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Background: People with HIV (PWH) are at increased risk for cardiometabolic comorbidities. We have reported that lifetime alcohol use among people with HIV (PWH) is associated with increased risk for metabolic syndrome. Dysfunctional adipose tissue and altered circulating adipokines mediate metabolic dysregulation. The objective of this study was to determine the associations of circulating adipokine concentration with metabolic measures, and the moderating effects of lifetime and recent alcohol use in PWH., Methods: This is a cross-sectional analysis of data from 357 PWH at their baseline visit of the longitudinal New Orleans Alcohol and HIV (NOAH) study. The concentrations of four circulating adipokines (adiponectin, leptin, resistin, and fatty acid-binding protein 4 [FABP4]) and their associations with five metabolic measures (triglycerides, cholesterol, Hemoglobin A1c, Homeostatic Model Assessment for Insulin Resistance, and metabolic syndrome) were examined., Results: Higher circulating adiponectin was associated with increased odds of normal triglyceride, cholesterol, and Hemoglobin A1c levels. Increased leptin and FABP4 concentrations were associated with decreased odds of normal triglyceride and cholesterol levels. Increased leptin and FABP4 concentrations were associated with increased odds of insulin resistance and meeting criteria for metabolic syndrome. Increased circulating resistin concentration was associated with decreased odds of normal triglyceride levels and increased odds of meeting criteria for metabolic syndrome. Additionally, among PWH with increased lifetime alcohol use, higher adiponectin concentration was associated with decreased odds of meeting criteria for metabolic syndrome., Conclusions: These data suggest the interplay between adiponectin, leptin, FABP4, and resistin may contribute to metabolic stability among PWH. Moreover, lifetime, but not recent, alcohol use moderates the relationship between adipokines and metabolic measures. These data highlight the relevance of functional adipose tissue mass and associated circulating adipokine levels in maintaining metabolic homeostasis, and its moderation by lifetime alcohol consumption., (© 2024 Research Society on Alcohol.)

Adverse childhood experiences (ACEs) and financial hardship are associated with increased likelihood of heavier alcohol use and health challenges in adulthood among persons living with HIV (PWH). We examined whether retrospectively captured lifetime drinking trajectories are a pathway through which childhood hardships affect current health in a sample of 365 adult PWH. Childhood economic hardship and ACEs were used as main predictors. Measures of alcohol use included age at first drink and lifetime drinking trajectories. Health indicators included health-related quality of life, frailty, number of comorbidities, and symptoms of anxiety, depression, and post-traumatic stress disorder (PTSD). Structural equation modeling (SEM) was applied to estimate both direct and indirect pathways between childhood hardship and physical and mental health. Participants were mostly male; Black (84%); and averaged 48 years of age. SEM results supported both direct and indirect pathways between childhood experiences and adult health. ACEs were connected to physical health directly and mental health both directly and indirectly through age at first drink and drinking heaviness during ages 10-20. Childhood economic hardship related to mental health indirectly through higher drinking levels during ages 10-20. Childhood adverse experiences, economic hardship, and early drinking patterns appear to accumulate, resulting in later life physical and mental health concerns for PWH. Findings support taking a life course approach to health. This includes considering individual trauma histories in HIV care engagement and taking preventative approaches which support the economic and social well-being of vulnerable children to improve health in subsequent decades., (© 2024. The Author(s).)

Intestinal barrier is a first line of defense that prevents entry of various harmful substances from the lumen into the systemic environment. Impaired barrier function with consequent translocation of harmful substances into systemic circulation ("leaky gut") is a central theme in many gastrointestinal, autoimmune, mental, and metabolic diseases. Probiotics have emerged as a promising strategy to maintain intestinal integrity and address "leaky gut". Using in silico, in vitro and avian in vivo analyses, we previously showed that two novel L. reuteri strains, PTA-126787 (L. reuteri 3630) and PTA-126788 (L. reuteri 3632), isolated from broiler chickens possess favorable safety profiles. Consistent with a recent study, here we show that L. reuteri 3630 and 3632 are phylogenetically similar to human L. reuteri strains. Daily administration of high doses of L. reuteri 3630 and 3632 to Sprague Dawley rats for 28 days was found to be safe with no adverse effects. More importantly, administration of L. reuteri 3630 and 3632 significantly reduced markers associated with alcohol-induced leaky gut, by downregulating inflammatory cytokines and upregulating anti-inflammatory cytokines in an alcohol model of leaky gut in mice. While L. reuteri 3630 cells and supernatant showed no activation, L. reuteri 3632 cells but not supernatant showed activation of AhR, a key transcription factor that regulates gut and immune homeostasis. L. reuteri 3630 is creamish white in morphology typical of Lactobacillus species and L. reuteri 3632 displays a unique orange pigmentation, which was stable even after passaging for 480 generations. We identified a rare polyketide biosynthetic gene cluster in L. reuteri 3632 that likely encodes for the orange-pigmented secondary metabolite. Similar to L. reuteri 3632 cells, the purified orange metabolite activated AhR. All together, these data provide evidence on the phylogenetic relatedness, safety, efficacy, and one of the likely mechanisms of action of L. reuteri 3630 and 3632 for potential probiotic applications to address "leaky gut" and associated pathologies in humans., (© 2024. The Author(s).)

