 21 days after treatment (G21) by chi-square test and paired sample t test. Results (1) The positive rates of SIBO in pregnant women in the clinical hypothyroidism group and control group were 48.5% and 24.8%, respectively. (2) The incidence of abdominal distention and constipation in the clinical hypothyroidism group was significantly higher than that in the control group, and the risk of abdominal distention and constipation in SIBO-positive pregnant women was higher than that in SIBO-negative pregnant women. (3) The serum levels of hypersensitive C-reactive protein (hsCRP), IL-10, IL-6, TNF-α, low-density lipoprotein (LDL), total cholesterol (TC), free fatty acids (FFAs) and apolipoprotein B (ApoB) in the hypothyroidism group during pregnancy were higher than those in the control group. (4) After 21 days of probiotics combined with prebiotics, the incidence of pure methane positivity in the methane-hydrogen breath test in the G21 group was significantly reduced, and the average abundance of hydrogen and methane at each time point in the G21 group was lower than that in the G0 group. (5) The incidence of constipation in the G21 group was significantly lower than before treatment. (6) The levels of serum TSH, hsCRP, IL-6, TNF-α, TC and LDL in pregnant women after probiotics combined with prebiotics were lower than those before treatment. Conclusion Probiotics combined with prebiotics are effective in the treatment of pregnant patients with clinical hypothyroidism complicated with SIBO, providing a new idea to treat pregnant patients with clinical hypothyroidism complicated with SIBO.
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Mohammadi Z, Poustchi H, Hekmatdoost A, Etemadi A, Eghtesad S, Sharafkhah M, Stewart D, Ghanbari R, Chlipala GE, Bishehsari F, Merat S, Malekzadeh R. Gut microbiota profile in patients with nonalcoholic fatty liver disease and presumed nonalcoholic steatohepatitis. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2022; 27:54. [PMID: 36092483 PMCID: PMC9450256 DOI: 10.4103/jrms.jrms_673_21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 01/06/2022] [Accepted: 01/31/2022] [Indexed: 11/13/2022]
Abstract
BACKGROUND The main composition of intestinal microbiota in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) patients has not yet been elucidated. In this, case-control study, we identified differences of intestinal microbiota in male patients with NAFLD, presumed NASH, and healthy controls. MATERIALS AND METHODS We compared gut microbial composition of 25 patients with NAFLD, 13 patients with presumed NASH, and 12 healthy controls. Demographic information as well as clinical, nutritional, and physical activity data was gathered. Stool and blood samples were collected to perform the laboratory analysis. The taxonomic composition of gut microbiota was assessed using V4 regions of microbial small subunit ribosomal Ribonucleic acid genes sequencing of stool samples. RESULTS Firmicutes, Actinobacteria, and Bacteroidetes were the most frequently phyla in all groups. Our results revealed that Veillonella was the only genus with significantly different amounts in presumed NASH patients compared with patients with NAFLD (P = 2.76 × 10-6, q = 2.07 × 10-4, logFC = 5.52). CONCLUSION This pilot study was the first study to compare gut microbial composition in patients with NAFLD and presumed NASH in the Middle East. Given the potential effects of gut microbiota on the management and prevention of NAFLD, larger, prospective studies are recommended to confirm this study's findings.
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Affiliation(s)
- Zahra Mohammadi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Poustchi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Azita Hekmatdoost
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arash Etemadi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Sareh Eghtesad
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Sharafkhah
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Delisha Stewart
- Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, USA
| | - Reza Ghanbari
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - George Edward Chlipala
- Research Informatics Core, Research Resources Center, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Faraz Bishehsari
- Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, Illinois, USA
| | - Shahin Merat
- Digestive Disease Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Malekzadeh
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Bacil GP, Cogliati B, Cardoso DR, Barbisan LF, Romualdo GR. Are isothiocyanates and polyphenols from Brassicaceae vegetables emerging as preventive/therapeutic strategies for NAFLD? The landscape of recent preclinical findings. Food Funct 2022; 13:8348-8362. [PMID: 35899794 DOI: 10.1039/d2fo01488b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a lipid impairment-related chronic metabolic disease that affects almost 25% of the worldwide population and has become the leading cause of liver transplantation in the United States of America (USA). NAFLD may progress from simple hepatic steatosis (HS) to nonalcoholic steatohepatitis (NASH), which occurs simultaneously in an inflammatory and fibrotic microenvironment and affects approximately 5% of the global population. Recently, NASH has been suggested to be a relevant driver in progressive liver cirrhosis and a population-attributable factor in hepatocellular carcinoma patients. Moreover, predictions show that NAFLD-related annual health costs in the USA have reached ∼$100 bi., but effective therapies are still scarce. Thus, new preventative strategies for this hepatic disease urgently need to be developed. The Brassicaceae vegetable family includes almost 350 genera and 3500 species and these are one of the main types of vegetables harvested and produced worldwide. These vegetables are well-known sources of glucobrassicin-derivative molecules, such as isothiocyanates and phenolic compounds, which have shown antioxidant and antilipogenic effects in preclinical NAFLD data. In this review, we gathered prominent evidence of the in vivo and in vitro effects of these vegetable-derived nutraceutical compounds on the gut-liver-adipose axis, which is a well-known regulator of NAFLD and may represent a new strategy for disease control.
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Affiliation(s)
- Gabriel P Bacil
- São Paulo State University (UNESP), Botucatu Medical School, Department of Pathology, Botucatu, SP, Brazil.
| | - Bruno Cogliati
- University of São Paulo (USP), School of Veterinary and Animal Science, Department of Pathology, São Paulo, SP, Brazil
| | - Daniel R Cardoso
- University of São Paulo (USP), São Carlos Institute of Chemistry (IQSC), São Carlos, SP, Brazil
| | - Luís Fernando Barbisan
- São Paulo State University (UNESP), Department of Structural and Functional Biology, SP, Brazil
| | - Guilherme R Romualdo
- São Paulo State University (UNESP), Botucatu Medical School, Department of Pathology, Botucatu, SP, Brazil. .,São Paulo State University (UNESP), Department of Structural and Functional Biology, SP, Brazil
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21
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Arvanitakis K, Koufakis T, Kotsa K, Germanidis G. The effects of sodium-glucose cotransporter 2 inhibitors on hepatocellular carcinoma: From molecular mechanisms to potential clinical implications. Pharmacol Res 2022; 181:106261. [PMID: 35588918 DOI: 10.1016/j.phrs.2022.106261] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 05/11/2022] [Accepted: 05/12/2022] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) occurs in the setting of prolonged liver inflammation, hepatocyte necrosis and regeneration in patients with cirrhosis. Despite the progress made in the medical management of the disorder during the past decades, the available pharmacological options remain limited, leading to poor survival rates and quality of life for patients with HCC. Sodium-glucose cotransporter 2 inhibitors (SGLT2) originally emerged as drugs for the treatment of hyperglycemia; however, they soon demonstrated important extra-glycemic properties, which led to their evaluation as potential treatments for a wide range of non-metabolic disorders. Evidence from animal studies suggests that SGLT2i have the potential to modulate molecular pathways that affect hallmarks of HCC, including inflammatory responses, cell proliferation, and oxidative stress. The impressive benefits of neurohormonal modulation observed with SGLT2i in congestive heart failure set the stage for human trials in cirrhotic ascites. However, future studies need to evaluate several aspects of the benefit to risk ratio of such a therapeutic strategy, including the co-administration with antineoplastic agents and diuretics, infections, use in hospitalized individuals, renal safety and hypovolemia. In this narrative review, we discuss the putative role of SGLT2i in the treatment of patients with HCC, starting with the mechanisms that could justify a possible benefit and ending with potential clinical implications and areas for future research.
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Affiliation(s)
- Konstantinos Arvanitakis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece
| | - Georgios Germanidis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece.
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22
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Gupta B, Rai R, Oertel M, Raeman R. Intestinal Barrier Dysfunction in Fatty Liver Disease: Roles of Microbiota, Mucosal Immune System, and Bile Acids. Semin Liver Dis 2022; 42:122-137. [PMID: 35738255 PMCID: PMC9307091 DOI: 10.1055/s-0042-1748037] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of progressive liver diseases ranging from simple steatosis to steatohepatitis and fibrosis. Globally, NAFLD is the leading cause of morbidity and mortality associated with chronic liver disease, and NAFLD patients are at a higher risk of developing cirrhosis and hepatocellular carcinoma. While there is a consensus that inflammation plays a key role in promoting NAFLD progression, the underlying mechanisms are not well understood. Recent clinical and experimental evidence suggest that increased hepatic translocation of gut microbial antigens, secondary to diet-induced impairment of the intestinal barrier may be important in driving hepatic inflammation in NAFLD. Here, we briefly review various endogenous and exogenous factors influencing the intestinal barrier and present recent advances in our understanding of cellular and molecular mechanisms underlying intestinal barrier dysfunction in NAFLD.
