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Differences in Bacterial Translocation and Liver Injury in Ethanol Versus Diet-Induced Liver Disease

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Abstract

Background

Alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) are two of the most common etiologies of chronic liver disease worldwide. Changes in intestinal permeability and increased gut microbial translocation have been posited as important contributors to inflammation in both ALD and NAFLD. However, gut microbial translocation has not been compared between the two etiologies and can lead to better understanding of the differences in their pathogenesis to liver disease.

Methods

We compared serum and liver markers in the following five models of liver disease to understand the differences in the role of gut microbial translocation on liver disease progression caused by ethanol versus Western diet: (1) 8-week chronic ethanol feeding model. (2) 2-week chronic-plus-binge (National Institute on Alcohol Abuse and Alcoholism (NIAAA)) ethanol feeding model. (3) 2-week chronic-plus-binge (NIAAA) ethanol feeding model in microbiota-humanized gnotobiotic mice colonized with stool from patients with alcohol-associated hepatitis. (4) 20-week Western-diet-feeding model of NASH. (5) 20-week Western-diet-feeding model in microbiota-humanized gnotobiotic mice colonized with stool from NASH patients.

Results

Translocation of bacterial lipopolysaccharide to the peripheral circulation was seen in both ethanol-induced and diet-induced liver disease, but translocation of bacteria itself was restricted to only ethanol-induced liver disease. Moreover, the diet-induced steatohepatitis models developed more significant liver injury, inflammation, and fibrosis compared with ethanol-induced liver disease models, and this positively correlated with the level of lipopolysaccharide translocation.

Conclusions

More significant liver injury, inflammation, and fibrosis are seen in diet-induced steatohepatitis, which positively correlates with translocation of bacterial components, but not intact bacteria.

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Acknowledgments

C.H. is supported by T32 DK007202. This study was supported in part by a Pilot and Feasibility Award from the Southern California Research Center for ALPD and Cirrhosis funded by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health P50AA011999 (to C.L.H.), NIH grants K12 HD85036, University of California San Diego Altman Clinical and Translational Research Institute (ACTRI)/NIH grant KL2TR001444, Pinnacle Research Award in Liver Diseases Grant #PNC22-159963 from the American Association for the Study of Liver Diseases Foundation (to P.H.), NIH grants R01 AA24726, R37 AA020703, U01 AA026939, U01 AA026939-04S1, by Award Number BX004594 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development, and a Biocodex Microbiota Foundation Grant (to B.S.) and services provided by NIH centers P50 AA011999 and the San Diego Digestive Diseases Research Center (SDDRC) P30 DK120515.

Funding

Foundation for the National Institutes of Health,T32 DK007202,Cynthia L. Hsu,K12 HD85036, Phillipp Hartmann, R01 AA24726,Bernd G. Schnabl, R37 AA020703,Bernd G. Schnabl, U01 AA026939,Bernd G. Schnabl,U01 AA026939-04S1,Bernd G. Schnabl,P30 DK120515, P50 AA011999, National Institute of Environmental Health Sciences,KL2TR001444,Phillipp Hartmann,American Association for the Study of Liver Diseases,PNC22-159963, Phillipp Hartmann, U.S. Department of Veterans Affairs,BX004594,Bernd G. Schnabl, Biocodex Microbiota Foundation

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Authors and Affiliations

  1. Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, MC0063, USA

    Cynthia L. Hsu, Yanhan Wang, Yi Duan, Huikuan Chu, Cristina Llorente, Rongrong Zhou & Bernd Schnabl

  2. Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA

    Yanhan Wang, Yi Duan, Huikuan Chu, Rongrong Zhou & Bernd Schnabl

  3. Department of Pediatrics, University of California San Diego, La Jolla, CA, USA

    Phillipp Hartmann

  4. Division of Gastroenterology, Hepatology & Nutrition, Rady Children’s Hospital San Diego, San Diego, CA, USA

    Phillipp Hartmann

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  1. Cynthia L. Hsu
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Corresponding author

Correspondence to Bernd Schnabl.

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Conflicts of interest

B.S. has been consulting for Ambys Medicines, Ferring Research Institute, Gelesis, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals and Takeda. B.S.’s institution UC San Diego has received research support from Axial Biotherapeutics, BiomX, CymaBay Therapeutics, NGM Biopharmaceuticals, Prodigy Biotech and Synlogic Operating Company. B.S. is founder of Nterica Bio. UC San Diego has filed several patents with Y.D., C.L. and B.S. as inventors related to this work.

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Supplementary Information

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10620_2023_7860_MOESM1_ESM.tiff

Supplementary file1 Bacterial composition of AH and NASH patient microbiota used to colonize germ-free mice. Mean relative abundance of the top 21 most abundant bacterial genera; 0-1 corresponds to 0%-100% abundance. (TIFF 2990 KB)

10620_2023_7860_MOESM2_ESM.tiff

Supplementary file2 Intestinal permeability in ethanol and diet-induced liver disease models. Fecal albumin levels in the five different models of liver disease. (TIFF 3554 KB)

10620_2023_7860_MOESM3_ESM.tiff

Supplementary file3 Hepatic inflammation is positively correlated with LPS translocation. Pearson’s correlation of (a) Ccl2, (b) Cxcl1, (c) Tnf, and (d) Il1b mRNAs and serum LPS concentrations in mice from all groups. (TIFF 12773 KB)

10620_2023_7860_MOESM4_ESM.tiff

Supplementary file4 Hepatic fibrosis and TLR signalling is positively correlated with LPS translocation. Pearson’s correlation of (a) Col1a1, (b) Tgfb1, (c) Acta2, (d) Tlr4, and (e) Tlr2 mRNAs and serum LPS concentrations in mice from all groups. (TIFF 19027 KB)

10620_2023_7860_MOESM5_ESM.tiff

Supplementary file5 Diet-induced steatohepatitis is associated with increased steatosis. Hepatic triglyceride content in the five models of liver disease. P values between mice in the control versus treatment groups were determined by two-sided Student t-test. *P < 0.05, **P < 0.01, ***P < 0.001. (TIFF 3544 KB)

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Hsu, C.L., Wang, Y., Duan, Y. et al. Differences in Bacterial Translocation and Liver Injury in Ethanol Versus Diet-Induced Liver Disease. Dig Dis Sci 68, 3059–3069 (2023). https://doi.org/10.1007/s10620-023-07860-1

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  • DOI: https://doi.org/10.1007/s10620-023-07860-1

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