The popularity of e-cigarettes (vaping) has soared, creating a public health crisis among teens and young adults. Chronic vaping can induce gut inflammation and reduce intestinal barrier function through the production of the proinflammatory molecule hydrogen sulfide (H 2 S). This is particularly concerning for people with HIV (PWH) as they already face impaired immune function and are at a higher risk for metabolic dysregulation, diabetes, and chronic liver disease. Furthermore, PWH experience unhealthy behaviors, making it crucial to understand the systemic metabolic dysregulation and pathophysiological mechanisms associated with vaping in this population. Here, we employed liquid chromatography-mass spectrometry (LC-MS)-based metabolomics to investigate the upper respiratory, circulation, and gut metabolic profiles of PWH who vape (n = 7) and smoke combustible tobacco/marijuana (n = 6) compared to control participants who did not vape or smoke (n = 10). This hypothesis-generating exploratory study revealed systemic alterations in purine, neurotransmitter, and vitamin B metabolisms and tissue-specific changes in inflammatory pathways and cryptic sulfur cycling associated with vaping and combustible tobacco/marijuana smoking in PWH. In addition, this study provides the first link between microbial-derived metabolite 2,3-dihydroxypropane-1-sulfonate (DHPS) and vaping/smoking (tobacco and marijuana)-induced metabolic dyshomeostasis in the gut. These findings highlight the importance of identifying the full biological and clinical significance of the physiological changes and risks associated with vaping.

Background: Human immunodeficiency virus (HIV) profoundly impacts the nervous system, leading to neurological deficits including HIV-associated neurocognitive disorder (HAND). HAND represents the most common neurological comorbidity among people with HIV (PWH), and alcohol use may exacerbate cognitive deficits, especially in vulnerable populations. This study investigated relationships between alcohol use and cognition in an underserved cohort of PWH, on the hypothesis that alcohol misuse exacerbates cognitive deficits., Methods: Data collected from participants (n = 259; 66.7% male; mean age 52 ± 10 years) enrolled in the New Orleans Alcohol Use in HIV (NOAH) study were utilized for cross-sectional analysis. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA), and alcohol use was comprehensively measured using four metrics: the Alcohol Use Disorders Identification Test (AUDIT), 30-day timeline follow back (TLFB), lifetime drinking history, and phosphatidylethanol (PEth) levels., Results: The average MoCA score among participants was 20.7 ± 4.5, with 86.5% demonstrating cognitive impairment (MoCA < 26). Individuals with MoCA scores below 18 (moderately or severely cognitively impaired) had a higher frequency of recent severe alcohol misuse and greater lifetime alcohol consumption. Participants at increased risk for AUD (AUDIT ≥ 16) also had worse global cognition and memory task performance than those with lower AUDIT scores; this was particularly true among those aged 50 and older. Analysis of the MoCA sub-score data indicated that participants with increased AUD risk had impairments in the cognitive domains of language and memory., Conclusions: Our findings demonstrate a high prevalence of cognitive impairment in the NOAH cohort and suggest that alcohol misuse contributes to global cognitive deficits in PWH, especially among individuals aged 50 and older. Further exploration of the impact of alcohol use on specific cognitive domains, including memory and language, should incorporate additional cognitive tasks. These findings highlight the importance of considering alcohol use and AUD risk as significant factors that may exacerbate cognitive deficits in vulnerable populations, including older PWH., (© 2024 Research Society on Alcohol.)

Alcohol use disorder (AUD) is a complex and widespread disease with limited pharmacotherapies. Preclinical animal models of AUD use a variety of voluntary alcohol consumption procedures to recapitulate different phases of AUD, including binge alcohol consumption and dependence. However, voluntary alcohol consumption in mice is widely variable, making it difficult to reproduce results across labs. Accumulating evidence indicates that different brands of commercially available rodent chow can profoundly influence alcohol intake. In this study, we investigated the effects of three commercially available and widely used rodent diet formulations on alcohol consumption and preference in C57BL/6 J mice using the 24 h intermittent access procedure. The three brands of chow tested were LabDiet 5,001 (LD5001), LabDiet 5,053 (LD5053), and Teklad 2019S (TL2019S) from two companies (Research Diets and Envigo, respectively). Mice fed LD5001 and LD5053 displayed higher levels of alcohol consumption and preference compared to mice fed TL2019S. We also found that alcohol consumption and preference could be rapidly switched by changing the diet 48 h prior to alcohol administration. Sucrose, saccharin, and quinine preferences were not altered, suggesting that the diets did not alter sweet and bitter taste perception. We also found that mice fed LD5001 displayed increased quinine-resistant alcohol intake compared to mice fed TL2019S, suggesting that diets could influence the development of compulsive behaviors such as alcohol consumption. We profiled the gut microbiome of water- and alcohol-drinking mice that were maintained on different diets and found significant differences in bacterial alpha- and beta-diversities, which could impact the gut-brain axis signaling and alcohol consumption., Competing Interests: 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., (Copyright © 2024 Zaparte, Dore, White, Paliarin, Gabriel, Copenhaver, Basavanhalli, Garcia, Vaddavalli, Luo, Taylor, Welsh and Maiya.)

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.

The gut microbiome plays a critical role in maintaining overall health and immune function. However, dysbiosis, an imbalance in microbiome composition, can have profound effects on various aspects of human health, including susceptibility to viral infections. Despite numerous studies investigating the influence of viral infections on gut microbiome, the impact of gut dysbiosis on viral infection and pathogenesis remains relatively understudied. The clinical variability observed in SARS-CoV-2 and seasonal influenza infections, and the presence of natural HIV suppressors, suggests that host-intrinsic factors, including the gut microbiome, may contribute to viral pathogenesis. The gut microbiome has been shown to influence the host immune system by regulating intestinal homeostasis through interactions with immune cells. This review aims to enhance our understanding of how viral infections perturb the gut microbiome and mucosal immune cells, affecting host susceptibility and response to viral infections. Specifically, we focus on exploring the interactions between gamma delta (γδ) T cells and gut microbes in the context of inflammatory viral pathogenesis and examine studies highlighting the role of the gut microbiome in viral disease outcomes. Furthermore, we discuss emerging evidence and potential future directions for microbiome modulation therapy in the context of viral pathogenesis.

