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Preclinical studies have shown that chronic alcohol abuse leads to alterations in the gastrointestinal microbiota that are associated with behavior changes, physiological alterations, and immunological effects. However, such studies have been limited in their ability to evaluate the direct effects of alcohol-associated dysbiosis. To address this, we developed a humanized alcohol-microbiota mouse model to systematically evaluate the immunological effects of chronic alcohol abuse mediated by intestinal dysbiosis. Germ-free mice were colonized with human fecal microbiota from individuals with high and low Alcohol Use Disorders Identification Test (AUDIT) scores and bred to produce human alcohol-associated microbiota or human control-microbiota F1 progenies. F1 offspring colonized with fecal microbiota from individuals with high AUDIT scores had increased susceptibility to Klebsiella pneumoniae and Streptococcus pneumoniae pneumonia, as determined by increased mortality rates, pulmonary bacterial burden, and post-infection lung damage. These findings highlight the importance of considering both the direct effects of alcohol and alcohol-induced dysbiosis when investigating the mechanisms behind alcohol-related disorders and treatment strategies.

People living with HIV (PLWH) are at increased risk for noncommunicable diseases such as lung disease in part due to opportunistic infections including pneumonia. HIV infection is associated with increased prevalence of impaired lung function and abnormal gas exchange. Alcohol use disorder (AUD) is exceedingly common in PLWH and is associated with higher risk of pneumonia in PLWH. Alcohol use may lead to lung damage through several mechanisms. Data on the long-term effect of AUD on pulmonary function in PLWH are sparse and conflicting. To evaluate this relationship, we conducted a cross-sectional analysis of adult PLWH in care in Louisiana. We hypothesized that chronic alcohol use would be associated with subsequent pulmonary dysfunction in a dose-dependent fashion. All participants performed standardized spirometry on study entry. In total, 350 participants with acceptable spirometry were included in this analysis. Thirty-one percent of participants were female. Women reported less lifetime alcohol use and less smoking; however, they reported more chronic respiratory symptoms. In adjusted models, total lifetime alcohol use was not associated with spirometry measures of pulmonary function. HIV-related variables (CD4 count and viral load) were also not associated with measures of pulmonary function. We then conducted sex-stratified analyses to eliminate residual confounding of sex and similarly found no association of total lifetime alcohol use and pulmonary function. We found no association of AUDIT score or early life alcohol use and pulmonary function. In latent class factor analysis, current heavy alcohol use was associated with lower measures of pulmonary function as compared to former heavy alcohol use. In summary, in this cohort of New Orleanian men and women living with HIV with robust measures of alcohol use, though total lifetime alcohol use and early life alcohol use were not associated with pulmonary function, current heavy alcohol use was associated with impaired pulmonary function., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Chronic alcohol consumption is associated with a compromised innate and adaptive immune responses to infectious disease. Mucosa-associated invariant T (MAIT) cells play a critical role in antibacterial host defense. However, whether alcohol-associated deficits in innate and adaptive immune responses are mediated by alterations in MAIT cells remains unclear., Methods: To investigate the impact of alcohol on MAIT cells, mice were treated with binge-on-chronic alcohol for 10 days and sacrificed at day 11. MAIT cells in the barrier organs (lung, liver, and intestine) were characterized by flow cytometry. Two additional sets of animals were used to examine the involvement of gut microbiota on alcohol-induced MAIT cell changes: (1) Cecal microbiota from alcohol-fed (AF) mice were adoptive transferred into antibiotic-pretreated mice and (2) AF mice were treated with antibiotics during the experiment. MAIT cells in the barrier organs were measured via flow cytometry., Results: Binge-on-chronic alcohol feeding led to a significant reduction in the abundance of MAIT cells in the barrier tissues. However, CD69 expression on tissue-associated MAIT cells was increased in AF mice compared with pair-fed (PF) mice. The expression of Th1 cytokines and the corresponding transcriptional factor was tissue specific, showing downregulation in the intestine and increases in the lung and liver in AF animals. Transplantation of fecal microbiota from AF mice resulted in a MAIT cell profile aligned to that of AF mouse donor. Antibiotic treatment abolished the MAIT cell differences between AF and PF animals., Conclusion: MAIT cells in the intestine, liver, and lung are perturbed by alcohol use and these changes are partially attributable to alcohol-associated dysbiosis. MAIT cell dysfunction may contribute to alcohol-induced innate and adaptive immunity and consequently end-organ pathophysiology., (© 2021 by the Research Society on Alcoholism.)

