Prevalence of Small Intestinal Bacterial Overgrowth Syndrome in Patients with Non-Alcoholic Fatty Liver Disease/Non-Alcoholic Steatohepatitis: A Cross-Sectional Study

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial, wide-spectrum liver disorder. Small intestinal bacterial overgrowth (SIBO) is characterized by an increase in the number and/or type of colonic bacteria in the upper gastrointestinal tract. SIBO, through energy salvage and induction of inflammation, may be a pathophysiological factor for NAFLD development and progression. Aim/Methods: Consecutive patients with histological, biochemical, or radiological diagnosis of any stage of NAFLD (non-alcoholic fatty liver [NAFL], non-alcoholic steatohepatitis [NASH], cirrhosis) underwent upper gastrointestinal endoscopy. Duodenal fluid (2cc) was aspirated from the 3rd–4th part of duodenum into sterile containers. SIBO was defined as ≥103 aerobic colony-forming units (CFU)/mL of duodenal aspirate and/or the presence of colonic-type bacteria. Patients without any liver disease undergoing gastroscopy due to gastroesophageal reflux disease (GERD) comprised the healthy control (HC) group. Concentrations (pg/mL) of tumor necrosis factor alpha (TNFα), interleukin (IL)-1β, and IL-6 were also measured in the duodenal fluid. The primary endpoint was to evaluate the prevalence of SIBO in NAFLD patients, while the comparison of SIBO prevalence among NAFLD patients and healthy controls was a secondary endpoint. Results: We enrolled 125 patients (51 NAFL, 27 NASH, 17 cirrhosis, and 30 HC) aged 54 ± 11.9 years and with a weight of 88.3 ± 19.6 kg (NAFLD vs. HC 90.7 ± 19.1 vs. 80.8 ± 19.6 kg, p = 0.02). Overall, SIBO was diagnosed in 23/125 (18.4%) patients, with Gram-negative bacteria being the predominant species (19/23; 82.6%). SIBO prevalence was higher in the NAFLD cohort compared to HC (22/95; 23.2% vs. 1/30; 3.3%, p = 0.014). Patients with NASH had higher SIBO prevalence (6/27; 22.2%) compared to NAFL individuals (8/51; 15.7%), but this difference did not reach statistical significance (p = 0.11). Patients with NASH-associated cirrhosis had a higher SIBO prevalence compared to patients with NAFL (8/17; 47.1% vs. 8/51; 15.7%, p = 0.02), while SIBO prevalence between patients with NASH-associated cirrhosis and NASH was not statistically different (8/17; 47.1% vs. 6/27; 22.2%, p = 0.11). Mean concentration of TNF-α, IL-1β, and IL-6 did not differ among the different groups. Conclusion: The prevalence of SIBO is significantly higher in a cohort of patients with NAFLD compared to healthy controls. Moreover, SIBO is more prevalent in patients with NASH-associated cirrhosis compared to patients with NAFL.

[1]  T. Pintar,et al.  Small Intestinal Bacterial Overgrowth in Patients with Roux-en-Y Gastric Bypass and One-Anastomosis Gastric Bypass , 2022, Obesity Surgery.

[2]  M. Noureddin,et al.  AGA Clinical Practice Update: Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Lean Individuals: Expert Review. , 2022, Gastroenterology.

[3]  E. Rinninella,et al.  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 , 2022, Frontiers in Medicine.

[4]  H. Tilg,et al.  Global multi-stakeholder endorsement of the MAFLD definition. , 2022, The lancet. Gastroenterology & hepatology.

[5]  A. Papaefthymiou,et al.  Inflammatory Bowel Disease-associated Fatty Liver Disease: the Potential Effect of Biologic Agents. , 2021, Journal of Crohn's & Colitis.

[6]  M. Alizadeh,et al.  Contribution of gut microbiota to nonalcoholic fatty liver disease: Pathways of mechanisms. , 2021, Clinical nutrition ESPEN.

[7]  A. Mijić,et al.  Small intestinal bacterial overgrowth and non‐alcoholic fatty liver disease diagnosed by transient elastography and liver biopsy , 2021, International journal of clinical practice.