Background: Antiretroviral therapy has improved life expectancy among people living with HIV (PLWH). Despite increased longevity, PLWH are at increased risk of age-related comorbidities, including frailty. We examined the relationship between body composition and frailty among PLWH, and moderation of this relationship by substance use, physical activity (PA), and physical function., Methods: Participants (n = 341; 71% male, 48 ± 10 years, body mass index (BMI) = 27.3 ± 7.0 kg/m 2 ) enrolled in the New Orleans Alcohol Use in HIV (NOAH) study underwent measures of body composition, muscle strength, and gait speed. Whole blood phosphatidylethanol (PEth) was measured, and substance use and PA were self-reported. Frailty risk measures included the 58-Item Deficit Index (DI58) and the Veterans Aging Cohort Study (VACS) Index 1.0, where higher scores indicate greater frailty risk., Results: Multivariable linear regression adjusted for age, sex, and race showed that higher fat-free mass index (FFMI), body fat (%), waist-to-hip ratio, and body mass index (BMI) ≥ 25.0 kg/m 2 vs. < 25.0 kg/m 2 were significantly (p < 0.05) associated with decreased frailty risk measured by the VACS Index, whereas adjusted analyses showed no association between body composition variables and the DI58 score. Recent alcohol use, muscle strength, and PA, but not lifetime alcohol use or gait speed, significantly moderated associations between body composition variables and frailty risk with medium-to-large effect sizes. Subgroup analyses revealed a negative relationship between DI58 and FFMI among people with PEth > 8 ng/ml and negative relationships of VACS Index with FFMI and WHR in people with lower muscle strength. Overweight or obese BMI categories were positively associated with DI58 in people with lower muscle strength or higher PA level but negatively associated in those with higher muscle strength., Conclusions: Our findings indicate that body composition has significant modulatory effects on frailty risk in PLWH, where obesity increases the risk of frailty and greater muscle mass may be protective, even in individuals who use alcohol. These results highlight the importance of considering body composition, physical activity, and physical function in assessing frailty risk in PLWH, particularly among individuals who use alcohol. Moreover, they support the implementation of physical activity interventions to ameliorate the risk of frailty in aging PLWH., (© 2022 Research Society on Alcoholism.)

Objective: We characterized lifetime drinking trajectories among persons living with HIV (PLWH) and examined how trajectories are related to health., Method: Adults (ages 20-71) were recruited between 2015 and 2017 for a cohort study examining the impact of alcohol use on geriatric comorbidities in PLWH in New Orleans. The New Orleans Alcohol Use in HIV (NOAH) Study ( n = 356; 68.8% male) included in-person interviews, anthropometric measurements, and biospecimen collection. Average monthly drinks per decade of life was derived from participants' reported average quantity and frequency of alcoholic beverages for each decade. Health indicators included CD4 count, viral load, health-related quality of life, frailty, comorbidities, body mass index, heavy drinking, anxiety, depression, and posttraumatic stress disorder. Participants also reported lifetime experiences with homelessness and incarceration. Latent curve modeling was applied in MPlus to derive lifetime drinking trajectories. Latent trajectory parameters were modeled as predictors of physical, mental, and social health, controlling for demographics., Results: Alcohol consumption increased significantly between the teen years and midlife (31-40), declining thereafter through ages 50-60. Significant interindividual differences were observed in all trajectory parameters. Persons with higher starting points of alcohol consumption showed worse mental health (depression and anxiety) and social experiences (homelessness and incarceration history) at study baseline. A steeper increase in volume of alcohol consumption after ages 10-20 was associated with worse health-related quality of life, greater frailty and comorbidities, and greater odds of current heavy drinking., Conclusions: Understanding lifetime alcohol consumption patterns is important in addressing physical and mental health among adult PLWH.

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.)

The gut microbiota has a fundamental role in the development and the maturation of the host immune system. Both innate and adaptive immune cells have critical functions in microbial pathogen containment and clearance, but the regulation of the commensal microbiome ecosystem in the gastrointestinal tract by these major immune cell populations is incompletely defined. The role of specific innate and adaptive immune cell in the regulation of the microbiota in the intestinal tract biogeographically was investigated. Dendritic cells, macrophages, CD4+ T-cells, CD8+ T-cells, and B-cells were depleted using monoclonal antibodies and clodronate liposomes, and the microbial communities were determined by 16S rRNA gene sequencing. With specific immune cell depletion, distinct microbiota changes were observed. In general, immune cell depleted mice had higher microbiota richness and evenness at all gut anatomical sites. At each gut segment, samples from immune cell-depleted animals clustered away from the isotype/liposome control mice. This was especially dramatic for the small intestinal microbiota. Specifically, Enterobacteriaceae, Bacteroides acidifaciens, and Mucispirillum schaedleri were highly enriched in the mucosa and lumen of the small intestine in immune cell-deficient animals. Further, the mucosal microbiota had higher microbiota evenness compared with luminal microbiota at all gut segments, and the UniFrac distance between B cell depleted and isotype control mice was the largest in the duodenum followed by the ileum and colon. Taken together, the data suggest that innate and adaptive immune cells specifically contribute to the regulation of the gut microbiota's biogeographical distribution along the gastrointestinal tract, and microbiota in the duodenum mucosa are more responsive to host immune changes compared with other anatomical sites., (© 2022 The Societies and John Wiley & Sons Australia, Ltd.)