Background: Inflammation persists among persons with human immunodeficiency virus (PWH) despite effective antiretroviral therapy and may contribute to T-cell dysfunction. Alcohol use is prevalent among PWH and promotes intestinal leak, dysbiosis, and a proinflammatory milieu. Whether alcohol use is associated with T-cell late differentiation remains to be investigated., Methods: Data and samples from PWH (N = 359 of 365) enrolled in the New Orleans Alcohol Use in HIV Study were used. Alcohol use was assessed by self-report (Alcohol Use Disorders Identification Test; lifetime alcohol exposure; 30-day Alcohol Timeline Followback) and phosphatidylethanol (PEth) quantitation. In a subset of participants, fecal bacterial content was assessed by ribosomal 16S marker gene deep sequencing and quantitative polymerase chain reaction. Intestinal leak was assessed by fecal-to-plasma α-1-antitrypsin (A1AT) enzyme-linked immunosorbent assay ratio. Peripheral T-cell populations were quantified by flow cytometry., Results: Alcohol Use Disorder Identification Test scores were positively associated with activated-senescent, exhausted, and terminal effector memory CD45RA+CD8+ but not CD4+ T cells (cells/μL) after confounder adjustment (P < .050). Phosphatidylethanol was positively associated with A1AT (P < .050). The PEth and activated-senescent CD8+ were associated with bacterial β-diversity (P < .050) and positively associated with the relative abundance of coabundant Prevotellaceae members (q < .100)., Conclusions: Alcohol use among PWH is associated with CD8+ T-cell late differentiation, intestinal leak, and dysbiosis. Alcohol-associated dysbiosis is implicated in CD8+ T-cell senescence., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Unhealthy alcohol use is prevalent among persons living with HIV (PLWH). Aging and increased survival of PLWH on antiretroviral therapy (ART) are complicated by metabolic dysregulation and increased risk of insulin resistance (IR) and diabetes mellitus. The objective of this study was to determine the prevalence and association of IR with unhealthy alcohol use in adult in-care PLWH. A cross-sectional analysis of metabolic parameters and alcohol use characteristics was conducted in adult PLWH enrolled in the New Orleans Alcohol Use in HIV (NOAH) Study. IR was estimated using homeostatic model assessment (HOMA-IR), triglyceride index, and McAuley index and beta cell function (HOMA-β). Alcohol use was assessed using Alcohol Use Disorders Identification Test (AUDIT)-C, 30-day timeline followback (TLFB), lifetime drinking history, and phosphatidylethanol (PEth) measures. A total of 351 participants, with a mean age [±standard deviation (SD)] of 48.1 ± 10.4 years, were included (69.6% male). Of these, 57% had an AUDIT-C score of 4 or greater, indicating unhealthy alcohol use. Mean body mass index (BMI) was 27.2 ± 7.0 kg/m 2 , 36.4% met criteria for metabolic syndrome, and 14% were diagnosed with diabetes. After adjusting for education, race, BMI, smoking status, viral load, CD4 count, use of protease inhibitors, statins, or metformin; physical activity and diabetes diagnosis, HOMA-IR, and McAuley index were negatively associated with AUDIT-C, and HOMA-β cell function was negatively associated with AUDIT-C, PEth, and TLFB. Cross-sectional analysis of NOAH participants indicates that alcohol use is associated with decreased HOMA-β cell function, suggesting dysregulation of endocrine pancreatic function.

