Through the Looking-Glass: Psychoneuroimmunology and the Microbiome-Gut-Brain Axis in the Modern Antiretroviral Therapy Era

Abstract

Objective: Depression, substance use disorders, and other neuropsychiatric comorbidities are common in people with HIV (PWH), but the underlying mechanisms are not sufficiently understood. HIV-induced damage to the gastrointestinal tract potentiates residual immune dysregulation in PWH receiving effective antiretroviral therapy. However, few studies among PWH have examined the relevance of microbiomegut-brain axis: bidirectional crosstalk between the gastrointestinal tract, immune system, and central nervous system. Methods: A narrative review was conducted to integrate findings from 159 articles relevant to psychoneuroimmunology (PNI) and microbiome-gut-brain axis research in PWH. Results: Early PNI studies demonstrated that neuroendocrine signaling via the hypothalamic-pituitary-adrenal axis and autonomic nervous system could partially account for the associations of psychological factors with clinical HIV progression. This review highlights the need for PNI studies examining the mechanistic relevance of the gut microbiota for residual immune dysregulation, tryptophan catabolism, and oxytocin release as key biological determinants of neuropsychiatric comorbidities in PWH (i.e., body-to-mind pathways). It also underscores the continued relevance of neuroendocrine signaling via the hypothalamic-pituitary-adrenal axis, autonomic nervous system, and oxytocin release in modifying microbiome-gut-brain axis functioning (i.e., mind-to-body pathways). Conclusions: Advancing our understanding of PNI and microbiome-gut-brain axis pathways relevant to depression, substance use disorders, and other neuropsychiatric comorbidities in PWH can guide the development of novel biobehavioral interventions to optimize health outcomes. Recommendations are provided for biobehavioral and neurobehavioral research investigating bidirectional PNI and microbiomegut-brain axis pathways among PWH in the modern antiretroviral therapy era.

HIV-1–Host Interaction in Gut-Associated Lymphoid Tissue (GALT): Effects on Local Environment and Comorbidities

“…Other hypothesised mechanisms are molecular mimicry to bacterial antigens leading to dysfunctional adaptive immune responses, the production of bacterial metabolites that may directly damage the brain and were supposed to be related to specific neurodegenerative disorders, including Alzheimer's disease, and vagal dysfunction related to HIV-associated autonomic neuropathy, associated with intestinal bacterial overgrowth and changes in immune and gastrointestinal functions [161,[166][167][168]. Moreover, the vagus nerve is essential for reducing intestinal permeability in HIV infection, thus preventing microbial products from penetrating the lamina propria and entering the circulation to amplify the immune dysregulation and inflammation [169]. HIV neuropathogenesis may also occur through the mechanisms of oxidative stress and metabolic disturbances indirectly linked to gut bacterial processes [161], and neuroinflammation is exacerbated by the persistent replication of HIV in CNS unhindered by ART, as the penetrability of these compounds through the blood-brain barrier is variable and incomplete [170].…”

The Interaction of HIV With Mental Health in the Modern Antiretroviral Therapy Era

“…This special issue concludes with a review article by Carrico and colleagues ( 39 ) that places these findings in a broader context, focusing on the bidirectional nature of mind-body relationship in the mental health among people living with HIV. The interrelationships between established psychoneuroimmunologic mechanisms and microbiome-gut-brain axis interactions are highlighted with recommendations for future biobehavioral research to investigate the bidirectional pathways linking the biological and behavioral processes with mental health in PWH.…”

Tryptophan–Kynurenine Pathway Activation and Cognition in Virally Suppressed Women With HIV

“…Plasma markers of inflammation and monocyte activation have been linked to cognitive outcomes; however, how this relates to plasma tryptophan and kynurenine is unexplored. 25–29…”

“…Plasma markers of inflammation and monocyte activation have been linked to cognitive outcomes; however, how this relates to plasma tryptophan and kynurenine is unexplored. [25][26][27][28][29] The tryptophan-kynurenine (TK) pathway has been studied in the context of HIV. A recent review found increased IDO activation (using K:T ratio as a surrogate marker) is associated with age and chronic inflammation in PWH.…”