HIV and comorbidities - the importance of gut inflammation and the kynurenine pathway

Abstract

Purpose of review: The purpose of this article is to review alterations in microbiota composition, diversity, and functional features in the context of chronic inflammation and comorbidities associated with HIV infection.

Recent findings: The gut microbiome is an important mediator of host immunity, and disruption of gut homeostasis can contribute to both systemic inflammation and immune activation. Ageing and HIV share features of intestinal damage, microbial translocation and alterations in bacterial composition that contribute to a proinflammatory state and development of age-related comorbidities. One such inflammatory pathway reviewed is the nicotinamide adenine dinucleotide (NAD+) producing kynurenine pathway (KP). Kynurenine metabolites regulate many biological processes including host-microbiome communication, immunity and oxidative stress and the KP in turn is influenced by the microbiome environment. Age-associated decline in NAD+ is implicated as a driving factor in many age-associated diseases, including those seen in people with HIV (PWH). Recent studies have shown that KP can influence metabolic changes in PWH, including increased abdominal adiposity and cardiovascular disease. Furthermore, KP activity increases with age in the general population, but it is elevated in PWH at all ages compared to age-matched controls. Host or microbiome-mediated targeting of this pathway has merits to increase healthy longevity and has potential therapeutic applications in PWH.

Summary: As a growing proportion of PWH age, many face increased risks of developing age-related comorbidities. Chronic inflammation, a pillar of geroscience, the science of ageing and of age-related disease, is influenced by the gut microbiome and its metabolites. Combined, these contribute to a systemic inflammatory signature. Advances in geroscience-based approaches and therapeutics offer a novel paradigm for addressing age-related diseases and chronic inflammation in HIV infection. Whether targeted inhibition of KP activity alleviates pathological conditions or promotes successful ageing in PWH remains to be determined.

Figure 1. The Kynurenine Pathway.

In the kynurenine pathway, TRP is metabolized to kynurenine (KYN) by tryptophan 2,3-dioxygenase (TDO), found mostly in hepatic tissue or indoleamine 2,3-dioxygenase (IDO), an enzyme found in most tissues that is stimulated by steroid hormones, cytokines and growth factors. Kynurenine is then either metabolized to kynurenic acid (KA) or to 3-hydroxykynurenine (3-HK). Under basal conditions, most of kynurenine is metabolized to KA, a N-methyl-D-aspartate (NMDA) and α7-nicotinic acetylcholine (α7nACh) receptor antagonist. However, inflammation, oxidative stress and pro-inflammatory cytokines will shift kynurenine metabolism to 3-HK. Further metabolism through this pathway results in quinolinic acid (QA), a metabolite that is a NMDA receptor agonist and an oxidative stressor. The KP produces several other biologically active metabolites, including the redox cofactors oxidized NAD+. NAD is a common mediator of various biological processes, including energy metabolism, mitochondrial function, calcium homeostasis and generation of oxidative stress. TRP metabolites like serotonin, quinolinic acid, and kynurenic acid have important implications in neurotransmission, growth and inflammation. IDO, indoleamine 2,3-dioxygenase; NAD, nicotinamide adenine dinucleotide.

Figure 2. Biological phenotype of ageing and therapeutic modification strategies.