Peripheral Blood Endotoxin Levels Are Not Associated With Small Intestinal Bacterial Overgrowth in Nonalcoholic Fatty Liver Disease Without Cirrhosis

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.

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

“…This finding would suggest that the intermediate stage of liver disease, either of metabolic or alcoholic abuse origin, does not seem to impact or to be affected by deranged upper GI tract dysbiosis, namely, SIBO. This finding is in contrast with other reports in the literature that suggest bigger prevalence of SIBO in NASH vs. NAFLD, or at least its evolving histologic stage of ballooning ( 17 , 18 ). In the present study there is lack of histopathology data, a more direct measure of LF than fibroscan.…”

“…However, SIBO prevalence in NAFLD is significantly variable, ranging between 17, 26.2, and 60% according to the reports ( 32 – 37 ). More recently, Guimaraes et al described SIBO prevalence in a population of patients with NAFLD to be of 26.2 % ( 18 ). However, in this study, only patients with NAFLD and NASH were studied compared to our investigation.…”

“…Serum endotoxin measurement was performed by a chromogenic Limulus Amebocyte Lysate (LAL) assay with a QCL-1000™ LAL Endpoint Assay (Lonza, NJ, United States) commercial analysis kit on sera previously stored at −70°C ( 18 ).…”

“…In detail, several systematic reviews of literature and meta-analyses have confirmed a statistical association between SIBO and NAFLD stages ( 16 , 17 ). However, recent original research studies by Guimaraes and Nier have shown how the pathophysiological link between SIBO and NAFLD stages is far from being explained ( 18 , 19 ). Indeed, another index of gut dysbiosis, namely, peripheral blood endotoxemia (one of the most common PAMPs), seems to be involved in the passage from NAFLD to the NASH stage of liver disease ( 18 , 19 ).…”

Advances in the diagnosis and therapy of liver cirrhosis: a systematic review / Avanços no diagnóstico e terapia da cirrose hepática: uma revisão sistemática

“…Curry et al (2015) conducted an open phase 3 study involving HCV genotypes with sofosbuvir-velpatasvir or without ribavirin involving patients who developed decompensated cirrhosis. The study involved 267 patients using the drugs for 12 and 24weeks and had reached the conclusion that there are high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis Guimarães et al (2020). determined the relationship between BIS and serum endotoxin levels in non-cirrhotic patients with NAFLD, with the clinical, laboratory and histopathological aspects of the disease and the relationship between BIS and serum endotoxin levels before and after antibiotic treatment.…”