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Affiliation(s)
- Biki Gupta
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ravi Rai
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michael Oertel
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania,Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Reben Raeman
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania,Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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23
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Scarpellini E, Abenavoli L, Cassano V, Rinninella E, Sorge M, Capretti F, Rasetti C, Svegliati Baroni G, Luzza F, Santori P, Sciacqua A. The Apparent Asymmetrical Relationship Between Small Bowel Bacterial Overgrowth, Endotoxemia, and Liver Steatosis and Fibrosis in Cirrhotic and Non-Cirrhotic Patients: A Single-Center Pilot Study. Front Med (Lausanne) 2022; 9:872428. [PMID: 35559337 PMCID: PMC9090439 DOI: 10.3389/fmed.2022.872428] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 03/18/2022] [Indexed: 11/18/2022] Open
Abstract
Introduction Gut microbiota are a complex ecosystem harboring our intestine. They maintain human body equilibrium, while their derangement, namely, “dysbiosis“, has been associated with several gastrointestinal diseases, such as liver steatosis (NAFLD) and liver cirrhosis. Small intestinal bacterial overgrowth (SIBO) is an example of dysbiosis of the upper gastrointestinal (GI) tract. Aim The aim of this study is to evaluate the relationship between SIBO and levels of endotoxemia and grade of liver steatosis (LS) and liver fibrosis (LF) in hepatologic patients. Materials and Methods Consecutive outpatients referred to our hepatology clinic were tested for SIBO by the lactulose breath test (LBT) and peripheral blood levels of endotoxemia; LS grading and LF were assessed by abdominal ultrasound and transient elastography, respectively. Results Fifty-two consecutive patients (17 with alcohol abuse (4.5 ± 0.8 alcohol units per day), 4 with HCV and 2 with HBV infection, 24 of metabolic origin, 2 of autoimmune origin, and 3 with cholangiopathies; mean age 54.7 ± 8.3 years, 31 F, BMI 24.1 ± 1.1 Kg/m2) and 14 healthy volunteers (HV) (mean age 50.1 ± 4.3 years, 9 F, BMI 23.3 ± 1.1 Kg/m2) were enrolled. SIBO prevalence was significantly higher in cirrhotic (LC) vs. non-cirrhotic (LNC) patients and vs. HV (all, p < 0.05), with a significant positive trend according to Child-Pugh status (all, p < 0.05). SIBO prevalence was not correlated with LS stages (all, p = NS). Consensually, endotoxin levels were significantly higher in LC vs. LNC and vs. HV (all, p < 0.05) and significantly correlated with LF in patients with LC, according to Child-Pugh status (all, p < 0.05). Conclusion This study shows that SIBO prevalence and relative endotoxin blood levels seem to be significantly associated with the grade of LF vs. LS in LC. SIBO is also present under pre-cirrhotic conditions, but its prevalence seems to correlate with liver disease irreversible derangement.
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Affiliation(s)
- E. Scarpellini
- Hepatology and Internal Medicine Unit, “Madonna del Soccorso” General Hospital, San Benedetto del Tronto, Italy
- T.A.R.G.I.D., Gasthuisberg University Hospital, KULeuven, Lueven, Belgium
- *Correspondence: E. Scarpellini
| | - L. Abenavoli
- Department of Health Sciences, University “Magna Græcia”, Catanzaro, Italy
| | - V. Cassano
- Department of Medical and Surgical Sciences, University “Magna Græcia”, Catanzaro, Italy
| | - E. Rinninella
- Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - M. Sorge
- Gastroenterology and Endoscopy Unit “Madonna del Soccorso” General Hospital, San Benedetto del Tronto, Italy
| | - F. Capretti
- Gastroenterology and Endoscopy Unit “Madonna del Soccorso” General Hospital, San Benedetto del Tronto, Italy
| | - C. Rasetti
- Hepatology and Internal Medicine Unit, “Madonna del Soccorso” General Hospital, San Benedetto del Tronto, Italy
| | - G. Svegliati Baroni
- Gastroenterology Clinic, “Riuniti University Hospital”, Polytechnics University of Marche, Ancona, Italy
| | - F. Luzza
- Department of Health Sciences, University “Magna Græcia”, Catanzaro, Italy
| | - P. Santori
- Hepatology and Internal Medicine Unit, “Madonna del Soccorso” General Hospital, San Benedetto del Tronto, Italy
| | - A. Sciacqua
- Department of Medical and Surgical Sciences, University “Magna Græcia”, Catanzaro, Italy
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24
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Souza CAD, Rocha R, Costa PRDF, Almeida NS, Cotrim HP. PROBIOTIC, PREBIOTIC OR SYMBIOTIC SUPPLEMENTATION IMPACTS ON INTESTINAL MICROBIOTA IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE: A SYSTEMATIC REVIEW. ARQUIVOS DE GASTROENTEROLOGIA 2022; 59:123-128. [PMID: 35442322 DOI: 10.1590/s0004-2803.202200001-21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 08/24/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Supplementation with probiotics, prebiotics and symbiotics has shown positive effects on clinical markers and risk factors for non-alcoholic fatty liver disease (NAFLD). OBJECTIVE To evaluate the effect of supplementation with probiotic, prebiotic or symbiotic on intestinal microbiota in NAFLD patients. METHODS Two investigators conducted independently search for articles in the Medline databases, via PubMed, Web of Science, Embase, Scopus, Lilacs, Central Cochrane Library, Clinical Trials.gov and on the Ovid platform for the gray literature search. RESULTS A total of 3,423 papers were identified by searching the electronic databases; 1,560 of them were duplicate and they were excluded; 1,825 articles were excluded after reading the title and abstract. A total of 39 articles were select to reading, however only four articles met the eligibility criteria to include in this systematic review. Three of the included studies that used prebiotic or symbiotic supplementation showed that after the intervention there were changes in the intestinal microbiota pattern. Only in one study such changes were not observed. A high risk of bias was observed in most assessments. CONCLUSION Although there is a possible change in the gut microbiota of individuals with NAFLD after supplementation with symbiotics or prebiotics, a clinical indication as part of NAFLD treatment is not yet possible.
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Affiliation(s)
- Claudineia Almeida de Souza
- Universidade Federal da Bahia, Programa de Pós-Graduação em Alimentação, Nutrição e Saúde, Salvador, BA, Brasil
| | - Raquel Rocha
- Universidade Federal da Bahia, Programa de Pós-Graduação em Alimentação, Nutrição e Saúde, Salvador, BA, Brasil
| | | | - Naiade Silveira Almeida
- Universidade Federal da Bahia, Programa de Pós-Graduação em Medicina e Saúde, Salvador, BA, Brasil
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Portincasa P, Bonfrate L, Khalil M, Angelis MD, Calabrese FM, D’Amato M, Wang DQH, Di Ciaula A. Intestinal Barrier and Permeability in Health, Obesity and NAFLD. Biomedicines 2021; 10:83. [PMID: 35052763 PMCID: PMC8773010 DOI: 10.3390/biomedicines10010083] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/20/2021] [Accepted: 12/28/2021] [Indexed: 02/07/2023] Open
Abstract
The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal barrier is characterized by the selective permeability of nutrients, metabolites, water, and bacterial products, and processes are governed by cellular, neural, immune, and hormonal factors. Disrupted gut permeability (leaky gut syndrome) can represent a predisposing or aggravating condition in obesity and the metabolically associated liver steatosis (nonalcoholic fatty liver disease, NAFLD). In what follows, we describe the morphological-functional features of the intestinal barrier, the role of major modifiers of the intestinal barrier, and discuss the recent evidence pointing to the key role of intestinal permeability in obesity/NAFLD.
