AUTHOR=Zhang Yifan , Jiang Weiwei , Xu Jun , Wu Na , Wang Yang , Lin Tianyu , Liu Yun , Liu Yulan 

TITLE=E. coli NF73-1 Isolated From NASH Patients Aggravates NAFLD in Mice by Translocating Into the Liver and Stimulating M1 Polarization

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2020.535940

DOI=10.3389/fcimb.2020.535940

ISSN=2235-2988

ABSTRACT=<sec><title>Objective</title><p>The gut microbiota is associated with nonalcoholic fatty liver disease (NAFLD). We isolated the <italic>Escherichia coli</italic> strain NF73-1 from the intestines of a NASH patient and then investigated its effect and underlying mechanism.</p></sec><sec><title>Methods</title><p>16S ribosomal RNA (16S rRNA) amplicon sequencing was used to detect bacterial profiles in healthy controls, NAFLD patients and NASH patients. Highly enriched <italic>E. coli</italic> strains were cultured and isolated from NASH patients. Whole-genome sequencing and comparative genomics were performed to investigate gene expression. Depending on the diet, male C57BL/6J mice were further grouped in normal diet (ND) and high-fat diet (HFD) groups. To avoid disturbing the bacterial microbiota, some of the ND and HFD mice were grouped as “bacteria-depleted” mice and treated with a cocktail of broad-spectrum antibiotic complex (ABX) from the 8<sup>th</sup> to 10<sup>th</sup> week. Then, <italic>E. coli</italic> NF73-1, the bacterial strain isolated from NASH patients, was administered transgastrically for 6 weeks to investigate its effect and mechanism in the pathogenic progression of NAFLD.</p></sec><sec><title>Results</title><p>The relative abundance of <italic>Escherichia</italic> increased significantly in the mucosa of NAFLD patients, especially NASH patients. The results from whole-genome sequencing and comparative genomics showed a specific gene expression profile in <italic>E. coli</italic> strain NF73-1, which was isolated from the intestinal mucosa of NASH patients. <italic>E. coli</italic> NF73-1 accelerates NAFLD independently. Only in the HFD-NF73-1 and HFD-ABX-NF73-1 groups were EGFP-labeled <italic>E. coli</italic> NF73-1 detected in the liver and intestine. Subsequently, translocation of <italic>E. coli</italic> NF73-1 into the liver led to an increase in hepatic M1 macrophages via the TLR2/NLRP3 pathway. Hepatic M1 macrophages induced by <italic>E. coli</italic> NF73-1 activated mTOR-S6K1-SREBP-1/PPAR-α signaling, causing a metabolic switch from triglyceride oxidation toward triglyceride synthesis in NAFLD mice.</p></sec><sec><title>Conclusions</title><p><italic>E. coli</italic> NF73-1 is a critical trigger in the progression of NAFLD. <italic>E. coli</italic> NF73-1 might be a specific strain for NAFLD patients.</p></sec>