Liver Bacterial Dysbiosis With Non-Tuberculosis Mycobacteria Occurs in SIV-Infected Macaques and Persists During Antiretroviral Therapy.

Bridget S Fisher,Benjamin J Burwitz,Katherine A Fancher,Donald L Sodora,Michael Gale,Nichole R Klatt,Andrew T Gustin,Jeremy Smedley,Matthew P Wood,Nina Derby,Cole Fisher

doi:10.3389/fimmu.2021.793842

Abstract

Liver disease is a significant contributor to morbidity and mortality in HIV-infected individuals, even during successful viral suppression with combination antiretroviral therapy (cART). Similar to HIV infection, SIV infection of rhesus macaques is associated with gut microbiome dysbiosis and microbial translocation that can be detected systemically in the blood. As microbes leaving the intestines must first pass through the liver via the portal vein, we evaluated the livers of both SIV-infected (SIV+) and SIV-infected cART treated (SIV+cART) rhesus macaques for evidence of microbial changes compared to uninfected macaques. Dysbiosis was observed in both the SIV+ and SIV+cART macaques, encompassing changes in the relative abundance of several genera, including a reduction in the levels of Lactobacillus and Staphylococcus. Most strikingly, we found an increase in the relative abundance and absolute quantity of bacteria within the Mycobacterium genus in both SIV+ and SIV+cART macaques. Multi-gene sequencing identified a species of atypical mycobacteria similar to the opportunistic pathogen M. smegmatis. Phosphatidyl inositol lipoarabinomannan (PILAM) (a glycolipid cell wall component found in atypical mycobacteria) stimulation in primary human hepatocytes resulted in an upregulation of inflammatory transcriptional responses, including an increase in the chemokines associated with neutrophil recruitment (CXCL1, CXCL5, and CXCL6). These studies provide key insights into SIV associated changes in hepatic microbial composition and indicate a link between microbial components and immune cell recruitment in SIV+ and SIV+cART treated macaques.

Highlights

HIV infection continues to be a major public health concern with approximately 37.6 million people living with HIV at the end of 2020 [1]
The liver microbiome was evaluated at the genus level in macaques that were uninfected, SIV+, and SIV+combination antiretroviral therapy (cART) through 16S rRNA gene sequencing [41]
Proteobacteria made up 6 of the 10 genera with sequences present at greater than 10% prevalence in the complete cohort, in agreement with previous studies showing a high prevalence of Proteobacteria in the macaque liver [32]

Summary

Introduction

HIV infection continues to be a major public health concern with approximately 37.6 million people living with HIV at the end of 2020 [1]. HIV+ individuals experience a greater burden of co-morbidities, often at a markedly younger age, including cardiovascular disease, frailty, cognitive decline, and liver disease [4,5,6]. Among these chronic health conditions, liver disease is especially prevalent, most notably non-alcoholic fatty liver disease (NAFLD), and is a leading cause of death in HIV+ individuals [7, 8]. CART itself has previously been associated with hepatotoxicity [14, 15], NAFLD has continued to be an issue in HIV patients taking more recently developed and less hepatotoxic cART regimens [16].

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Results

Conclusion