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Affiliation(s)
- Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
| | - Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Maria De Angelis
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Francesco Maria Calabrese
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Mauro D’Amato
- Gastrointestinal Genetics Lab, CIC bioGUNE-BRTA, 48160 Derio, Spain;
- Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York, NY 10461, USA;
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
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Kuang L, Zhou W, Jiang Y. Association of small intestinal bacterial overgrowth with nonalcoholic fatty liver disease in children: A meta-analysis. PLoS One 2021; 16:e0260479. [PMID: 34855819 PMCID: PMC8638857 DOI: 10.1371/journal.pone.0260479] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022] Open
Abstract
It has been suggested that small intestinal bacterial overgrowth (SIBO) could cause nonalcoholic fatty liver disease (NAFLD), but this association was not examined in children by meta-analysis. This meta-analysis aimed to determine the association between SIBO and NAFLD in children. The electronic databases PubMed, Embase, and Cochrane Library were searched for studies published before April 22, 2021. The outcome was the association between SIBO and NAFLD. Three studies and 205 children were included. All three studies reported the association between SIBO and NAFLD. Children with SIBO were more likely to have NAFLD (odds ratio = 5.27, 95% confidence interval (CI): 1.66-16.68, P<0.001; I2 = 63.5%, Pheterogeneity = 0.065). When directly pooling the reported relative risks (RR) from two studies, children with NAFLD had an over 2-fold increased relative risk of developing SIBO (RR = 2.17, 05%CI: 1.66-2.82, P<0.001; I2 = 0.0%, Pheterogeneity = 0.837). This meta-analysis reports a possible association between SIBO and NAFLD in children.
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Affiliation(s)
- Linghan Kuang
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Wei Zhou
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Yongmei Jiang
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
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Potoupni V, Georgiadou M, Chatzigriva E, Polychronidou G, Markou E, Zapantis Gakis C, Filimidou I, Karagianni M, Anastasilakis D, Evripidou K, Ftergioti A, Togkaridou M, Tsaftaridis N, Apostolopoulos A, Polyzos SA. Circulating tumor necrosis factor-α levels in non-alcoholic fatty liver disease: A systematic review and a meta-analysis. J Gastroenterol Hepatol 2021; 36:3002-3014. [PMID: 34289181 DOI: 10.1111/jgh.15631] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/22/2021] [Accepted: 07/17/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM To synthesize data on circulating tumor necrosis factor (TNF)-α levels between patients with histologically confirmed non-alcoholic fatty liver disease (NAFLD) (simple steatosis or non-alcoholic fatty liver [NAFL] and/or non-alcoholic steatohepatitis [NASH]) and controls. METHODS We performed a systematic search in PubMed, Scopus, and Cochrane Library. Fifty-six studies, published between 2003 and 2019, were finally included, reporting data from 5848 individuals (1634 controls and 4214 NAFLD patients). RESULTS Higher circulating TNF-α levels were observed in NAFLD patients than controls (standardized mean difference [SMD] 0.84; 95% confidence interval [95% CI] 0.59-1.09), NAFL patients than controls (SMD 0.56; 95% CI 0.27-0.85), NASH patients than controls (SMD 0.93; 95% CI 0.64-1.22), and NASH than NAFL patients (SMD 0.31; 95% CI 0.16-0.46). There were only minimal changes in the comparisons between groups after excluding studies with morbidly obese populations (n = 11), or pediatric/adolescent populations (n = 6), or other than enzyme-linked immunosorbent assay method of TNF-α measurement (n = 8). There was high heterogeneity among studies in all comparisons, which was not essentially affected after sensitivity analyses. The meta-regression analysis revealed that the male ratio was positively associated with TNF-α SMD in the comparison between patients with NASH and NAFL (beta = 0.809; 95% CI 0.052-1.566) and accounted for 36% (P = 0.037) of the heterogeneity in this pair of comparison. TNF-α SMD was not associated with age, body mass index, and alanine aminotransferase in any pair of comparisons. CONCLUSIONS Circulating TNF-α levels were higher in patients with NAFLD compared with controls. Higher levels of circulating TNF-α were also associated with the severity of NAFLD.
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Affiliation(s)
- Victoria Potoupni
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Maria Georgiadou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eftychia Chatzigriva
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Georgia Polychronidou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Erietta Markou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Christos Zapantis Gakis
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioanna Filimidou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Myriam Karagianni
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitrios Anastasilakis
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kleo Evripidou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Argyro Ftergioti
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Marianthi Togkaridou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Nikolaos Tsaftaridis
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Apostolos Apostolopoulos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Bruneau A, Hundertmark J, Guillot A, Tacke F. Molecular and Cellular Mediators of the Gut-Liver Axis in the Progression of Liver Diseases. Front Med (Lausanne) 2021; 8:725390. [PMID: 34650994 PMCID: PMC8505679 DOI: 10.3389/fmed.2021.725390] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/01/2021] [Indexed: 12/15/2022] Open
Abstract
The gut-liver axis covers the bidirectional communication between the gut and the liver, and thus includes signals from liver-to-gut (e.g., bile acids, immunoglobulins) and from gut-to-liver (e.g., nutrients, microbiota-derived products, and recirculating bile acids). In a healthy individual, liver homeostasis is tightly controlled by the mostly tolerogenic liver resident macrophages, the Kupffer cells, capturing the gut-derived antigens from the blood circulation. However, disturbances of the gut-liver axis have been associated to the progression of varying chronic liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and primary sclerosing cholangitis. Notably, changes of the gut microbiome, or intestinal dysbiosis, combined with increased intestinal permeability, leads to the translocation of gut-derived bacteria or their metabolites into the portal vein. In the context of concomitant or subsequent liver inflammation, the liver is then infiltrated by responsive immune cells (e.g., monocytes, neutrophils, lymphoid, or dendritic cells), and microbiota-derived products may provoke or exacerbate innate immune responses, hence perpetuating liver inflammation and fibrosis, and potentiating the risks of developing cirrhosis. Similarly, food derived antigens, bile acids, danger-, and pathogen-associated molecular patterns are able to reshape the liver immune microenvironment. Immune cell intracellular signaling components, such as inflammasome activation, toll-like receptor or nucleotide-binding oligomerization domain-like receptors signaling, are potent targets of interest for the modulation of the immune response. This review describes the current understanding of the cellular landscape and molecular pathways involved in the gut-liver axis and implicated in chronic liver disease progression. We also provide an overview of innovative therapeutic approaches and current clinical trials aiming at targeting the gut-liver axis for the treatment of patients with chronic liver and/or intestinal diseases.
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Affiliation(s)
- Alix Bruneau
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Jana Hundertmark
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Adrien Guillot
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
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29
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Ohtani N, Hara E. Gut-liver axis-mediated mechanism of liver cancer: A special focus on the role of gut microbiota. Cancer Sci 2021; 112:4433-4443. [PMID: 34533882 PMCID: PMC8586687 DOI: 10.1111/cas.15142] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/10/2021] [Accepted: 09/12/2021] [Indexed: 12/15/2022] Open
Abstract
Gut microbiota and the mammalian host share a symbiotic relationship, in which the host provides a suitable ecosystem for the gut bacteria to digest indigestible nutrients and produce useful metabolites. Although gut microbiota primarily reside in and influence the intestine, they also regulate liver function via absorption and subsequent transfer of microbial components and metabolites through the portal vein to the liver. Due to this transfer, the liver may be continuously exposed to gut‐derived metabolites and components. For example, short‐chain fatty acids (SCFA) produced by gut microbiota, through the fermentation of dietary fiber, can suppress inflammation via regulatory T cell induction through SCFA‐induced epigenetic mechanisms. Additionally, secondary bile acids (BA), such as deoxycholic acid, produced by gut bacteria through the 7α‐dehydroxylation of primary BAs, are thought to induce DNA damage and contribute to the remodeling of tumor microenvironments. Other substances that are also thought to influence liver function include lipopolysaccharides (components of the outer membrane of gram‐negative bacteria) and lipoteichoic acid (cell wall component of Gram‐positive bacteria), which are ligands of innate immune receptors, Toll‐like receptor‐4, and Toll‐like receptor‐2, respectively, through which inflammatory signaling is elicited. In this review, we focus on the role of gut microbiota in the liver microenvironment, describing the anatomy of the gut‐liver axis, the role of gut microbial metabolites, and the relationships that exist between gut microbiota and liver diseases, including liver cancer.