CD4 + T cell differentiation to pro-inflammatory and immunosuppressive subsets depends on immunometabolism. Pro-inflammatory CD4 + subsets rely on glycolysis, while immunosuppressive Treg cells require functional mitochondria for their differentiation and function. Previous pre-clinical studies have shown that ethanol (EtOH) administration increases pro-inflammatory CD4 + T cell subsets; whether this shift in immunophenotype is linked to alterations in CD4 + T cell metabolism had not been previously examined. The objective of this study was to determine whether ethanol alters CD4 + immunometabolism, and whether this affects CD4 + T cell differentiation. Naïve human CD4 + T cells were plated on anti-CD3 coated plates with soluble anti-CD28, and differentiated with IL-12 in the presence of ethanol (0 and 50 mM) for 3 days. Both Tbet-expressing (Th1) and FOXP3-expressing (Treg) CD4 + T cells increased after differentiation. Ethanol dysregulated CD4 + T cell differentiation by increasing Th1 and decreasing Treg CD4 + T cell subsets. Ethanol increased glycolysis and impaired oxidative phosphorylation in differentiated CD4 + T cells. Moreover, the glycolytic inhibitor 2-deoxyglucose (2-DG) prevented the ethanol-mediated increase in Tbet-expressing CD4 + T cells but did not attenuate the decrease in FOXP3 expression in differentiated CD4 + T cells. Ethanol increased Treg mitochondrial volume and altered expression of genes implicated in mitophagy and autophagosome formation ( PINK1 and ATG7) . These results suggest that ethanol impairs CD4 + T cell immunometabolism and disrupts mitochondrial repair processes as it promotes CD4 + T cell differentiation to a pro-inflammatory phenotype., Competing Interests: 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., (Copyright © 2022 McTernan, Levitt, Welsh, Simon, Siggins and Molina.)

Aims: To assess whether binge drinking and heavy alcohol use are associated with increased sugar and fat consumption among a Southern cohort of people living with HIV (PWH)., Methods: This was a cross-sectional analysis of PWH enrolled in the New Orleans Alcohol use in HIV (NOAH) Study (n = 215). Binge and heavy drinking were identified through a 30-day Alcohol Timeline-Followback and dietary intake was assessed through a 24-hour dietary recall., Results: Participants were 65.4% male, 83.3% Black, with a mean age of 49.2 ± 9.9. Heavy drinkers consumed more total calories than abstainers (P = 0.035) and low-to-moderate drinkers (P = 0.024), and binge drinkers consumed more calories than non-binge drinkers (P = 0.025). Binge and heavy drinkers had significantly higher intake of total and saturated fat in grams. However, substantially increased caloric intake among these participants led to non-significant associations for alcohol use with high total and saturated fat intake as a percent of total energy intake (%TEI). Binge drinkers had lower odds of consuming high sugar as a %TEI (odds ratio: 0.31 [0.14, 0.68]). Additionally, sugar intake predicted total and saturated fat intake, and this association was slightly higher among binge drinkers (total fat P-value: 0.12)., Conclusions: In this population of PWH, while binge and heavy drinking predicted higher caloric and fat intake in grams, binge drinkers were less likely to consume a high-sugar diet. This analysis suggests that interventions focused on reduced alcohol use may be especially beneficial in reducing metabolic disease burden in PWH if supplemented with information on incorporating lower energy-dense foods with reduced fat., (© The Author(s) 2021. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Like humans, outbred Sprague-Dawley CD rats exhibit a polygenic pattern of inheritance of the obese phenotype and not all individuals exposed to a high calorie intake develop obesity. We hypothesized that differences in gut microbiota composition account for phenotype differences between obese prone (OP) and obese resistant (OR) rats. We studied the gut microbiota composition of OPand OR rats after a high fat (HF) diet and how they respond to fermentation of resistant starch (RS). In phase 1 of the study 28 OP and 28 OR rats were fed a HF diet. In order to determine causal role of microbiota on phenotypes, In phase 2, a microbiota transplant between the two phenotypes was performed before switching all rats to a HF diet supplemented with 20% RS. We determined microbiota composition by 16S sequencing and predicted microbiota function by PICRUSt2. Despite a similar calorie intake, in phase 2 OP rats gained more weight and accumulated more abdominal fat in both phase 1 and 2 compared to OR rats ( P < 0.001; n = 6). The OP rats fermented RS more robustly compared with OR rats with an increase in total bacteria, short chain fatty acids, and increased weight of the cecum, but microbiota of OP rats had much lower alpha diversity and evenness. The microbiota of OP rats, had higher amounts of bacteria from order Bacteroidales, specifically family Muribaculaceae ( S24-7 ), which is known to possess several starch degrading enzymes and was reported in previous studies to increase with fermentation of RS. The OR rats fermented RS less but had higher bacterial diversity and evenness and had significantly higher bacterial counts from phylum Firmicutes particularl y order Clostridiales, genus Clostridium and an uncultured bacterium of the genus Akkermansia . The microbiota of OR rats had enhanced bacterial chemotaxis, phosphotransferase system (PTS), and fatty acid biosynthesis compared to OP rats whose microbiota had higher glycan degradation and LPS biosynthesis pathways. The microbiota transplant did not change obesity phenotype or microbiota composition. In conclusion, a higher alpha-diversity and evenness of the microbiota and higher proportions of Clostridiales and Akkermansia in OR rats were associated with a better metabolic phenotype with lower body fat. However, robust RS fermentation caused a lower diversity and evenness and did not result in a leaner phenotype., Competing Interests: JG was employed by company BIO-CAT. The remaining 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., (Copyright © 2021 Obanda, Keenan, Page, Raggio, Taylor, Marx, Stout, Guice, Luo, Welsh, Coulon and Husseneder.)

The intestinal microbiota generates many different metabolites which are critical for the regulation of host signaling pathways. In fact, a wide-range of diseases are associated with increased levels of local or systemic microbe-derived metabolites. In contrast, certain bacterial metabolites, such as tryptophan metabolites, are known to contribute to both local and systemic homeostasis. Chronic alcohol consumption is accompanied by alterations to intestinal microbial communities, and their functional capacities. However, little is known about the role of alcohol-associated dysbiosis on host defense against bacterial pneumonia. Our previous work using fecal transplantation demonstrated that alcohol-associated intestinal dysbiosis, independent of ethanol consumption, increased susceptibility to Klebsiella pneumonia. Here, we demonstrate that intestinal microbiota treatments mitigate the increased risk of alcohol-associated pneumonia. Treatment with the microbial metabolite indole or with probiotics reduced pulmonary and extrapulmonary bacterial burden, restored immune responses, and improved cellular trafficking required for host defense. Protective effects were, in part, mediated by aryl hydrocarbon receptors (AhR), as inhibition of AhR diminished the protective effects. Thus, alcohol appears to impair the production/processing of tryptophan catabolites resulting in immune dysregulation and impaired cellular trafficking. These data support microbiota therapeutics as novel strategies to mitigate the increased risk for alcohol-associated bacterial pneumonia., (© 2021. The Author(s).)