Background: High frequency of alcohol use among people living with HIV (PLWH) warrants careful assessment and screening to better understand its impact on HIV disease progression and development of comorbidities. Due to the limitations of the tools used to measure alcohol use, the links to health consequences are not fully understood., Methods: We completed a cross-sectional analysis to examine the prevalence of alcohol consumption using multiple alcohol assessment tools and their correlation and consistency in a cohort of PLWH (N = 365) enrolled in the New Orleans Alcohol Use in HIV (NOAH) Study. Alcohol use was assessed with the Alcohol Use Disorders Identification Test (AUDIT), timeline followback (TLFB) Calendar, lifetime drinking history, Alcohol and Drug Addiction Severity Index, and blood levels of phosphatidylethanol (PEth). Spearman's correlations were estimated for continuous measures of alcohol consumption; Wilcoxon rank-sum tests were used to compare means; and logistic regression was used to estimate odds of alcohol use by demographic characteristics., Results: Self-report of current alcohol use varied from 58.9 to 73.7% depending on the assessment. All the self-reported alcohol measures showed statistically significant correlations with the biological marker PEth. The highest correlation was with TLFB grams (r = 0.67, p < 0.001). Using TLFB, 73.7% of the cohort reported using alcohol in the last 30 days, and 61.6% had a positive PEth value. The prevalence of risky drinkers, meeting the TLFB > 3 (women) or >4 (men) drinks/day or>7 (women) or>14 (men) drinks/week, was 49.0%. Medium-risk drinking defined as an AUDIT score ≥ 8 was reported in 40.3%, and high-risk drinkers/probable AUD (AUDIT score ≥ 16) was met by 17.0% of the cohort., Conclusions: Our results demonstrate the importance of comprehensive assessments for alcohol use, including self-report via multiple assessment tools administered by trained staff, as well as the addition of biomarkers for improved classification of subjects into different drinking categories., (© 2020 by the Research Society on Alcoholism.)

Background: The average lifespan of persons living with HIV (PLWH) on antiretroviral therapy approximates the general population. However, PLWH are susceptible to early aging and frailty. Behaviors such as alcohol consumption may contribute to frailty among PLWH., Objective: To determine the relationships between recent and lifetime alcohol use and frailty among PLWH., Design: Cross-sectional, prospective cohort study of in-care PLWH (n = 365) participating in the New Orleans Alcohol Use in HIV Study., Methods: Recent alcohol exposure was measured by the 30-day alcohol timeline follow-back (TLFB) assessment and by whole-blood-spot phosphatidylethanol (PEth) quantitation. Lifetime alcohol exposure (LAE) was estimated by a modified lifetime drinking history instrument. Frailty was assessed by a 58-item deficit index (DI58) and the phenotypic frailty index (PFI). The Veterans Aging Cohort Study Risk Index 2.0 was calculated., Results: Using generalized linear regression, LAE was positively associated with the DI58 (95% CI 0.001--0.006) and PFI severity (95% CI 0.004--0.023) after adjustment for age and other factors. Conversely, recent alcohol exposure was negatively associated with the DI58 [TLFB 95% CI: (-0.126 to -0.034), PEth: (-0.163 to -0.058)] and PFI severity [TLFB 95% CI (-0.404 to -0.015), PEth (-0.406 to 0.034)]. The VACS was not associated with alcohol use. Median per-decade alcohol exposure peaked in the second decade and tapered with aging thereafter. Increasing LAE and decreasing TLFB were co-associated with a specific subset of health deficits., Conclusion: Lifetime alcohol use is positively associated with frailty among PLWH. Specific health deficits may discourage alcohol consumption in some PLWH.