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Affiliation(s)
- Naoko Ohtani
- Department of Pathophysiology, Graduate School of Medicine, Osaka City University, Osaka, Japan.,AMED-CREST, AMED, Japan Agency for Medical Research and Development, Tokyo, Japan
| | - Eiji Hara
- Research Institute for Microbial Diseases, Osaka University, Suita, Japan.,Immunology Frontier Research Center (IFReC), Osaka University, Suita, Japan.,Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Japan
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30
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Kessoku T, Kobayashi T, Tanaka K, Yamamoto A, Takahashi K, Iwaki M, Ozaki A, Kasai Y, Nogami A, Honda Y, Ogawa Y, Kato S, Imajo K, Higurashi T, Hosono K, Yoneda M, Usuda H, Wada K, Saito S, Nakajima A. The Role of Leaky Gut in Nonalcoholic Fatty Liver Disease: A Novel Therapeutic Target. Int J Mol Sci 2021; 22:ijms22158161. [PMID: 34360923 PMCID: PMC8347478 DOI: 10.3390/ijms22158161] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver directly accepts blood from the gut and is, therefore, exposed to intestinal bacteria. Recent studies have demonstrated a relationship between gut bacteria and nonalcoholic fatty liver disease (NAFLD). Approximately 10–20% of NAFLD patients develop nonalcoholic steatohepatitis (NASH), and endotoxins produced by Gram-negative bacilli may be involved in NAFLD pathogenesis. NAFLD hyperendotoxicemia has intestinal and hepatic factors. The intestinal factors include impaired intestinal barrier function (leaky gut syndrome) and dysbiosis due to increased abundance of ethanol-producing bacteria, which can change endogenous alcohol concentrations. The hepatic factors include hyperleptinemia, which is associated with an excessive response to endotoxins, leading to intrahepatic inflammation and fibrosis. Clinically, the relationship between gut bacteria and NAFLD has been targeted in some randomized controlled trials of probiotics and other agents, but the results have been inconsistent. A recent randomized, placebo-controlled study explored the utility of lubiprostone, a treatment for constipation, in restoring intestinal barrier function and improving the outcomes of NAFLD patients, marking a new phase in the development of novel therapies targeting the intestinal barrier. This review summarizes recent data from studies in animal models and randomized clinical trials on the role of the gut–liver axis in NAFLD pathogenesis and progression.
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Affiliation(s)
- Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Correspondence: ; Tel.: +81-45-787-2640; Fax: +81-45-784-3546
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kosuke Tanaka
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Atsushi Yamamoto
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kota Takahashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Anna Ozaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Yuki Kasai
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Yuji Ogawa
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Shingo Kato
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Takuma Higurashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kunihiro Hosono
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Haruki Usuda
- Department of Pharmacology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo, Shimane 693-8501, Japan; (H.U.); (K.W.)
| | - Koichiro Wada
- Department of Pharmacology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo, Shimane 693-8501, Japan; (H.U.); (K.W.)
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
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Han N, Pan Z, Liu G, Yang R, Yujing B. Hypoxia: The "Invisible Pusher" of Gut Microbiota. Front Microbiol 2021; 12:690600. [PMID: 34367091 PMCID: PMC8339470 DOI: 10.3389/fmicb.2021.690600] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 06/25/2021] [Indexed: 12/20/2022] Open
Abstract
Oxygen is important to the human body. Cell survival and operations depend on oxygen. When the body becomes hypoxic, it affects the organs, tissues and cells and can cause irreversible damage. Hypoxia can occur under various conditions, including external environmental hypoxia and internal hypoxia. The gut microbiota plays different roles under hypoxic conditions, and its products and metabolites interact with susceptible tissues. This review was conducted to elucidate the complex relationship between hypoxia and the gut microbiota under different conditions. We describe the changes of intestinal microbiota under different hypoxic conditions: external environment and internal environment. For external environment, altitude was the mayor cause induced hypoxia. With the increase of altitude, hypoxia will become more serious, and meanwhile gut microbiota also changed obviously. Body internal environment also became hypoxia because of some diseases (such as cancer, neonatal necrotizing enterocolitis, even COVID-19). In addition to the disease itself, this hypoxia can also lead to changes of gut microbiota. The relationship between hypoxia and the gut microbiota are discussed under these conditions.
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Affiliation(s)
- Ni Han
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Zhiyuan Pan
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Guangwei Liu
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - Ruifu Yang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Bi Yujing
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
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32
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Yamamoto K, Ikeya T, Okuyama S, Fukuda K, Kobayashi D. The association between non-alcoholic fatty liver disease (with or without metabolic syndrome) and extrahepatic cancer development. J Gastroenterol Hepatol 2021; 36:1971-1978. [PMID: 33201570 DOI: 10.1111/jgh.15350] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/17/2020] [Accepted: 11/07/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIM This study was designed to determine whether non-alcoholic fatty liver disease (NAFLD), with or without metabolic syndrome (MetS), is a risk factor for cancer development. METHODS We conducted a retrospective longitudinal study at the Center for Preventive Medicine, St. Luke's International Hospital. Among all participants who underwent a health checkup between 2005 and 2019, cancer development tendencies were compared between those who were diagnosed with NAFLD and those who were not. Further evaluation was conducted among NAFLD-diagnosed participants with versus without MetS in the same manner. Those with a history of a specific liver disease, any type of cancer, or alcohol consumption in any amount at the time of the initial visit were excluded from the study. RESULTS Data were collected from 30 172 participants who underwent health checkups, among whom 4394 (14.6%) had NAFLD. Over the 14-year follow-up period, 2086 participants (6.9%) developed cancer. Participants with NAFLD had a higher incidence of digestive organ neoplasms (odds ratio [OR]: 1.34, 95% confidence interval [CI]: 1.07-1.67), especially in the stomach (OR: 1.40, 95% CI: 1.02-1.94) and small intestine (OR: 2.80, 95% CI: 0.87-8.96), than did those without NAFLD. Participants with NAFLD and MetS had significantly lower rates of neoplasms in respiratory and intrathoracic organs (OR: 0.35 95% CI: 0.14-0.88) and male genital organs (OR: 0.46 95% CI: 0.24-0.87) than did individuals without NAFLD. CONCLUSIONS Non-alcoholic fatty liver disease is associated with the development of gastrointestinal malignancies, while MetS is a negative risk factor for lung and prostate cancer.
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Affiliation(s)
- Kazuki Yamamoto
- Department of Gastroenterology, St. Luke's International Hospital, Tokyo, Japan
| | - Takashi Ikeya
- Department of Gastroenterology, St. Luke's International Hospital, Tokyo, Japan
| | - Shuhei Okuyama
- Department of Gastroenterology, St. Luke's International Hospital, Tokyo, Japan
| | - Katsuyuki Fukuda
- Department of Gastroenterology, St. Luke's International Hospital, Tokyo, Japan
| | - Daiki Kobayashi
- Department of Medicine, St. Luke's International Hospital, Tokyo, Japan.,Department of Epidemiology, St. Luke's Graduate School of Public Health, Tokyo, Japan.,Fujita Health University, Toyoake, Japan
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Ahadi M, Molooghi K, Masoudifar N, Namdar AB, Vossoughinia H, Farzanehfar M. A review of non-alcoholic fatty liver disease in non-obese and lean individuals. J Gastroenterol Hepatol 2021; 36:1497-1507. [PMID: 33217052 DOI: 10.1111/jgh.15353] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 10/26/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of hepatic disorders. It represents a wide range of chronic liver diseases in patients with no history of significant alcohol consumption, starting with simple steatosis and progressing towards non-alcoholic steatohepatitis, cirrhosis, and ultimately hepatocellular carcinoma. NAFLD is usually associated with type 2 diabetes mellitus, dyslipidemia, metabolic syndrome, and obesity. This disease has mostly been studied in obese individuals; however, it has been widely reported and studied among the lean/non-obese population in recent years. The pathogenesis of NAFLD in non-obese patients is associated with various genetic predispositions, particularly a patatin-like phospholipase domain-containing protein 3 G allele polymorphism, which results in the accumulation of triglyceride in the liver and resistance to insulin. Additionally, dietary factors such as high fructose consumption seem to play a substantial role in the pathology of non-obese NAFLD. Although there is not enough evidence on the treatment of NAFLD in non-obese patients, the standard approach is to advise altering one's lifestyle in order to diminish visceral adiposity. Dietary modification, weight loss, and increased physical activity are highly recommended. We aimed to review and summarize the existing information on the prevalence, pathogenesis, genetic predispositions, diagnosis, and treatment of NAFLD in non-obese patients according to the latest literature.