[8]  Shanshan Zhu,et al.  Small intestinal bacterial overgrowth and orocecal transit time in patients of nonalcoholic fatty liver disease , 2020, European journal of gastroenterology & hepatology.

[9]  OUP accepted manuscript , 2021, Journal of Crohn's & Colitis.

[10]  E. Parise,et al.  PERIPHERAL BLOOD ENDOTOXIN LEVELS ARE NOT ASSOCIATED WITH SMALL INTESTINAL BACTERIAL OVERGROWTH IN NONALCOHOLIC FATTY LIVER DISEASE WITHOUT CIRRHOSIS. , 2020, Arquivos de gastroenterologia.

[11]  M. Pimentel,et al.  High Prevalence of Small Intestinal Bacterial Overgrowth among Functional Dyspepsia Patients , 2020, Digestive Diseases.

[12]  F. Pace,et al.  Non-alcoholic Steatohepatitis: Comparison of Intestinal Microbiota between Different Metabolic Profiles. A Pilot Study. , 2020, Journal of gastrointestinal and liver diseases : JGLD.

[13]  M. Rehan,et al.  Capsule robot for gut microbiota sampling using shape memory alloy spring , 2020, The international journal of medical robotics + computer assisted surgery : MRCAS.

[14]  G. Barlow,et al.  The duodenal microbiome is altered in small intestinal bacterial overgrowth , 2020, PloS one.

[15]  Jose Fernando Waimin,et al.  Smart capsule for non-invasive sampling and studying of the gastrointestinal microbiome , 2020, RSC advances.

[16]  U. Ghoshal,et al.  Gut microbiota abnormalities, small intestinal bacterial overgrowth, and non-alcoholic fatty liver disease: An emerging paradigm , 2020, Indian Journal of Gastroenterology.

[17]  M. Pimentel,et al.  ACG Clinical Guideline: Small Intestinal Bacterial Overgrowth. , 2020, The American journal of gastroenterology.

[18]  S. Pungpapong,et al.  Small intestinal bacterial overgrowth and nonalcoholic fatty liver disease: a systematic review and meta-analysis , 2020, European journal of gastroenterology & hepatology.

[19]  J. González-Navajas,et al.  Circulating levels of butyrate are inversely related to portal hypertension, endotoxemia, and systemic inflammation in patients with cirrhosis , 2019, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  R. Gani,et al.  The role of Small Intestinal Bacterial Overgrowth (SIBO) in Non-alcoholic Fatty Liver Disease (NAFLD) patients evaluated using Controlled Attenuation Parameter (CAP) Transient Elastography (TE): a tertiary referral center experience , 2019, BMC Gastroenterology.

[21]  M. Kukla,et al.  Small intestinal bacterial overgrowth and nonalcoholic fatty liver disease , 2019, Clinical and experimental hepatology.

[22]  E. Giamarellos‐Bourboulis,et al.  Effect of a Preparation of Four Probiotics on Symptoms of Patients with Irritable Bowel Syndrome: Association with Intestinal Bacterial Overgrowth , 2018, Probiotics and Antimicrobial Proteins.

[23]  A. Gastaldelli,et al.  Author Correction: Lack of NLRP3-inflammasome leads to gut-liver axis derangement, gut dysbiosis and a worsened phenotype in a mouse model of NAFLD , 2017, Scientific Reports.

[24]  U. Ghoshal,et al.  Low-grade small intestinal bacterial overgrowth is common in patients with non-alcoholic steatohepatitis on quantitative jejunal aspirate culture , 2017, Indian Journal of Gastroenterology.

[25]  Henry C. Lin,et al.  Hydrogen and Methane-Based Breath Testing in Gastrointestinal Disorders: The North American Consensus , 2017, The American Journal of Gastroenterology.

[26]  R. Saouaf,et al.  Magnetic resonance imaging and transient elastography in the management of Nonalcoholic Fatty Liver Disease (NAFLD) , 2017, Expert review of clinical pharmacology.

[27]  Shujie Chen,et al.  Meta-analysis: proton pump inhibitors moderately increase the risk of small intestinal bacterial overgrowth , 2017, Journal of Gastroenterology.

[28]  P. Hayes,et al.  The impact of proton pump inhibitor therapy on patients with liver disease , 2016, Alimentary pharmacology & therapeutics.