Biological age captures some of the variance in life expectancy for which chronological age is not accountable, and it quantifies the heterogeneity in the presentation of the aging phenotype in various individuals. Among the many quantitative measures of biological age, the mathematically uncomplicated frailty/deficit index is simply the proportion of the total health deficits in various health items surveyed in different individuals. We used 3 different statistical methods that are popular in machine learning to select 17-28 health items that together are highly predictive of survival/mortality, from independent study cohorts. From the selected sets, we calculated frailty indexes and Klemera-Doubal's biological age estimates, and then compared their mortality prediction performance using Cox proportional hazards regression models. Our results indicate that the frailty index outperforms age and Klemera-Doubal's biological age estimates, especially among the oldest old who are most prone to biological aging-caused mortality. We also showed that a DNA methylation index, which was generated by applying the frailty/deficit index calculation method to 38 CpG sites that were selected using the same machine learning algorithms, can predict mortality even better than the best performing frailty index constructed from health, function, and blood chemistry., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Intracellular reduction-oxidation (RedOx) status mediates a myriad of critical biological processes. Importantly, RedOx status regulates the differentiation of hematopoietic stem and progenitor cells (HSPCs), mesenchymal stromal cells (MSCs) and maturation of CD8+ T Lymphocytes. In most cells, mitochondria are the greatest contributors of intracellular reactive oxygen species (ROS). Excess ROS leads to mitochondrial DNA (mtDNA) damage and protein depletion. We have developed a fluorescence-activated cell sorting (FACS)-based protocol to simultaneously analyze RedOx status and mtDNA integrity. This simultaneous analysis includes measurements of ROS (reduced glutathione (GSH)), ATP5H (nuclear encoded protein), MTCO1 (mitochondrial DNA encoded protein), and cell surface markers to allow discrimination of different cell populations. Using the ratio of MTCO1 to ATP5H median fluorescence intensity (MFI), we can gain an understanding of mtDNA genomic stability, since MTCO1 levels are decreased when mtDNA becomes significantly damaged. Furthermore, this workflow can be optimized for sorting cells, using any of the above parameters, allowing for downstream quantification of mtDNA genome copies/nucleus by quantitative PCR (qPCR). This unique methodology can be used to enhance analyses of the impacts of pharmacological interventions, as well as physiological and pathophysiological processes on RedOx status along with mitochondrial dynamics in most cell types., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

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.)

HIV-associated inflammation has been implicated in the premature aging and increased risk of age-associated comorbidities in cART-treated individuals. However, the immune mechanisms underlying the chronic inflammatory state of cART-suppressed HIV infection remain unclear. Here, we investigated the role of γδT cells, a group of innate IL-17 producing T lymphocytes, in the development of systemic inflammation and leaky gut phenotype during cART-suppressed SIV infection of macaques. Plasma levels of inflammatory mediators, intestinal epithelial barrier disruption (IEBD) and microbial translocation (MT) biomarkers, and Th1/Th17-type cytokine functions were longitudinally assessed in blood and gut mucosa of SIV-infected, cART-suppressed macaques. Among the various gut mucosal IL-17/IL-22-producing T lymphocyte subsets including Th17, γδT, CD161 + CD8 + T, and MAIT cells, a specific decline in the Vδ2 subset of γδT cells and impaired IL-17/IL-22 production in γδT cells significantly correlated with the subsequent increase in plasma IEBD/MT markers (IFABP, LPS-binding protein, and sCD14) and pro-inflammatory cytokines (IL-6, IL-1β, IP10, etc.) despite continued viral suppression during long-term cART. Further, the plasma inflammatory cytokine signature during long-term cART was distinct from acute SIV infection and resembled the inflammatory cytokine profile of uninfected aging (inflammaging) macaques. Overall, our data suggest that during cART-suppressed chronic SIV infection, dysregulation of IL-17/IL-22 cytokine effector functions and decline of Vδ2 γδT cell subsets may contribute to gut epithelial barrier disruption and development of a distinct plasma inflammatory signature characteristic of inflammaging. Our results advance the current understanding of the impact of chronic HIV/SIV infection on γδT cell functions and demonstrate that in the setting of long-term cART, the loss of epithelial barrier-protective functions of Vδ2 T cells and ensuing IEBD/MT occurs before the hallmark expansion of Vδ1 subsets and skewed Vδ2/Vδ1 ratio. Thus, our work suggests that novel therapeutic approaches toward restoring IL-17/IL-22 cytokine functions of intestinal Vδ2 T cells may be beneficial in preserving gut epithelial barrier function and reducing chronic inflammation in HIV-infected individuals., Competing Interests: 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., (Copyright © 2021 Walker, Slisarenko, Gerrets, Grasperge, Mattison, Kissinger, Welsh, Veazey, Jazwinski and Rout.)

Gastrointestinal tract (GIT) responses to a high-amylose resistant starch (RS) product were compared to those observed when RS was combined with whole grain (WG) and to controls with low RS intake in rats fed moderate or high fat diets. Regardless of fat intake, rats fed RS or WG + RS diets had higher cecum weights, higher intestinal quantities of short chain fatty acids, and lower intestinal content pH, and their GIT cells had increased gene expression for gluconeogenesis and barrier function compared to controls. Whereas RS resulted in greater GIT content acetate and propionate and lowest pH, the WG + RS diets yielded higher butyrate. Rats fed the RS diet with MF had higher cecum weights than those fed either the RS diet with HF or the WG + RS diet with either MF or HF. Diets containing combinations of RS and other dietary fibers should be considered for RS-mediated GIT benefits.