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Affiliation(s)
- Mitra Ahadi
- Department of Gastroenterology and Hepatology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kasra Molooghi
- School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negin Masoudifar
- School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Beheshti Namdar
- Department of Gastroenterology and Hepatology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hassan Vossoughinia
- Department of Gastroenterology and Hepatology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammadreza Farzanehfar
- Department of Gastroenterology and Hepatology, Mashhad University of Medical Sciences, Mashhad, Iran
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Bakhshimoghaddam F, Alizadeh M. Contribution of gut microbiota to nonalcoholic fatty liver disease: Pathways of mechanisms. Clin Nutr ESPEN 2021; 44:61-68. [PMID: 34330514 DOI: 10.1016/j.clnesp.2021.05.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/22/2021] [Accepted: 05/11/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is a common, multifactorial liver disease with rapidly increasing prevalence. During the past decade, several lines of evidence have suggested that gut microbiota dysbiosis represents a major factor contributing to NAFLD occurrence and its progression. METHOD We have performed a review of the published data on the relationship between gut microbiota and risk factors for NAFLD and the role that gut-liver axis plays in the pathogenesis of NAFLD. RESULTS Accumulated evidence has indicated that dysfunction of the gut-liver axis, including increased intestinal permeability, small intestinal bacterial overgrowth, microbiota-derived mediators, and intestinal dysbiosis contribute to the progression and development of NAFLD. CONCLUSIONS The findings of this review suggest that lifestyle modification and manipulation of gut microbiota can be considered as a therapeutic target for NAFLD management. However, important documents supporting the role of gut microbiota in NAFLD come from animal studies; therefore, information from studies on humans could lead to novel therapeutics for this highly common disorder.
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Affiliation(s)
- Farnush Bakhshimoghaddam
- Student Research Committee, Department of Nutrition, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Mohammad Alizadeh
- Department of Nutrition, Food and Beverages Safety Research Center, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
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Mikolasevic I, Delija B, Mijic A, Stevanovic T, Skenderevic N, Sosa I, Krznaric-Zrnic I, Abram M, Krznaric Z, Domislovic V, Filipec Kanizaj T, Radic-Kristo D, Cubranic A, Grubesic A, Nakov R, Skrobonja I, Stimac D, Hauser G. Small intestinal bacterial overgrowth and non-alcoholic fatty liver disease diagnosed by transient elastography and liver biopsy. Int J Clin Pract 2021; 75:e13947. [PMID: 33406286 DOI: 10.1111/ijcp.13947] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 12/14/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND We aimed to determine if there was a higher incidence of small intestinal bacterial overgrowth (SIBO) in non-alcoholic fatty liver disease (NAFLD) than in patients without NAFLD. Moreover, we assessed whether patients with significant fibrosis (SF) had a higher incidence of SIBO compared with patients with non-significant or no liver fibrosis. METHODS NAFLD was diagnosed in 117 patients by using Fibroscan with a controlled attenuation parameter (CAP) as well as liver biopsy (LB). SIBO was defined by esophagogastroduodenoscopy with an aspiration of the descending duodenum. RESULTS Patients with non-alcoholic steatohepatitis (NASH) and those with SF on LB had a significantly higher incidence of SIBO than patients without NASH and those without SF, respectively (P < .05). According to histological characteristics, there was a higher proportion of patients in the SIBO group with higher steatosis and fibrosis grade, lobular and portal inflammation, and ballooning grade (P < .001). In multivariate analysis, significant predictors associated with SF and NASH were type 2 diabetes mellitus (T2DM) and SIBO. Moreover, in multivariate analysis, significant predictors that were independently associated with SIBO were T2DM, fibrosis stage and ballooning grade (OR 8.80 (2.07-37.37), 2.50 (1.16-5.37) and 27.6 (6.41-119), respectively). The most commonly isolated were gram-negative bacteria, predominantly Escherichia coli and Klebsiella pneumoniae. CONCLUSION In this relatively large population of patients, we used a gold standard for both SIBO (quantitative culture of duodenum's descending part aspirate) and NAFLD (LB), and we demonstrated that NASH patients and those with SF had a higher incidence of SIBO. Moreover, significant predictors independently associated with SIBO were T2DM, fibrosis stage and ballooning grade. Although TE is a well-investigated method for steatosis and fibrosis detection, in our study, independent predictors of SIBO were histological characteristics of NAFLD, while elastographic parameters did not reach statistical significance.
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Affiliation(s)
- Ivana Mikolasevic
- Department of Gastroenterology, UHC Rijeka, Rijeka, Croatia
- Faculty of Medicine, University of Rijeka, Rijeka, Croatia
- Department of Gastroenterology, UH Merkur, Zagreb, Croatia
| | - Bozena Delija
- Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Ana Mijic
- Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | | | | | - Ivan Sosa
- Department of Forensic Medicine and Criminalistics, University of Rijeka Faculty of Medicine, Rijeka, Croatia
| | | | - Maja Abram
- Faculty of Medicine, University of Rijeka, Rijeka, Croatia
- Department of Clinical Microbiology, UHC Rijeka, Rijeka, Croatia
| | - Zeljko Krznaric
- Department of Gastroenterology and Hepatology, UHC Zagreb, Zagreb, Croatia
- Faculty of Medicine, UHC Zagreb, Zagreb, Croatia
| | - Viktor Domislovic
- Department of Gastroenterology and Hepatology, UHC Zagreb, Zagreb, Croatia
| | - Tajana Filipec Kanizaj
- Department of Gastroenterology, UH Merkur, Zagreb, Croatia
- Faculty of Medicine, UHC Zagreb, Zagreb, Croatia
| | - Delfa Radic-Kristo
- Faculty of Medicine, UHC Zagreb, Zagreb, Croatia
- Department of Hematology, UH Merkur, Zagreb, Croatia
| | - Aleksandar Cubranic
- Department of Gastroenterology, UHC Rijeka, Rijeka, Croatia
- Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Aron Grubesic
- Faculty of Medicine, University of Rijeka, Rijeka, Croatia
- Department of Hematology, UHC Rijeka, Rijeka, Croatia
| | - Radislav Nakov
- Queen Yoanna University Hospital, Medical University of Sofia, Sofia, Bulgaria
| | - Ivana Skrobonja
- Department of Clinical Microbiology, UHC Rijeka, Rijeka, Croatia
| | - Davor Stimac
- Department of Gastroenterology, UHC Rijeka, Rijeka, Croatia
- Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Goran Hauser
- Department of Gastroenterology, UHC Rijeka, Rijeka, Croatia
- Faculty of Medicine, University of Rijeka, Rijeka, Croatia
- Faculty of Health Studies, UHC Rijeka, Rijeka, Croatia
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Yamamoto K, Ikeya T, Okuyama S, Fukuda K, Kobayashi D. Association between the Frequency of Daily Toothbrushing and Development of Nonalcoholic Fatty Liver Disease. Dig Dis 2021; 39:646-652. [PMID: 33535206 DOI: 10.1159/000514930] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 01/22/2021] [Indexed: 02/02/2023]
Abstract
UNLABELLED Background & Aim: This study aimed to evaluate the association between the frequency of daily toothbrushing and the development of nonalcoholic fatty liver disease (NAFLD). METHODS A retrospective longitudinal study was conducted from 2005 to 2012 at the Center for Preventive Medicine at St. Luke's International Hospital, Japan. Data on all participants who underwent a health checkup during the study period were collected. NAFLD was diagnosed by abdominal ultrasonography, and all participants who were diagnosed with NAFLD at the time of their initial visit, consumed alcohol in any amount, or had received only one health checkup were excluded. The questionnaire for the frequency of daily toothbrushing was conducted as part of health checkups. The primary outcome was the risk of developing NAFLD according to the frequency of daily toothbrushing (1-2 times a day or 3 times a day) compared to those who brush teeth once or less than once a day. RESULTS Data were collected from 25,804 people. A total of 3,289 (12.7%) participants developed NAFLD. The mean age was 45.2 years, and 6,901 (26.7%) of the participants were male. The risk of developing NAFLD significantly decreased with increased frequency of daily toothbrushing. Adjusted odds ratios (ORs) are as follows: brushing teeth 1-2 times a day (OR: 0.85, 95% confidence interval [CI]: 0.77-0.95) and 3 times a day (OR: 0.74, 95% CI: 0.67-0.82). CONCLUSION Frequent toothbrushing was shown to significantly reduce the risk of developing NAFLD.
