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Review
. 2022 Jan 18:12:758230.
doi: 10.3389/fphys.2021.758230. eCollection 2021.

Pathophysiological Consequences of At-Risk Alcohol Use; Implications for Comorbidity Risk in Persons Living With Human Immunodeficiency Virus

Liz Simon  1 , Scott Edwards  1 , Patricia E Molina  1
Affiliations
Review

Pathophysiological Consequences of At-Risk Alcohol Use; Implications for Comorbidity Risk in Persons Living With Human Immunodeficiency Virus

Liz Simon et al. Front Physiol. .

Abstract

At-risk alcohol use is a significant risk factor associated with multisystemic pathophysiological effects leading to multiorgan injury and contributing to 5.3% of all deaths worldwide. The alcohol-mediated cellular and molecular alterations are particularly salient in vulnerable populations, such as people living with HIV (PLWH), diminishing their physiological reserve, and accelerating the aging process. This review presents salient alcohol-associated mechanisms involved in exacerbation of cardiometabolic and neuropathological comorbidities and their implications in the context of HIV disease. The review integrates consideration of environmental factors, such as consumption of a Western diet and its interactions with alcohol-induced metabolic and neurocognitive dyshomeostasis. Major alcohol-mediated mechanisms that contribute to cardiometabolic comorbidity include impaired substrate utilization and storage, endothelial dysfunction, dysregulation of the renin-angiotensin-aldosterone system, and hypertension. Neuroinflammation and loss of neurotrophic support in vulnerable brain regions significantly contribute to alcohol-associated development of neurological deficits and alcohol use disorder risk. Collectively, evidence suggests that at-risk alcohol use exacerbates cardiometabolic and neurocognitive pathologies and accelerates biological aging leading to the development of geriatric comorbidities manifested as frailty in PLWH.

Keywords: HIV; alcohol; cardiometabolic comorbidity; diet; neuropathology.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Interaction of at-risk alcohol use and HIV infection. Chronic stressors including unhealthy alcohol consumption and HIV infection affect several biological processes and synergize with gut immunopathological effects of alcohol, decreasing gut mucosal barrier integrity, promoting dysbiosis, and gut bacteria and toxin leak. Alcohol metabolism generates toxic by-products that, in turn, can promote tissue and cell injury. Pathophysiological processes frequently linked to alcohol metabolism including oxidative stress, mitochondrial injury, altered growth factor signaling, nutritional deficits, and epigenetic modifications. These synergize with systemic immune activation, inflammation, and cell senescence and exhaustion driven by gut leak, enhancing tissue injury and dysregulation of homeostatic mechanisms increasing risk for cardiometabolic syndrome (CMS). The cluster of target organ dyshomeostasis associated with CMS is associated with increased risk for neurocognitive deficits and pain syndromes that can exacerbate or accelerate biological aging. ROS, reactive oxygen species; RAS, renin angiotensin system; HTN, hypertension; CMS, cardiometabolic syndrome. Created with Biorender.com.
FIGURE 2
FIGURE 2
Mechanisms implicated in alcohol interactions with risk and pathogenesis of cardiometabolic syndrome. Alcohol associated metabolic instability, alterations in endothelial function, extracellular remodeling, and dysregulation of the renin-angiotensin aldosterone system are salient mechanisms that contribute to increased risk for CMS. Alcohol alters the gut microbiome, impacting on gut mucosal immunity and barrier function. The chronic immune activation associated with gut leak results in immune activation, exhaustion, and senescence, underlying immunometabolic dysregulation. Across tissues, alcohol produces alterations in cellular energy metabolism disrupting mitochondrial function and homeostatic responses. Several of these mechanisms are regulated by epigenomic alterations reflected by changes in microRNA profiles, histone methyltransferases and deacetylase expression, and activity. Alcohol-induced multi-organ alterations may result from inter-organ cross talk. Alcohol-induced tissue injury in one organ (i.e., adipose tissue) can result in release of mediators (i.e., adipokines, cytokines, microvesicles, etc.) that target distant organs amplifying alcohol’s deleterious effects. Created with Biorender.com.
FIGURE 3
FIGURE 3
Alcohol-mediated metabolic instability. Alcohol produces carbohydrate, lipid, and protein metabolic dysregulation directly, and indirectly through the generation of its metabolites. Principal target organs include the liver, adipose tissue, and skeletal muscle (SKM). Alcohol-associated alterations in synthesis and breakdown of carbohydrates, lipids, and proteins, result in metabolic instability and increase the risk for cardiometabolic syndrome (CMS). Created with Biorender.com.
FIGURE 4
FIGURE 4
Alcohol-induced biphasic effects on endothelial function. Acutely, moderate doses of alcohol increase production of nitric oxide and result in transient vasodilation. Chronic, heavy alcohol consumption produces oxidative stress and activates vasoconstrictor pathways including endothelins (ET) and angiotensin II formation (Ang II) that lead to endothelial dysfunction and altered response to vasoactive mediators. ET, endothelin; Ang II, angiotensin II; NE, norepinephrine; eNOS, endothelial nitric oxide synthase; AGES, advance glycation end products; ECM, extracellular matrix. Created with Biorender.com.
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