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.

We have previously demonstrated promotion of diethylnitrosamine (DEN) initiated liver tumorigenesis after feeding diets high in fat or ethanol (EtOH) to male mice. This was accompanied by hepatic induction of the proto-oncogene PIKE (Agap2). Switch of dietary protein from casein to soy protein isolate (SPI) significantly reduced tumor formation in these models. We have linked EtOH consumption in mice to microbial dysbiosis. Adoptive transfer studies demonstrate that microbiota from mice fed ethanol can induce hepatic steatosis in the absence of ethanol suggesting that microbiota or the microbial metabolome play key roles in development of fatty liver disease. Feeding SPI significantly changed gut bacteria in mice increasing alpha diversity (P < 0.05) and levels of Clostidiales spp. Feeding soy formula to piglets also resulted in significant changes in microbiota, the pattern of bile acid metabolites and in inhibition of the intestinal-hepatic FXR/FGF19-SHP pathway which has been linked to both steatosis and hepatocyte proliferation. Moreover, feeding SPI also resulted in induction of hepatic PPARα signaling and inhibition of PIKE mRNA expression coincident with inhibition of steatosis and cancer prevention. Feeding studies in the DEN model with differing dietary fats demonstrated tumor promotion specific to the saturated fat, cocoa butter relative to diets containing olive oil or corn oil associated with microbial dysbiosis including dramatic increases in Lachnospiraceae particularly from the genus Coprococcus. Immunohistochemical analysis demonstrated that tumors from EtOH-fed mice and patients with alcohol-associated HCC also expressed high levels of a novel cytochrome P450 enzyme CYP2W1. Additional adoptive transfer experiments and studies in knockout mice are required to determine the exact relationship between soy effects on the microbiota, expression of PIKE, CYP2W1, PPARα activation and prevention of tumorigenesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.)

Aim: This cross-sectional analysis of the New Orleans Alcohol Use in HIV (NOAH) study assesses whether current and lifetime alcohol use in people living with HIV (PLWH) are associated with greater liver disease and how hepatitis C-viral (HCV) co-infection (HIV/HCV+) modifies the association., Methods: Alcohol use was measured by Lifetime Drinking History (LDH), a 30-day Timeline Followback calendar, the Alcohol Use Disorder Identification Test, and phosphatidylethanol. Liver disease was estimated by alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST platelet ratio-index (APRI), fibrosis-4 index (FIB-4) and nonalcoholic fatty liver disease-fibrosis score. Associations between alcohol consumption and liver disease were estimated with multivariable logistic regression. Models were adjusted for age, sex, body-mass index, hepatitis B and HIV viral load., Results: Participants (N = 353) were majority male (69%) and black (84%) with a mean age of 48.3 ± 10 years. LDH was significantly associated with advanced liver fibrosis (FIB-4 aOR = 22.22 [1.22-403.72]) only among HIV/HCV+ participants with an LDH of 100-600 kg. HIV/HCV+ participants had a higher prevalence of intermediate and advanced liver disease markers than HIV/HCV- (P < 0.0001). Advanced markers of liver disease were most strongly associated with hazardous drinking (≥40(women)/60(men) grams/day) (APRI aOR = 15.87 (3.22-78.12); FIB-4 aOR = 6.76 (1.81-7.16)) and PEth ≥400 ng/ml (APRI aOR = 17.52 (2.55-120.54); FIB-4 aOR = 17.75 (3.30-95.630)., Conclusion: Results indicate a greater association of current alcohol use with liver disease than lifetime alcohol use, which varied by HCV status. These findings stress the importance of reducing alcohol use in PLWH to decrease risk of liver disease and fibrosis., (© The Author(s) 2019. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

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.

Beyond their role in bone and lung homeostasis, mesenchymal stem cells (MSCs) are becoming popular in cell therapy. Various insults may disrupt the repair mechanisms involving MSCs. One such insult is smoking, which is a major risk factor for osteoporosis and respiratory diseases. Upon cigarette smoke-induced damage, a series of reparatory mechanisms ensue; one such mechanism involves Glycosaminoglycans (GAG). One of these GAGs, namely hyaluronic acid (HA), serves as a potential therapeutic target in lung injury. However, much of its mechanisms of action through its major receptor CD44 remains unexplored. Our previous studies have identified and functionally validated that both cortactin (CTTN: marker of motility) and Survivin (BIRC5: required for cell survival) act as novel HA/CD44-downstream transcriptional targets underpinning cell motility. Here, human MSCs were treated with " Water-pipe " smoke to investigate the effects of cigarette smoke condensate (CSC) on these HA-CD44 novel signaling pathways. Our results show that CSC decreased the expression of both CD44 and its downstream targets CTTN and BIRC5 in MSCs, and that HA reversed these effects. Interestingly, CSC inhibited migration and invasion of MSCs upon CD44-targeted RNAi treatment. This shows the importance of CD44-HA/CTTN and CD44-HA/BIRC5 signaling pathways in MSC motility, and further suggests that these signaling pathways may provide a novel mechanism implicated in migration of MSCs during repair of lung tissue injury. These findings suggest that one should use caution before utilizing MSC from donors with history of smoking, and further pave the way towards the development of targeted therapeutic approaches against CD44-associated diseases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

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.)