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Affiliation(s)
- Kazuki Yamamoto
- Department of Gastroenterology, St. Luke's International Hospital, Tokyo, Japan
| | - Takashi Ikeya
- Department of Gastroenterology, St. Luke's International Hospital, Tokyo, Japan
| | - Shuhei Okuyama
- Department of Gastroenterology, St. Luke's International Hospital, Tokyo, Japan
| | - Katsuyuki Fukuda
- Department of Gastroenterology, St. Luke's International Hospital, Tokyo, Japan
| | - Daiki Kobayashi
- Department of Medicine, St. Luke's International Hospital, Tokyo, Japan.,Department of Epidemiology, St. Luke's Graduate School of Public Health, Tokyo, Japan.,Department of Medicine, Fujita Health University, Toyoake, Japan
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You N, Xu J, Wang L, Zhuo L, Zhou J, Song Y, Ali A, Luo Y, Yang J, Yang W, Zheng M, Xu J, Shao L, Shi J. Fecal Fungi Dysbiosis in Nonalcoholic Fatty Liver Disease. Obesity (Silver Spring) 2021; 29:350-358. [PMID: 33491316 DOI: 10.1002/oby.23073] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 09/28/2020] [Accepted: 10/11/2020] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) can systematically harm more aspects of human health than just the liver. In addition to the potential roles of the gut microbiota in NAFLD, commensal fungi can functionally replace intestinal bacteria in maintaining the host immune response in the gut by reversing disease susceptibility. Therefore, gut commensal fungi should be studied to help understand NAFLD. METHODS The fungal compositions of 79 patients with NAFLD and 34 matched healthy subjects were studied via internal transcribed spacer sequencing. In the NAFLD group, 32 patients underwent liver biopsies to evaluate the associations between gut fungi and NAFLD development. RESULTS The fungal microbiota distribution was skewed in the patients with NAFLD. The relative abundances of Talaromyces, Paraphaeosphaeria, Lycoperdon, Curvularia, Phialemoniopsis, Paraboeremia, Sarcinomyces, Cladophialophora, and Sordaria were higher in patients with NAFLD, whereas the abundances of Leptosphaeria, Pseudopithomyces, and Fusicolla were decreased. Patients with NAFLD exhibited more co-occurring fungal intrakingdom correlations. Several fungi were found to be associated with liver injury, lipid metabolism, and the development of NAFLD. CONCLUSIONS This study found that gut fungi may play some roles in NAFLD development. Research on gut fungi may be of great value in diagnosing and monitoring NAFLD.
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Affiliation(s)
- Ningning You
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province, Affiliated Hospital of Wenzhou Medical University, Taizhou, Zhejiang, China
- Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jiali Xu
- Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Liyan Wang
- Fourth Clinical Medicine College, Zhejiang Chinese Medical University, Zhejiang, China
| | - Lili Zhuo
- Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jingxin Zhou
- Department of Hematology, Suqian First People's Hospital, Suqian, Jiangsu, China
| | - Yu Song
- Fourth Clinical Medicine College, Zhejiang Chinese Medical University, Zhejiang, China
| | - Aliaweis Ali
- Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yan Luo
- Institute of Translational Medicine, The Affiliated Hospital of Hangzhou Normal University-Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jin Yang
- Institute of Translational Medicine, The Affiliated Hospital of Hangzhou Normal University-Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Wenjun Yang
- Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Minghua Zheng
- Nonalcoholic Fatty Liver Disease Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jing Xu
- Department of Endocrinology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Li Shao
- Institute of Translational Medicine, The Affiliated Hospital of Hangzhou Normal University-Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Junping Shi
- Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
- Institute of Translational Medicine, The Affiliated Hospital of Hangzhou Normal University-Hangzhou Normal University, Hangzhou, Zhejiang, China
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Kjær MB, George J, Kazankov K, Grønbæk H. Current perspectives on the pathophysiology of metabolic associated fatty liver disease: are macrophages a viable target for therapy? Expert Rev Gastroenterol Hepatol 2021; 15:51-64. [PMID: 32878486 DOI: 10.1080/17474124.2020.1817740] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Metabolic associated fatty liver disease (MAFLD) is a new nomenclature for fatty liver replacing nonalcoholic fatty liver disease (NAFLD). MAFLD has emerged as the leading cause of liver-related morbidity and mortality with increasing incidence due to its close association with the global epidemic of obesity and type 2 diabetes mellitus. Macrophages play a key role in MAFLD development and progression of steatohepatitis and fibrosis. Therefore, targeting macrophages may be a new therapeutic approach for MAFLD and MAFLD with steatohepatitis. AREAS COVERED We provide a comprehensive review of the significant role of macrophages in MAFLD. Further, we evaluate the current status of lifestyle interventions and pharmacological treatments with a focus on effects mediated through direct or indirect targeting of macrophages. EXPERT OPINION Targeting macrophages holds promise as a treatment option for the management of MAFLD and steatohepatitis. Improved stratification of patients according to MAFLD phenotype would contribute to more adequate design enhancing the yield of clinical trials ultimately leading to personalized medicine for patients with MAFLD. Furthermore, reflecting the multifactorial pathogenesis of MAFLD, combination therapies based on the various pathophysiological driver events including as pertinent to this review, macrophage recruitment, polarization and action, present an intriguing target for future investigation.
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Affiliation(s)
- Mikkel Breinholt Kjær
- Department of Hepatology and Gastroenterology, Aarhus University Hospital , Aarhus, Denmark
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney , Sydney, Australia
| | - Konstantin Kazankov
- Department of Hepatology and Gastroenterology, Aarhus University Hospital , Aarhus, Denmark
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital , Aarhus, Denmark
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GUIMARÃES VM, SANTOS VN, BORGES PSDA, DE FARIAS JLR, GRILLO P, PARISE ER. PERIPHERAL BLOOD ENDOTOXIN LEVELS ARE NOT ASSOCIATED WITH SMALL INTESTINAL BACTERIAL OVERGROWTH IN NONALCOHOLIC FATTY LIVER DISEASE WITHOUT CIRRHOSIS. ARQUIVOS DE GASTROENTEROLOGIA 2020; 57:471-476. [DOI: 10.1590/s0004-2803.202000000-82] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 08/26/2020] [Indexed: 02/07/2023]
Abstract
ABSTRACT BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease worldwide. Approximately 20% of individuals with NAFLD develop nonalcoholic steatohepatitis (NASH), which is associated with increased risk of cirrhosis, portal hypertension, and hepatocellular carcinoma. Intestinal microflora, including small intestinal bacterial overgrowth (SIBO), appear to play an important role in the pathogenesis of the disease, as demonstrated in several clinical and experimental studies, by altering intestinal permeability and allowing bacterial endotoxins to enter the circulation. OBJECTIVE: To determine the relationship between SIBO and endotoxin serum levels with clinical, laboratory, and histopathological aspects of NAFLD and the relationship between SIBO and endotoxin serum levels before and after antibiotic therapy. METHODS: Adult patients with a histological diagnosis of NAFLD, without cirrhosis were included. A comprehensive biochemistry panel, lactulose breath test (for diagnosis of SIBO), and serum endotoxin measurement (chromogenic LAL assay) were performed. SIBO was treated with metronidazole 250 mg q8h for 10 days and refractory cases were given ciprofloxacin 500 mg q12h for 10 days. RESULTS: Overall, 42 patients with a histopathological diagnosis of NAFLD were examined. The prevalence of SIBO was 26.2%. Comparison of demographic and biochemical parameters between patients with SIBO and those without SIBO revealed no statistically significant differences, except for use of proton pump inhibitors, which was significantly more frequent in patients with positive breath testing. The presence of SIBO was also associated with greater severity of hepatocellular ballooning on liver biopsy. Although the sample, as a whole, have elevated circulating endotoxin levels, we found no significant differences in this parameter between the groups with and without SIBO. Endotoxin values before and after antibiotic treatment did not differ, even on paired analysis, suggesting absence of any relationship between these factors. Serum endotoxin levels were inversely correlated with HDL levels, and directly correlated with triglyceride levels. CONCLUSION: Serum endotoxin levels did not differ between patients with and without SIBO, nor did these levels change after antibacterial therapy, virtually ruling out the possibility that elevated endotoxinemia in non-cirrhotic patients with NAFLD is associated with SIBO. Presence of SIBO was associated with greater severity of ballooning degeneration on liver biopsy, but not with a significantly higher prevalence of NASH. Additional studies are needed to evaluate the reproducibility and importance of this finding in patients with NAFLD and SIBO.
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de Barros F, Fonseca ABM. Bariatric surgery during the evolution of fatty liver-A randomized clinical trial comparing gastric bypass and sleeve gastrectomy based on transient elastography. Clin Obes 2020; 10:e12393. [PMID: 32885600 DOI: 10.1111/cob.12393] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 06/27/2020] [Accepted: 07/01/2020] [Indexed: 12/25/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is closely related to patients with obesity. For patients with NAFLD, bariatric surgery is the best treatment. However, the best technique to patient with severe NAFLD is still unknown. Currently available, the imaging methods for assessing and monitoring NAFLD are of limited use for diagnosing. In contrast, compared with liver biopsy and transient hepatic elastography (THE) has shown good accuracy in individuals with obesity. To prospectively compare the evolution of THE parameters of NAFLD right after the procedures: gastric bypass vs sleeve gastrectomy. Patients with obesity were randomized into two groups: gastric bypass and sleeve gastrectomy in a previous study. Iin a previous study one week before and three months after surgery the patients underwent evaluation by THE. The patients were also analyzed with controlled attenuation parameter (CAP), which assesses the degree of hepatic steatosis using the same device. Sleeve gastrectomy group showed a greater decrease in THE values (from 8.13 to 5.53 kPa) compared to the gastric bypass group (from 9.25 to 8.81 kPa; P = .004). CAP also revealed a greater decrease in sleeve subjects (from 287 to 242 dB/m) compared to gastric bypass subjects (from 290 to 276 dB/m; P < .0001). The absolute values of these differences also had a largest decrease with both methods in sleeve gastrectomy group (P = .013 and P = .005 for THE and CAP, respectively).Sleeve gastrectomy showed a greater decrease in both parameters (THE and CAP) than gastric bypass in the first months.