Aims: To characterize latent typologies of alcohol use among persons living with human immunodeficiency virus (HIV) (PLWH) and test their relationship with physical and mental health status., Methods: Baseline data from 365 adult in-care PLWH enrolled in the New Orleans Alcohol Use in HIV study were analyzed. Indicators of current and former heavy drinking, intoxication, withdrawal and dependence symptoms, alcohol-related problems and past contact with alcohol use treatment were drawn from validated scales. Physical and mental health measures included SF-36 subscales, medication non-adherence and anxiety, depressive and post-traumatic stress disorder symptoms. Latent class analysis was conducted to characterize alcohol drinking typologies. Logistic and ordinary least-squares regression were employed to test associations between alcohol use and health status., Results: Four latent classes were identified: heavy drinkers (36%), former heavy drinkers (14%), heavy drinkers with problems (12%) and low-risk drinkers/abstainers (38%). Controlling for background characteristics, low-risk drinkers/abstainers showed significantly better health compared to heavy drinkers with problems across most domains. Although current and former heavy drinkers without alcohol-related problems were similar to heavy drinkers with problems in most health domains, they presented worse mental health and energy compared to low-risk drinkers/abstainers., Conclusions: Heavy drinkers with alcohol-related problems evidenced the worst health status among PLWH, and should be considered for mental and physical health interventions. However, interventions to improve physical and mental health of PLWH should consider history of heavy alcohol use, as current alcohol use status alone may be insufficient for identifying groups at increased risk., (© The Author(s) 2019. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Background: HIV infection is now largely a chronic condition as a result of the success of antiretroviral therapy. However, several comorbidities have emerged in people living with HIV (PLWH), including alcohol use disorders and musculoskeletal disorders. Alcohol use has been associated with lower bone mineral density, alterations to circulating bone turnover markers, and hypocalcemia. The pathophysiological basis of bone loss in the PLWH population is unclear but has been suggested to be linked to oxidative stress and inflammation. To test the hypothesis that PLWH consuming excessive alcohol have altered markers of bone turnover and/or calcium homeostasis in association with oxidative stress, we correlated measurements of alcohol consumption with markers of oxidative stress and inflammation, serum calcium concentrations, and measurements of bone turnover, including c-terminal telopeptide cross-links (CTX-1) and osteocalcin., Methods: Data were drawn from cross-sectional baseline data from the ongoing New Orleans Alcohol Use in HIV (NOAH) study, comprised of 365 in care PLWH. Alcohol consumption measures (Alcohol Use Disorders Test, 30-day timeline follow-back calendar, and phosphatidylethanol [PEth]) were measured in a subcohort of 40 subjects selected based on highest and lowest PEth measurements. Multivariate linear regression was performed to test the relationships between alcohol consumption and systemic oxidative stress (4-hydroxynonenal; 4-HNE) and inflammation (c-reactive protein; CRP)., Results: Serum calcium and CTX-1 did not differ significantly between the high and low-PEth groups. Individuals in the high-PEth group had significantly lower serum osteocalcin (median low-PEth group: 13.42 ng/ml, inter-quartile range [IQR] 9.26 to 14.99 ng/ml; median high-PEth group 7.39 ng/ml, IQR 5.02 to 11.25 ng/ml; p = 0.0005, Wilcoxon rank-sum test). Osteocalcin negatively correlated with PEth (Spearman r = -0.45, p = 0.05) and self-reported measures after adjusting for covariates. Alcohol consumption showed mild, but significant, positive associations with serum 4-HNE, but not with CRP. Osteocalcin did not correlate with either 4-HNE or CRP., Conclusions: In this subcohort of PLWH, we detected significant associations between at-risk alcohol use and osteocalcin, and at-risk alcohol use and serum 4-HNE, suggesting suppression of bone formation independent of increased systemic oxidative stress with increasing alcohol consumption., (© 2019 by the Research Society on Alcoholism.)

Background: Pneumonia is common in persons living with the human immunodeficiency virus (HIV) (PLWH). Alcohol, cocaine, and marijuana impact pneumonia pathogenesis. We hypothesized that substance use was independently associated with pneumonia severity in PLWH and modified the effect of alcohol on pneumonia severity. Methods: Retrospective data analysis of PLWH admitted with a diagnosis of pneumonia was conducted. Alcohol use disorder was defined by the Alcohol Use Disorders Identification Test score ≥14. Drug use was quantified by self-report. Pneumonia severity was defined by the pneumonia severity index (PSI). Multivariable linear regression was used to test independent associations with pneumonia severity and effect modification by sex. Results: Of 196 PLWH, the mean age was 44 (SD = 9) years and the majority were men (71%). Ten percent ( n =  19) of subjects met criteria for an alcohol use disorder (AUD). In subjects reporting alcohol use, 25% reported concomitant crack/cocaine use and 16% reported marijuana use. PSI scores were higher with lifetime use of crack/cocaine (mean PSI: 63.1 vs. 57.3, P  = .06) and/or injection drug use (68.4 vs. 54.9, P  = .04). PSI scores were lower with active marijuana use (51.5 vs. 62.2, P  = .01). There was no significant difference in clinical outcomes. Sex modified the effect of drug use on PSI, with greater PSI scores in women with an AUD (β = 58.1, 95% confidence interval [CI]: 46.7 to 69.5, P  < .01), whereas active marijuana use mitigated the effect of AUD on PSI in men (β = -12.7, 95% CI: -18.8 to -6.6, P  < .01). Conclusions: Active alcohol and/or crack/cocaine use was associated with increased pneumonia severity in PLWH, with less severe pneumonia with marijuana use. Alcohol and marijuana effects on pneumonia severity differed by sex, with increased PSI in women and decreased PSI in men with concomitant marijuana and AUD.

