Dysbiosis of the Gut Microbiota Is Associated with HIV Disease Progression and Tryptophan Catabolism

Abstract

Progressive HIV infection is characterized by dysregulation of the intestinal immune barrier, translocation of immunostimulatory microbial products, and chronic systemic inflammation that is thought to drive progression of disease to AIDS. Elements of this pathologic process persist despite viral suppression during highly active antiretroviral therapy (HAART) and drivers of these phenomena remain poorly understood. Disrupted intestinal immunity can precipitate dysbiosis that induces chronic inflammation in the mucosa and periphery of mice. However, putative microbial drivers of HIV-associated immunopathology versus recovery have not been identified in humans. Using high-resolution bacterial community profiling, we identified a dysbiotic mucosal-adherent community enriched in Proteobacteria and depleted of Bacteroidia members that was associated with markers of mucosal immune disruption, T cell activation, and chronic inflammation in HIV-infected subjects. Furthermore, this dysbiosis was evident among HIV-infected subjects undergoing HAART, and the extent of dysbiosis correlated with activity of the kynurenine pathway of tryptophan metabolism and plasma concentrations of the inflammatory cytokine interleukin-6 (IL-6), two established markers of disease progression. Gut-resident bacteria with capacity to metabolize tryptophan through the kynurenine pathway were found to be enriched in HIV-infected subjects, strongly correlated with kynurenine levels in HIV-infected subjects, and capable of kynurenine production in vitro. These observations demonstrate a link between mucosal-adherent colonic bacteria and immunopathogenesis during progressive HIV infection, which is apparent even in the setting of viral suppression during HAART. This link suggests that gut-resident microbial populations may influence intestinal homeostasis during HIV disease.

Effects of Fecal Microbial Transplantation on Microbiome and Immunity in Simian Immunodeficiency Virus-Infected Macaques

“…One mechanism underlying the increased mortality is dysfunction of the gastrointestinal (GI) tract, which is associated with inflammation during HIV infection. Several lines of evidence support the role of GI dysfunction in HIV-related disease, including (i) a consistent association between mortality in HIV-infected individuals and markers of microbial translocation and gut epithelial dysfunction (2-4), (ii) the association of microbial products that translocate during HIV or simian immunodeficiency virus (SIV) infection and inflammation (5)(6)(7), and (iii) dysbiosis of the gut microbiome during HIV infection, which results in inflammation (8)(9)(10).…”

“…This is typically characterized by an overall loss of diversity, with alterations to the phyla Bacteroidetes, Firmicutes, and Proteobacteria (11). Specifically, the loss of beneficial bacterial genera, such as Bacteroides, Lactobacillus, and Bifidobacterium, has been observed and associated with pathogenesis (9,10,12,13). Furthermore, the levels of several pathogenic Proteobacteria have been observed to increase during HIV infection, including those within the genera Campylobacter, Escherichia, Acinetobacter, Desulfovibrio, and Pseudomonas, as have those of Prevotella species (9)(10)(11).…”

“…Specifically, the loss of beneficial bacterial genera, such as Bacteroides, Lactobacillus, and Bifidobacterium, has been observed and associated with pathogenesis (9,10,12,13). Furthermore, the levels of several pathogenic Proteobacteria have been observed to increase during HIV infection, including those within the genera Campylobacter, Escherichia, Acinetobacter, Desulfovibrio, and Pseudomonas, as have those of Prevotella species (9)(10)(11). Indeed, these bacteria have been found to be more adherent to the epithelium, to be more prone to translocate, and to be drivers of inflammation in the context of HIV and SIV infections (8)(9)(10)14).…”

Deciphering the tête-à-tête between the microbiota and the immune system

“…It is unclear whether the consistency within this small sample size should be taken to suggest that mucosally associated bacteria are more relevant than luminal bacteria for immunomodulation. Although some have suggested that biopsy samples are preferable to fecal samples for identification of immunoregulatory bacteria (61,62), all current examples of such bacteria identified in screens were isolated from fecal samples (39,40,42,43). This fact is perhaps not terribly surprising given that the fecal bacterial community represents a combination of luminal bacteria and shed, mucosally adherent bacteria (63).…”

Investigating a holobiont: Microbiota perturbations and transkingdom networks

“…36,37 One approach to identify the taxonomic profile of a microbial community is with 16S rRNA amplicon sequencing, in which highly variable regions of 16S ribosomal rRNA from all microbes in a sample are amplified by PCR and subject to high throughput sequencing 38 or hybridization to probes on a special microarray chip called Phylochip. 1,39 In the case of sequencing, relative abundances of taxa are calculated from copy number of amplicons from the corresponding taxa. Abundance profiles for different taxonomic ranks are commonly generated (i.e., strain, species, genus, family etc.)…”