[29]  M. Pimentel,et al.  Small intestinal bacterial overgrowth is associated with irritable bowel syndrome and is independent of proton pump inhibitor usage , 2016, BMC Gastroenterology.

[30]  Y. Chawla,et al.  Small intestinal bacterial overgrowth and toll‐like receptor signaling in patients with non‐alcoholic fatty liver disease , 2016, Journal of gastroenterology and hepatology.

[31]  K. Triantafyllou,et al.  Gut microbiota and non-alcoholic fatty liver disease. , 2015, Hepatobiliary & pancreatic diseases international : HBPD INT.

[32]  P. Malfertheiner,et al.  Kyoto global consensus report on Helicobacter pylori gastritis , 2015, Gut.

[33]  Clarence C Lee,et al.  Molecular assessment of differences in the duodenal microbiome in subjects with irritable bowel syndrome , 2015, Scandinavian journal of gastroenterology.

[34]  G. Barlow,et al.  The microbiome in non-alcoholic fatty liver disease: associations and implications , 2014, Annals of gastroenterology.

[35]  Y. Chawla,et al.  Obesity and NAFLD: the role of bacteria and microbiota. , 2014, Clinics in liver disease.

[36]  N. Bhala,et al.  Epidemiology and natural history of patients with NAFLD. , 2013, Current pharmaceutical design.

[37]  Masoumeh Sikaroodi,et al.  Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. , 2013, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[38]  Jun Yu,et al.  Molecular Characterization of the Fecal Microbiota in Patients with Nonalcoholic Steatohepatitis – A Longitudinal Study , 2013, PloS one.

[39]  E. Comelli,et al.  Intestinal microbiota in patients with nonalcoholic fatty liver disease , 2013, Hepatology.

[40]  Lixin Zhu,et al.  Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: A connection between endogenous alcohol and NASH , 2013, Hepatology.

[41]  K. Cusi,et al.  Corrigendum:The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association , 2012, The American Journal of Gastroenterology.

[42]  Natalie J. Wood Microbiota: Dysbiosis driven by inflammasome deficiency exacerbates hepatic steatosis and governs rate of NAFLD progression , 2012, Nature Reviews Gastroenterology &Hepatology.

[43]  M. Pimentel,et al.  The Prevalence of Overgrowth by Aerobic Bacteria in the Small Intestine by Small Bowel Culture: Relationship with Irritable Bowel Syndrome , 2012, Digestive Diseases and Sciences.

[44]  Richard A. Flavell,et al.  Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity , 2012, Nature.

[45]  E. Quigley,et al.  The role of the gut microbiota in nonalcoholic fatty liver disease , 2010, Nature Reviews Gastroenterology &Hepatology.

[46]  H. Tilg,et al.  Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis , 2010, Hepatology.

[47]  Cameron D. Palmer,et al.  PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease , 2010, Hepatology.

[48]  A. Schwiertz,et al.  Microbiota and SCFA in Lean and Overweight Healthy Subjects , 2010, Obesity.

[49]  P. Newsome,et al.  Pathogenesis of non-alcoholic fatty liver disease , 2009, QJM : monthly journal of the Association of Physicians.

[50]  G. La Torre,et al.  Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease , 2009, Hepatology.

[51]  S. Pocock,et al.  The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. , 2008, Journal of clinical epidemiology.

[52]  S. Msika,et al.  High Prevalence of Small Intestinal Bacterial Overgrowth in Patients with Morbid Obesity: A Contributor to Severe Hepatic Steatosis , 2008, Obesity surgery.

[53]  S. Pocock,et al.  The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. , 2007, Preventive medicine.

[54]  R. Knight,et al.  The Human Microbiome Project , 2007, Nature.

[55]  G. Marchesini,et al.  Insulin resistance: A metabolic pathway to chronic liver disease , 2005, Hepatology.

[56]  F. Bäckhed,et al.  Obesity alters gut microbial ecology. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[57]  G. Bedogni,et al.  Prevalence of and risk factors for nonalcoholic fatty liver disease: The Dionysos nutrition and liver study , 2005, Hepatology.

[58]  C. Day,et al.  Steatohepatitis: a tale of two "hits"? , 1998, Gastroenterology.