Individuals with alcohol use disorders (AUDs) are at an increased risk of pneumonia and acute respiratory distress syndrome. Data of the lung microbiome in the setting of AUDs are lacking. The objective of this study was to determine the microbial biogeography of the upper and lower respiratory tract in individuals with AUDs compared with non-AUD subjects. Gargle, protected bronchial brush, and bronchoalveolar lavage specimens were collected during research bronchoscopies. Bacterial 16S gene sequencing and phylogenetic analysis was performed, and the alterations to the respiratory tract microbiota and changes in microbial biogeography were determined. The microbial structure of the upper and lower respiratory tract was significantly altered in subjects with AUDs compared with controls. Subjects with AUD have greater microbial diversity [ P < 0.0001, effect size = 16 ± 1.7 observed taxa] and changes in microbial species relative abundances. Furthermore, microbial communities in the upper and lower respiratory tract displayed greater similarity in subjects with AUDs. Alcohol use is associated with an altered composition of the respiratory tract microbiota. Subjects with AUDs demonstrate convergence of the microbial phylogeny and taxonomic communities between distinct biogeographical sites within the respiratory tract. These results support a mechanistic pathway potentially explaining the increased incidence of pneumonia and lung diseases in patients with AUDs.

Purpose: Pneumonia is common and more severe in human immunodeficiency virus (HIV)-infected patients. Alcohol consumption in pneumonia patients without HIV is associated with excess mortality and morbidity. However, studies are lacking on the impact of alcohol on pneumonia and HIV. Our goal was to determine if alcohol use was an independent risk factor for pneumonia severity in HIV-infected patients., Methods: Secondary analysis of prospective cohort study data evaluating early bronchoscopy for pneumonia diagnosis in HIV patients between 2007 and 2011 was conducted. We defined AUDs using an alcohol use disorder identification test (AUDIT) score as follows: ≥8 indicates hazardous drinking and ≥14 indicates dependence. We quantified pneumonia severity using the pneumonia severity index (PSI). Multivariable linear regression was used to investigate the independent association between alcohol and pneumonia severity., Results: A total of 196 HIV+ individuals comprised our cohort. Most cohort subjects were middle-aged African American men. Most subjects (70 %) reported not taking antiretroviral therapy. The overall prevalence of hazardous drinking was 24 % in our cohort (48/196) with 10 % (19/196) meeting the criteria for alcohol dependence. Alcohol consumption was significantly associated with pneumonia severity (r = 0.25, p < 0.001). Hazardous drinking (β-coefficient 10.12, 95 % CI 2.95-17.29, p = 0.006) and alcohol dependence (β-coefficient 12.89, 95 % CI 2.59-23.18, p = 0.014) were independent risk factors for pneumonia severity. Reported homelessness and men who have sex with men (MSM) status remained independent risk factors for more severe pneumonia after adjustment for the effects of alcohol., Conclusions: In a cohort of HIV patients with pneumonia, presence of an AUD was an independent risk factor for pneumonia severity. Homelessness and MSM status were associated with greater pneumonia severity in AUD patients.

