Author information

¹Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

²Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

³Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.

⁴Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

⁵Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.

⁶Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

⁷Division of General Surgery, University of Toronto, Toronto, Ontario, Canada.

⁸Division of General Surgery, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.

⁹Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Abstract

Background and aims: Bacterial species and microbial pathways along with metabolites and clinical parameters may interact to contribute to non-alcoholic fatty liver disease (NAFLD) and disease severity. We used integrated machine learning models and a cross-validation approach to assess this interaction in bariatric patients.

Methods: 113 patients undergoing bariatric surgery had clinical and biochemical parameters, blood and stool metabolite measurements as well as faecal shotgun metagenome sequencing to profile the intestinal microbiome. Liver histology was classified as normal liver obese (NLO; n = 30), simple steatosis (SS; n = 41) or non-alcoholic steatohepatitis (NASH; n = 42); fibrosis was graded F0 to F4.

Results: We found that those with NASH versus NLO had an increase in potentially harmful E. coli, a reduction of potentially beneficial Alistipes putredinis and an increase in ALT and AST. There was higher serum glucose, faecal 3-(3-hydroxyphenyl)-3-hydroxypropionic acid and faecal cholic acid and lower serum glycerophospholipids. In NAFLD, those with severe fibrosis (F3-F4) versus F0 had lower abundance of anti-inflammatory species (Eubacterium ventriosum, Alistipes finegoldii and Bacteroides dorei) and higher AST, serum glucose, faecal acylcarnitines, serum isoleucine and homocysteine as well as lower serum glycerophospholipids. Pathways involved with amino acid biosynthesis and degradation were significantly more represented in those with NASH compared to NLO, with severe fibrosis having an overall stronger significant association with Superpathway of menaquinol-10 biosynthesis and Peptidoglycan biosynthesis IV.

Conclusions: In bariatric patients, NASH and severe fibrosis were associated with specific bacterial species, metabolic pathways and metabolites that may contribute to NAFLD pathogenesis and disease severity.