Markers of Gut Barrier Function and Microbial Translocation Associate with Lower Gut Microbial Diversity in People with HIV.

Ronald J Ellis,Jennifer E Iudicello,John Lin,Rob Knight,Robert K Heaton,Jean-Pierre Routy,Stéphane Isnard,Sara Gianella,Martin Hoenigl

doi:10.3390/v13101891

Ronald J Ellis, Jennifer E Iudicello + Show 7 more

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https://doi.org/10.3390/v13101891

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Abstract

People with human immunodeficiency virus (HIV) (PWH) have reduced gut barrier integrity (“leaky gut”) that permits diffusion of microbial antigens (microbial translocation) such as lipopolysaccharide (LPS) into the circulation, stimulating inflammation. A potential source of this disturbance, in addition to gut lymphoid tissue CD4+ T-cell depletion, is the interaction between the gut barrier and gut microbes themselves. We evaluated the relationship of gut barrier integrity, as indexed by plasma occludin levels (higher levels corresponding to greater loss of occludin from the gut barrier), to gut microbial diversity. PWH and people without HIV (PWoH) participants were recruited from community sources and provided stool, and 16S rRNA amplicon sequencing was used to characterize the gut microbiome. Microbial diversity was indexed by Faith’s phylogenetic diversity (PD). Participants were 50 PWH and 52 PWoH individuals, mean ± SD age 45.6 ± 14.5 years, 28 (27.5%) women, 50 (49.0%) non-white race/ethnicity. PWH had higher gut microbial diversity (Faith’s PD 14.2 ± 4.06 versus 11.7 ± 3.27; p = 0.0007), but occludin levels were not different (1.84 ± 0.311 versus 1.85 ± 0.274; p = 0.843). Lower gut microbial diversity was associated with higher plasma occludin levels in PWH (r = −0.251; p = 0.0111), but not in PWoH. A multivariable model demonstrated an interaction (p = 0.0459) such that the correlation between Faith’s PD and plasma occludin held only for PWH (r = −0.434; p = 0.0017), but not for PWoH individuals (r = −0.0227; p = 0.873). The pattern was similar for Shannon alpha diversity. Antiretroviral treatment and viral suppression status were not associated with gut microbial diversity (ps > 0.10). Plasma occludin levels were not significantly related to age, sex or ethnicity, nor to current or nadir CD4 or plasma viral load. Higher occludin levels were associated with higher plasma sCD14 and LPS, both markers of microbial translocation. Together, the findings suggest that damage to the gut epithelial barrier is an important mediator of microbial translocation and inflammation in PWH, and that reduced gut microbiome diversity may have an important role.

Highlights

The gut epithelial barrier is maintained by tight junctions (TJs), cellular border structures that allow the paracellular transport of some solutes and molecules while protecting against toxins in the gut lumen diffusing into the circulation, including lipids and microbialderived peptides [1,2]
We found evidence that lower gut microbial alpha diversity, as indexed by both the Faith’s phylogenetic diversity (PD) and Shannon indices, was linked to damage to the gut barrier as indexed by higher plasma occludin levels in people with HIV (PWH), but not in people without HIV (PWoH)
We found that PWH had significantly higher gut microbial diversity

Summary

Introduction

The gut epithelial barrier is maintained by tight junctions (TJs), cellular border structures that allow the paracellular transport of some solutes and molecules while protecting against toxins in the gut lumen diffusing into the circulation, including lipids and microbialderived peptides [1,2]. Occludin is one of a number of proteins that make up TJs [5,6,7,8], and expression of occludin is one of the most characteristic structural markers of tight junctions in polarized gut epithelial cells [9]. Pathologic states such as inflammatory bowel disease are associated with a leaky gut epithelial barrier, disruption of TJs, and dysregulation of occludin. In people with HIV (PWH), gut barrier integrity is compromised [15,16] This leads to translocation into the systemic circulation of microbial antigens such as lipopolysaccharide (LPS) and (1→3)-β-D-Glucan [16,17]. Higher systemic levels of soluble CD14 (sCD14) and LPS are markers of increased microbial translocation and are associated with systemic and CNS inflammation, immune activation [5], and neurocognitive impairment [20]

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