Alcohol use in persons living with HIV (PLWH) worsens the severity of bacterial pneumonia. However, the exact mechanism(s) by which this occurs remain ill-defined. We hypothesized that alcohol in the setting of HIV infection decreases Streptococcus pneumoniae clearance from the lung through mechanisms mediated by the gut microbiota. Humanized BLT (bone marrow, liver, thymus) mice were infected with 1 × 10 4 TCID 50 of HIV (BAL and JRCSF strains) via intraperitoneal (i.p.) injection. One week post-HIV infection, animals were switched to a Lieber-DeCarli 5% ethanol diet or an isocaloric control diet for 10 days. Alcohol-fed animals were also given two binges of 2 g/kg ethanol on days 5 and 10. Feces were also collected, banked, and the community structures were analyzed. Mice were then infected with 1 × 10 5  CFU (colony-forming units) of S. pneumoniae and were sacrificed 48 h later. HIV-infected mice had viral loads of ∼2 × 10 4 copies/mL of blood 1 week post-infection, and exhibited an ∼57% decrease in the number of circulating CD4+ T cells at the time of sacrifice. Fecal microbial community structure was significantly different in each of the feeding groups, as well as with HIV infection. Alcohol-fed mice had a significantly higher burden of S. pneumoniae 48 h post-infection, regardless of HIV status. In follow-up experiments, female C57BL/6 mice were treated with a cocktail of antibiotics daily for 2 weeks and recolonized by gavage with intestinal microbiota from HIV+ ethanol-fed, HIV+ pair-fed, HIV- ethanol-fed, or HIV- pair-fed mice. Recolonized mice were then infected with S. pneumoniae and were sacrificed 48 h later. The intestinal microbiota from alcohol-fed mice (regardless of HIV status) significantly impaired clearance of S. pneumoniae. Collectively, these data indicate that alcohol feeding, as well as alcohol-associated intestinal dysbiosis, compromise pulmonary host defenses against pneumococcal pneumonia. Determining whether HIV infection acts synergistically with alcohol use in impairing pulmonary host defenses will require additional study., (Copyright © 2018 Elsevier Inc. 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: Alcohol use causes significant disruption of intestinal microbial communities, yet exactly how these dysbiotic communities interact with the host is unclear. We sought to understand the role of microbial products associated with alcohol dysbiosis in mice on intestinal permeability and immune activation in an in vitro model system., Methods: Microbiota samples from binge-on-chronic alcohol-fed and pair-fed male and female mice were cultured in Gifu Anaerobic Broth for 24 hours under anaerobic conditions. Live/whole organisms were removed, and microbial products were collected and added to human peripheral blood mononuclear cells (PBMCs) or polarized C2BBe1 intestinal epithelial monolayers. Following stimulation, transepithelial electrical resistance (TEER) was measured using a volt/ohm meter and immune activation of PBMC was assessed via flow cytometry., Results: Microbial products from male and female alcohol-fed mice significantly decreased TEER (mean percentage change from baseline alcohol-fed 0.86 Ω/cm 2 vs. pair-fed 1.10 Ω/cm 2 ) compared to microbial products from control mice. Following ex vivo stimulation, immune activation of PBMC was assessed via flow cytometry. We found that microbial products from alcohol-fed mice significantly increased the percentage of CD38+ CD4+ (mean alcohol-fed 17.32% ± 0.683% standard deviation (SD) vs. mean pair-fed 14.2% ± 1.21% SD, p < 0.05) and CD8+ (mean alcohol-fed 20.28% ± 0.88% SD vs. mean pair-fed 12.58% ± 3.59% SD, p < 0.05) T cells., Conclusions: Collectively, these data suggest that microbial products contribute to immune activation and intestinal permeability associated with alcohol dysbiosis. Further, utilization of these ex vivo microbial product assays will allow us to rapidly assess the impact of microbial products on intestinal permeability and immune activation and to identify probiotic therapies to ameliorate these defects., (© 2019 by the Research Society on Alcoholism.)

Background: Alcohol use disorders (AUDs) are highly prevalent in people living with HIV (PLWH) and are associated with increased HIV risk behaviors, suboptimal treatment adherence, potential interaction with medication pharmacodynamics, and greater risk for disease progression. Preclinical studies show that chronic binge alcohol administration accelerates disease progression and aggravates pathogenesis in the simian immunodeficiency virus (SIV)-infected rhesus macaque model despite viral suppression by antiretroviral therapy., Methods: To translate preclinical findings in the rhesus macaque model of chronic binge alcohol administration and SIV infection and to address areas of uncertainty surrounding the biological mechanisms and socioenvironmental modifiers that contribute to the relationship between alcohol use and HIV-associated comorbidities, precocious aging, and disease progression, we designed a translational multiproject, longitudinal, cohort study, and the New Orleans Alcohol Use in HIV (NOAH) Study. The NOAH Study is led by a multidisciplinary team of scientists, with a research focus on the interaction of AUD and HIV. The overarching hypothesis is that alcohol use will lead to adverse health outcomes in PLWH. In this report, we describe the study design and baseline descriptive characteristics of our cohort., Results: Three-hundred and sixty-five participants completed the baseline testing. The cohort is predominantly male (69%) and African American (83.5%). The majority of participants report incomes below 200% of the federal poverty level. CD4 counts <200 cells/μl were found in 12.8% and viral loads <50 copies/ml were found in 73.6%. These HIV status variables did not differ based upon alcohol use., Conclusions: The NOAH Study facilitates bidirectional translational investigation of alcohol's impact on PLWH. Translation of preclinical findings to PLWH permits confirmation of basic biological mechanisms in humans and also allows incorporation of sociobehavioral factors that may affect biology but are challenging to replicate in preclinical models., (© 2019 by the Research Society on Alcoholism.)

