Therapeutically targeting the consequences of HIV-1-associated gastrointestinal dysbiosis: Implications for neurocognitive and affective alterations

Abstract

Approximately 50 % of the individuals living with human immunodeficiency virus type 1 (HIV-1) are plagued by debilitating neurocognitive impairments (NCI) and/or affective alterations. Sizeable alterations in the composition of the gut microbiome, or gastrointestinal dysbiosis, may underlie, at least in part, the NCI, apathy, and/or depression observed in this population. Herein, two interrelated aims will be critically addressed, including: 1) the evidence for, and functional implications of, gastrointestinal microbiome dysbiosis in HIV-1 seropositive individuals; and 2) the potential for therapeutically targeting the consequences of this dysbiosis for the treatment of HIV-1-associated NCI and affective alterations. First, gastrointestinal microbiome dysbiosis in HIV-1 seropositive individuals is characterized by decreased alpha (α) diversity, a decreased relative abundance of bacterial species belonging to the Bacteroidetes phylum, and geographic-specific alterations in Bacillota (formerly Firmicutes) spp. Fundamentally, changes in the relative abundance of Bacteroidetes and Bacillota spp. may underlie, at least in part, the deficits in γ-aminobutyric acid and serotonin neurotransmission, as well as prominent synaptodendritic dysfunction, observed in this population. Second, there is compelling evidence for the therapeutic utility of targeting synaptodendritic dysfunction as a method to enhance neurocognitive function and improve motivational dysregulation in HIV-1. Further research is needed to determine whether the therapeutics enhancing synaptic efficacy exert their effects by altering the gut microbiome. Taken together, understanding gastrointestinal microbiome dysbiosis resulting from chronic HIV-1 viral protein exposure may afford insight into the mechanisms underlying HIV-1-associated neurocognitive and/or affective alterations; mechanisms which can be subsequently targeted via novel therapeutics.

Keywords: Apathy; Brain-gut-microbiota Axis; Depression; HIV-1-associated neurocognitive disorders; Neurotransmission; Synaptic dysfunction.

Figure 1.

Characteristics of the 38 case-control studies comparing the gut microbiome in HIV-1 seropositive individuals with chronic infection and well-matched controls. Results from four alpha (α) diversity indices measuring community diversity (Shannon Index, Simpson Index) and community richness (Chao1 Index, Observed Species) are utilized to illustrate the significant inter-study heterogeneity observed within the field. The indicates no statistically significant difference between HIV-1 seropositive individuals and controls, whereas the and illustrate significant decreases and increases, respectively, in α diversity in HIV-1 seropositive individuals relative to case-controls.

Figure 2.

Graphical illustration of how alterations in the prevalence of Bacteroides (A), Prevotella (B), and Faecalibacterium (C) may alter brain function. (A) Decreased production of Bacteroides species in HIV-1 seropositive individuals may result in decreased production of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Bacteroides spp. produce GABA via the glutamate decarboxylase system. GABA is subsequently transported from the gastrointestinal system to the brain via vagal pathways, which express a high density of GABA_B receptors. (B) A higher concentration of lipopolysaccharides (LPS) is one of the consequences of the increased prevalence of Prevotella spp. in chronically infected HIV-1 seropositive individuals. LPS can leak into circulation via the impaired gastrointestinal barrier or be transmitted to the brain via the vagus nerve. Upon entering the brain (B’), LPS binds to microglia, leading to their activation and/or dysfunction, which may subsequently underlie neurite and/or synaptic damage. (C) Faecalibacterium spp. serve as one of the main producers of butyrate, which is involved in the production and/or release of the neurotransmitter serotonin (5-HT) in a dose-dependent manner. Alterations in Faecalibacterium, as observed in HIV-1 seropositive individuals, support decreased production and/or release of 5-HT.

Figure 3.

Studies finding statistically significant effects of HIV-1 serostatus on α diversity, measured using the Shannon Index, evaluated a significantly greater number of chronically infected HIV-1 seropositive individuals (Main Effect of Statistical Significance, F(1,33)=6.3, p<0.017). Three outliers, defined as being greater than 2.5 standard deviations above the mean, are indicated by the open blue circles and were not included in the analysis.