Activated CD8+ T-cells correlate with viral load and may foretell antiretroviral therapy (ART) failure. HIV infection has been suggested to accelerate immunosenescence through chronic persistent inflammation. Alcohol-use disorders (AUD) are prevalent in persons living with HIV/AIDS (PLWHA). We tested the hypothesis that hazardous alcohol consumption accelerates immune activation and immunosenescence. Immune activation and immunosenescence were examined in CD8+ T lymphocytes (CD3+CD4-CD8+) isolated from intestinal biopsies, axillary lymph nodes, and peripheral blood mononuclear cells (PBMCs) of chronic binge alcohol (CBA)-consuming simian immunodeficiency virus (SIV)-infected male rhesus macaques with and without antiretroviral therapy (ART; CBA/ART+, CBA/ART-) and in PBMCs isolated from a cohort of PLWHA. Polychromatic flow cytometry was used to phenotype cells isolated from intestinal biopsies, lymph nodes, and peripheral blood from rhesus macaques and PLWHA. The Alcohol Use Disorders Identification Test (AUDIT) identified hazardous alcohol drinking in PLWHA. Viral load was determined by RT-qPCR and telomere length was measured using qPCR. PBMC CD8+ T-cell activation (CD38+HLA-DR+) and immunosenescence (CD28-) were increased over baseline levels (857% ± 334, p < 0.05; 398% ± 80, p < 0.05, respectively) only in CBA animals not receiving ART. Viral load correlated with CD8+ T-cell immunosenescence in macaque PBMCs (r(s) = 0.49, p = 0.02). Activated immunosenescent T-cell (CD8+CD38+CD28-) frequencies in PBMCs from PLWHA significantly correlated with AUDIT scores (r(s) = 0.75, p = 0.001), while no correlation was observed with CD4+ T-cell and AUDIT scores (r(s) = -0.24, p = 0.38). Activated immunosenescent T-cells had shorter telomeres than CD8+ T-cells (CD8+CD28+) from PLWHA. Our results suggest that CBA and AUD augment immune activation and immunosenescence in SIV-infected macaques and PLWHA., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Chronic alcohol intoxication suppresses immune function and increases osteoporosis risk suggesting bone-tissue cytotoxicity. Human immunodeficiency virus infection leads to similar impairments. This study investigated the effects of chronic alcohol administration during the early stage of simian immunodeficiency virus (SIV) infection on hematopoietic stem and progenitor cells (HSPCs) and their differentiated progeny in the bone marrow and peripheral blood of rhesus macaques., Methods: Rhesus macaques were administered alcohol or sucrose daily for a period of 3 months prior to intrarectal inoculation with 250 TCID50 of SIVmac251 . Bone marrow aspirates and blood samples were taken prior to and 2 weeks after SIV infection. Bone marrow cells (BMCs) were assessed using flow cytometric phenotyping for upstream HSPCs and for differentiated cells of the monocyte-granulocyte lineages. Likewise, cells were quantitated in peripheral blood., Results: Of the bone marrow HSPCs, only the common lymphoid progenitor (CLP) was altered by alcohol administration pre-SIV (38 ± 9.4/10(6) BMCs vs. 226 ± 64.1/10(6) BMCs, sucrose vs. alcohol). Post-SIV, the frequency of CLPs in the bone marrow of alcohol-administered macaques decreased compared with the sucrose-administered macaques (107 ± 47.6/10(6) BMCs vs. 43 ± 16.3/10(6) BMCs). However, marrow mature cells of the monocyte lineage, specifically macrophages and osteoclast progenitors, were increased by both chronic alcohol administration and SIV infection (287% and 662%, respectively). As expected, mature cells such as granulocytes (polymorphonuclear cells), B cells, and CD4+ T cells in the peripheral blood were decreased by SIV infection (37 to 62% decline from preinfection), but not affected after 3 months of chronic alcohol administration., Conclusions: Chronic alcohol administration disrupts myelomonocytic development in the bone marrow during the early period of SIV infection promoting macrophage and osteoclast lineages. We predict this shift in CLP:macrophage/osteoclast balance creates an environment that favors bone resorption and immunosuppression., (Copyright © 2014 by the Research Society on Alcoholism.)