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Abstract Details
The Commensal Microbe Veillonella as a Marker for Response to an FGF19 Analog in Nonalcoholic Steatohepatitis
Hepatology. 2020 Aug 13. doi: 10.1002/hep.31523. Online ahead of print.
Rohit Loomba1, Lei Ling2, Duy M Dinh3, Alex M DePaoli2, Hsiao D Lieu2, Stephen A Harrison45, Arun J Sanyal6
Author information
1NAFLD Research Center, University of California, San Diego, United States.
2NGM Biopharmaceuticals, South San Francisco, United States.
3Diversigen, Houston, United States.
4University of Oxford, London, United Kingdom.
5Pinnacle Clinical Research, San Antonio, United States, San Antonio.
6Virginia Commonwealth University, Richmond, United States.
Abstract
Background & aims: The composition of the human gut microbiota is linked to health and disease, and knowledge of the impact of therapeutics on the microbiota is essential to decipher their biological roles and to gain new mechanistic insights. Here we report the effect of aldafermin, an analog of the gut hormone FGF19, versus placebo on the gut microbiota in a prospective, phase 2 study in patients with NASH.
Approach & results: 176 patients with biopsy-confirmed NASH (NAS ≥4), fibrosis (F1-F3 by NASH CRN criteria) and elevated liver fat content (≥8% by MRI-PDFF) received 0.3 mg (n=23), 1 mg (n=49), 3 mg (n=49), 6 mg (n=28) aldafermin or placebo (n=27) for 12 weeks. Stool samples were collected on day 1 and week 12 and profiled using 16S rRNA gene sequencing; 122 patients had paired stool microbiome profiles at both day 1 and week 12. Overall, the state of the gut microbial community was distinctly stable in patients treated with aldafermin, with all major phyla and genera unaltered during therapy. Patients treated with aldafermin showed a significant, dose-dependent enrichment in the rare genus Veillonella, a commensal microbe known to have lactate-degrading and performance-enhancing properties, which correlated with changes in serum bile acid profile.
Conclusions: Veillonella may be a bile acid-sensitive bacteria whose enrichment is enabled by aldafermin-mediated suppression of bile acid synthesis and in particular, decreases in toxic bile acids. This study provides an integrated analysis of gut microbiome, serum bile acid metabolome, imaging and histological measurements in clinical trials testing aldafermin for NASH. Our results reveal novel biology and provide better understanding of the intricacies of microbiome-host interactions.