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Affiliation(s)
- Fernando de Barros
- Department of General Surgery, Fluminense Federal University, Niterói, RJ, Brazil
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Lucius K. Nutritional and Botanical Approaches for Nonalcoholic Fatty Liver Disease. ALTERNATIVE AND COMPLEMENTARY THERAPIES 2020; 26:246-254. [DOI: 10.1089/act.2020.29303.klu] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Affiliation(s)
- Khara Lucius
- Khara Lucius, ND, FABNO, is a naturopathic doctor at the Center for Integrative Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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Kuchay MS, Choudhary NS, Mishra SK. Pathophysiological mechanisms underlying MAFLD. Diabetes Metab Syndr 2020; 14:1875-1887. [PMID: 32998095 DOI: 10.1016/j.dsx.2020.09.026] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/21/2020] [Accepted: 09/23/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The pathophysiology underlying metabolic associated fatty liver disease (MAFLD) involves a multitude of interlinked processes, including insulin resistance (IR) underlying the metabolic syndrome, lipotoxicity attributable to the accumulation of toxic lipid species, infiltration of proinflammatory cells causing hepatic injury and ultimately leading to hepatic stellate cell (HSC) activation and fibrogenesis. The proximal processes, such as IR, lipid overload and lipotoxicity are relatively well established, but the downstream molecular mechanisms, such as inflammatory processes, hepatocyte lipoapoptosis, and fibrogenesis are incompletely understood. METHODS A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases till June 2020, using relevant keywords (nonalcoholic fatty liver disease; metabolic associated fatty liver disease; nonalcoholic steatohepatitis; NASH pathogenesis) to extract relevant studies describing pathogenesis of MAFLD/MASH. RESULTS Several studies have reported new concepts underlying pathophysiology of MAFLD. Activation of HSCs is the common final pathway for diverse signals from damaged hepatocytes and proinflammatory cells. Activated HSCs then secrete excess extracellular matrix (ECM) which accumulates and impairs structure and function of the liver. TAZ (a transcriptional regulator), hedgehog (HH) ligands, transforming growth factor-β (TGF-β), bone morphogenetic protein 8B (BMP8B) and osteopontin play important roles in activating these HSCs. Dysfunctional gut microbiome, dysregulated bile acid metabolism, endogenous alcohol production, and intestinal fructose handling, modify individual susceptibility to MASH. CONCLUSIONS Newer concepts of pathophysiology underlying MASH, such as TAZ/Ihh pathway, extracellular vesicles, microRNA, dysfunctional gut microbiome and intestinal fructose handling present promising targets for the development of therapeutic agents.
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Affiliation(s)
- Mohammad Shafi Kuchay
- Division of Endocrinology and Metabolism, Medanta the Medicity Hospital, Gurugram, 122001, Haryana, India.
| | - Narendra Singh Choudhary
- Institute of Digestive and Hepatobiliary Sciences, Medanta-The Medicity Hospital, Gurugram, 122001, Haryana, India
| | - Sunil Kumar Mishra
- Division of Endocrinology and Metabolism, Medanta the Medicity Hospital, Gurugram, 122001, Haryana, India
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Noureddin M, Muthiah MD, Sanyal AJ. Drug discovery and treatment paradigms in nonalcoholic steatohepatitis. Endocrinol Diabetes Metab 2020; 3:e00105. [PMID: 33102791 PMCID: PMC7576222 DOI: 10.1002/edm2.105] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 11/05/2019] [Accepted: 11/09/2019] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in western populations, and is closely associated with features of the metabolic syndrome. The burden of disease is set to rise exponentially, and this is further compounded by the lack of good medications. In addition, these patients tend to have multiple comorbidities that may not be adequately managed. In this article, we review the biological basis of potential therapies in nonalcoholic steatohepatitis (NASH), the current drugs being tested in clinical trials, as well some practical considerations in managing patients in the clinic.
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Affiliation(s)
- Mazen Noureddin
- Division of Digestive and Liver DiseasesComprehensive Transplant CenterCedars Sinai Medical CenterLos AngelesCalifornia
| | - Mark D. Muthiah
- Department of MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore
- Division of Gastroenterology and HepatologyNational University HospitalNational University Health SystemSingapore
| | - Arun J. Sanyal
- Division of Gastroenterology, Hepatology and NutritionVirginia Commonwealth University School of MedicineRichmondVirginia
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Zhao P, Saltiel AR. From overnutrition to liver injury: AMP-activated protein kinase in nonalcoholic fatty liver diseases. J Biol Chem 2020; 295:12279-12289. [PMID: 32651233 PMCID: PMC7443502 DOI: 10.1074/jbc.rev120.011356] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/24/2020] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver diseases (NAFLDs), especially nonalcoholic steatohepatitis (NASH), have become a major cause of liver transplant and liver-associated death. However, the pathogenesis of NASH is still unclear. Currently, there is no FDA-approved medication to treat this devastating disease. AMP-activated protein kinase (AMPK) senses energy status and regulates metabolic processes to maintain homeostasis. The activity of AMPK is regulated by the availability of nutrients, such as carbohydrates, lipids, and amino acids. AMPK activity is increased by nutrient deprivation and inhibited by overnutrition, inflammation, and hypersecretion of certain anabolic hormones, such as insulin, during obesity. The repression of hepatic AMPK activity permits the transition from simple steatosis to hepatocellular death; thus, activation might ameliorate multiple aspects of NASH. Here we review the pathogenesis of NAFLD and the impact of AMPK activity state on hepatic steatosis, inflammation, liver injury, and fibrosis during the transition of NAFL to NASH and liver failure.
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Affiliation(s)
- Peng Zhao
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Alan R Saltiel
- Department of Medicine, University of California San Diego, La Jolla, California, USA; Department of Pharmacology, University of California San Diego, La Jolla, California, USA.
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45
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Hodges JK, Sasaki GY, Bruno RS. Anti-inflammatory activities of green tea catechins along the gut-liver axis in nonalcoholic fatty liver disease: lessons learned from preclinical and human studies. J Nutr Biochem 2020; 85:108478. [PMID: 32801031 DOI: 10.1016/j.jnutbio.2020.108478] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/02/2020] [Accepted: 07/23/2020] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD), which is the most prevalent hepatic disorder worldwide, affecting 25% of the general population, describes a spectrum of progressive liver conditions ranging from relatively benign liver steatosis and advancing to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Hallmark features of NASH are fatty hepatocytes and inflammatory cell infiltrates in association with increased activation of hepatic nuclear factor kappa-B (NFκB) that exacerbates liver injury. Because no pharmacological treatments exist for NAFLD, emphasis has been placed on dietary approaches to manage NASH risk. Anti-inflammatory bioactivities of catechin-rich green tea extract (GTE) have been well-studied, especially in preclinical models that have detailed its effects on inflammatory responses downstream of NFκB activation. This review will therefore discuss the experimental evidence that has advanced an understanding of the mechanisms by which GTE, either directly through its catechins or potentially indirectly through microbiota-derived metabolites, limits NFκB activation and NASH-associated liver injury. Specifically, it will describe the hepatic-level benefits of GTE that attenuate intracellular redox distress and pro-inflammatory signaling from extracellular receptors that otherwise activate NFκB. In addition, it will discuss the anti-inflammatory activities of GTE on gut barrier function as well as prebiotic and antimicrobial effects on gut microbial ecology that help to limit the translocation of gut-derived endotoxins (e.g. lipopolysaccharides) to the liver where they otherwise upregulate NFκB activation by Toll-like receptor-4 signaling. This summary is therefore expected to advance research translation of the hepatic- and intestinal-level benefits of GTE and its catechins to help manage NAFLD-associated morbidity.
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Affiliation(s)
- Joanna K Hodges
- Human Nutrition Program, The Ohio State University, Columbus, OH 43210
| | - Geoffrey Y Sasaki
- Human Nutrition Program, The Ohio State University, Columbus, OH 43210
| | - Richard S Bruno
- Human Nutrition Program, The Ohio State University, Columbus, OH 43210.
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Abstract
Acute on chronic liver failure (ACLF) is an inflammation-based disorder that occurs in patients with underlying liver disease and is characterized by hepatic and extrahepatic organ failure. Morbidity and mortality are high in patients with ACLF, and therefore prevention and early identification are critical to improve outcome. The purpose of this article is to define ACLF, describe ways to identify the expected outcome of ACLF after development, and illustrate interventions to prevent it and when it is not preventable reduce associated morbidity and mortality.
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Affiliation(s)
- Ariel Aday
- University of Texas Southwestern, 5323 Harry Hines Blvd, Dallas, TX 75390, USA
| | - Jacqueline G O'Leary
- University of Texas Southwestern, 5323 Harry Hines Blvd, Dallas, TX 75390, USA; Dallas Veterans Affairs Medical Center, 4500 South Lancaster Road, Dallas, TX 75216, USA.
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Lichota A, Gwozdzinski K, Szewczyk EM. Microbial Modulation of Coagulation Disorders in Venous Thromboembolism. J Inflamm Res 2020; 13:387-400. [PMID: 32801832 PMCID: PMC7406375 DOI: 10.2147/jir.s258839] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 06/19/2020] [Indexed: 12/24/2022] Open
Abstract
Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third leading cause of cardiovascular death in the world. Important risk factors of thrombosis include bed restraint, surgery, major trauma, long journeys, inflammation, pregnancy, and oral contraceptives, previous venous thromboembolism, cancer, and bacterial infections. Sepsis increases the risk of blood clot formation 2–20 times. In this review, we discussed various mechanisms related to the role of bacteria in venous thrombosis also taking into consideration the role of the human microbiome. Many known bacteria, such as Helicobacter pylori, Chlamydia pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, and Escherichia coli, causing infections may increase the risk of thrombotic complications through platelet activation or may lead to an inflammatory reaction involving the fibrinolytic system. Additionally, the bacteria participate in the production of factors causing or increasing the risk of cardiovascular diseases. An example can be trimethylamine N-oxide (TMAO) but also uremic toxins (indoxyl sulfate), short-chain fatty acids (SCFA) phytoestrogens, and bile acids. Finally, we presented the involvement of many bacteria in the development of venous thromboembolism and other cardiovascular diseases.
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Affiliation(s)
- Anna Lichota
- Department of Pharmaceutical Microbiology and Microbiological Diagnostics, Faculty of Pharmacy, Medical University of Lodz, Lodz, Poland
| | - Krzysztof Gwozdzinski
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Eligia M Szewczyk
- Department of Pharmaceutical Microbiology and Microbiological Diagnostics, Faculty of Pharmacy, Medical University of Lodz, Lodz, Poland
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Bertges ER, Chebli JMF. PREVALENCE AND FACTORS ASSOCIATED WITH SMALL INTESTINAL BACTERIAL OVERGROWTH IN PATIENTS WITH CROHN'S DISEASE: A RETROSPECTIVE STUDY AT A REFERRAL CENTER. ARQUIVOS DE GASTROENTEROLOGIA 2020; 57:283-288. [PMID: 33027485 DOI: 10.1590/s0004-2803.202000000-64] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 06/26/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Small intestinal bacterial overgrowth (SIBO) appears to be common in patients with Crohn's disease (CD). The rate of SIBO has been estimated at 25%-88% in this setting. However, different demographic, socioeconomic, and disease-related factors may exist between South American and North American or European populations that may limit the generalization of these findings, as the data are mainly derived from North American or European studies. OBJECTIVE We studied the prevalence and predictors of SIBO in CD outpatients. METHODS In this retrospective study, between June 2011 and June 2016, the medical records of 110 CD patients were assessed for presence of SIBO using the H2/CH4 glucose breath test. Univariate analysis was performed to investigate the potential association between SIBO and demographic, disease-related data, systemic markers of inflammation (C-reactive protein and erythrocyte sedimentation rate). RESULTS The SIBO rate was high in CD patients (30%). Patients with and without SIBO were comparable according to demographics, systemic inflammatory biomarkers, and disease characteristics, except to the stricturing phenotype more common in the SIBO-positive CD patients (48.5% vs 19.5%, P=0.001). CONCLUSION In Brazilian CD patients, SIBO is a highly prevalent condition. Stricturing phenotype demonstrated association with SIBO. An individualized screening plan followed by the timely treatment for SIBO should be carried out as part of quality of care improvement in CD individuals.
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Small intestinal bacterial overgrowth and nonalcoholic fatty liver disease: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2020; 32:601-608. [PMID: 31567712 DOI: 10.1097/meg.0000000000001541] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Recent studies have suggested that small intestinal bacterial overgrowth (SIBO) could be a predisposing factor for nonalcoholic fatty liver disease (NAFLD) although the results were inconsistent. This systematic review and meta-analysis was conducted with the aim to summarize all available data. METHODS A comprehensive literature review was conducted utilizing MEDLINE and EMBASE databases through September 2018 to identify all studies that compared the risk of NAFLD among patients with SIBO versus those without SIBO. Effect estimates from each study were extracted and combined together using the random effect, generic inverse variance method of DerSimonian and Laird. RESULTS A total of 10 studies with 1093 participants fulfilled the eligibility criteria and were included in the meta-analysis. A significant association between NAFLD and SIBO was observed with the pooled odds ratio of 3.82 (95% confidence interval, 1.93-7.59; I 65%). Funnel plot is relatively symmetric and is not suggestive of the presence of publication bias. CONCLUSION A significant association between NAFLD and SIBO was observed in this meta-analysis.
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Chong CYL, Orr D, Plank LD, Vatanen T, O’Sullivan JM, Murphy R. Randomised Double-Blind Placebo-Controlled Trial of Inulin with Metronidazole in Non-Alcoholic Fatty Liver Disease (NAFLD). Nutrients 2020; 12:nu12040937. [PMID: 32230987 PMCID: PMC7230525 DOI: 10.3390/nu12040937] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 03/19/2020] [Accepted: 03/24/2020] [Indexed: 12/17/2022] Open
Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) can be ameliorated by weight loss although difficult to maintain. Emerging evidence indicates that prebiotics and antibiotics improve NAFLD. Aim: To determine whether inulin supplementation after brief metronidazole therapy is effective in reducing alanine aminotransferase (ALT) and maintaining weight loss achieved through a very-low-calorie diet (VLCD) among people with NAFLD. Methods: Sixty-two people with NAFLD commenced 4-week VLCD using Optifast meal replacements (600 kcal/day). Sixty were then randomised into a 12-week double-blind, placebo-controlled, parallel three-arm trial: (1) 400 mg metronidazole twice daily in Week 1 then inulin 4 g twice daily OR (2) placebo twice daily in week one then inulin OR (3) placebo-placebo. Main outcomes were ALT and body weight at 12 weeks. Fecal microbiota changes were also evaluated. Results: Mean body mass index (BMI) and ALT reduced after VLCD by 2.4 kg/m2 and 11 U/L, respectively. ALT further decreased after metronidazole-inulin compared to after placebo-placebo (mean ALT change -19.6 vs. -0.2 U/L, respectively; p = 0.026); however, weight loss maintenance did not differ. VLCD treatment decreased the ratio of Firmicutes/Bacteroidetes (p = 0.002). Conclusion: Brief metronidazole followed by inulin supplementation can reduce ALT beyond that achieved after VLCD in patients with NAFLD.
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Affiliation(s)
- Clara Yieh Lin Chong
- Liggins Institute, The University of Auckland, Auckland 1142, New Zealand; (C.Y.L.C.); (T.V.); (J.M.O.)
| | - David Orr
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland 1023, New Zealand
- Correspondence: (D.O.); (R.M.); Tel.: +64-9-923-6313
| | - Lindsay D. Plank
- Department of Surgery, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand;
| | - Tommi Vatanen
- Liggins Institute, The University of Auckland, Auckland 1142, New Zealand; (C.Y.L.C.); (T.V.); (J.M.O.)
| | - Justin M. O’Sullivan
- Liggins Institute, The University of Auckland, Auckland 1142, New Zealand; (C.Y.L.C.); (T.V.); (J.M.O.)
| | - Rinki Murphy
- Department of Medicine, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand
- Correspondence: (D.O.); (R.M.); Tel.: +64-9-923-6313
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