People living with the human immunodeficiency virus (PLWH) may be particularly vulnerable to the consequences of non-tuberculous mycobacteria (NTM) given their defective T cell-mediated immunity and high rates of structural lung disease. To determine the prevalence of NTM in PLWH hospitalized with pneumonia and to assess the potential predictors of NTM isolation. Secondary data analysis of a prospective cohort study (2007-2011) of early bronchoscopy in PLWH presenting with suspected pneumonia was undertaken. Subjects with any species of NTM, henceforth described as 'NTM of undetermined significance' (NTM-US), isolated from sputum or bronchoalveolar lavage fluid (BALF), were included in the analysis. Potential predictors were chosen a priori. Among 196 HIV-infected subjects hospitalized with pneumonia, 96 had respiratory samples positive for NTM-US, with 91% of all NTM-US isolated from sputum compared with BALF. The overall prevalence of NTM-US was 49% (96/196). More NTM subjects were smokers ( P = 0.08), with a history of chronic obstructive pulmonary disease ( P = 0.08). Among those with pathogenic NTM, 39% (34/88) would have met American Thoracic Society microbiologic criteria for NTM pulmonary disease (17% of total cohort). Respiratory cultures, predominantly sputum samples, were positive for NTM-US in 45% of HIV-infected subjects admitted to hospital for pneumonia. Further research is needed to characterize the prevalence of NTM in PLWH and help establish specific diagnostic criteria in this population. .

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.

Objectives: Body composition alterations occur during aging. The purpose of the present analysis was to explore the functional consequences of the overlap of sarcopenia and osteoporosis, and the potential role of insulin-like growth factor 1 (IGF1) in their development in the oldest old., Setting and Participants: Eighty-seven nonagenarians from the Louisiana Healthy Aging Study were included., Measures: The definition of sarcopenia was based on appendicular lean mass (ALM). Osteoporosis was diagnosed based on bone mineral density (BMD) T score. Four phenotypes were compared: (1) healthy body composition, that is, nonosteoporotic nonsarcopenic (CO, control group), (2) osteoporotic (O, low BMD T score), (3) sarcopenic (S, low ALM), and (4) osteosarcopenic (OS, low BMD T score and low ALM). Sex- and age-specific IGF1-Standard Deviation Scores (SDS) were calculated. The Continuous Scale-Physical Functional Performance (CS-PFP) test was performed., Results: In OS men, IGF1-SDS values (-0.61 ±0.37 vs -0.04 ± 0.52, P = .02) were lower than those in CO males (control group), whereas IGF1-SDS were similar in the 4 body composition phenotypes in women. In men only, ALM was positively associated with IGF1-SDS values (P = .01) independent of age and C-reactive protein concentration. Regarding bone health, we found no association between IGF1-SDS values and BMD. IGF1-SDS was not associated with functional performance (CS-PFP) in men and women., Conclusions/implications: IGF1 sensitivity in skeletal muscle and bone may differ by sex in the oldest old. IGF1 status did not appear to affect physical functionality. Determinants and clinical and functional characteristics of osteosarcopenia need to be further investigated in order to define conclusive diagnostic criteria., (Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. All rights reserved.)

Background: The sequence of events preceding incident bacterial vaginosis (iBV) is unclear., Methods: African American women who have sex with women, who had no Amsel criteria and Nugent scores of 0-3, were followed for 90 days to detect iBV (defined as a Nugent score of 7-10 on at least 2-3 consecutive days), using self-collected vaginal swab specimens. For women with iBV (cases) and women maintaining normal vaginal flora (healthy women), 16S ribosomal RNA gene sequencing targeting V4 was performed. Longitudinal vaginal microbiome data were analyzed., Results: Of 204 women screened, 42 enrolled; of these, 45% developed iBV. Sequencing was performed on 448 specimens from 14 cases and 8 healthy women. Among healthy women, Lactobacillus crispatus dominated the vaginal microbiota in 75%. In contrast, prior to iBV, the vaginal microbiota in 79% of cases was dominated by Lactobacillus iners and/or Lactobacillus jensenii/Lactobacillus gasseri. The mean relative abundance of Prevotella bivia, Gardnerella vaginalis, Atopobium vaginae, and Megasphaera type I became significantly higher in cases 4 days before (P. bivia), 3 days before (G. vaginalis), and on the day of (A. vaginae and Megasphaera type I) iBV onset. The mean relative abundance of Sneathia sanguinegens, Finegoldia magna, BV-associated bacteria 1-3, and L. iners was not significantly different between groups before onset of iBV., Conclusion: G. vaginalis, P. bivia, A. vaginae, and Megasphaera type I may play significant roles in iBV.

Short Summary: : Effective combined antiretroviral therapy regimens have extended survival of persons living with HIV (PLWH). Heavy alcohol consumption is common in PLWH. This overview integrates evidence from clinical and preclinical research to identify salient alcohol-related mechanisms and comorbidities contributing to disease pathogenesis and accelerated aging and senescence in PLWH.

Objective: This study used CD obesity-prone (OP) and obesity-resistant (OR) rats to examine how weight gain and fat accretion relate to fermentation levels and microbiota composition after feeding resistant starch (RS)., Methods: After feeding OP rats and OR rats a high-fat (HF) diet for 4 weeks, rats were stratified into three groups: they were fed either an HF diet (group 1: HF-HF) or were switched to a low-fat (LF) diet (group 2: HF-LF) or an LF diet supplemented with 20% RS by weight for 4 weeks (group 3: HF-LFRS). Energy intake, body weight, fermentation variables, and microbiota composition were determined., Results: In OP rats, RS elicited robust fermentation (increased cecal contents, short-chain fatty acids, and serum glucagon-like peptide 1). Total bacteria, species of the Bacteroidales family S24-7, and the archaean Methanobrevibacter smithii increased. The robust fermentation did not elicit higher weight or fat accretion when compared with that of control rats fed the same isocaloric diets (HF-LF ± RS). In OR rats, body weight and fat accretion were also not different between HF-LF ± RS diets, but RS elicited minimal changes in fermentation and microbiota composition., Conclusions: Robust fermentation did not contribute to greater weight. Fermentation levels and changes in microbiota composition in response to dietary RS differed by obesity phenotype., (© 2018 The Obesity Society.)

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.

The human gastrointestinal microbiota plays a key homeostatic role in normal functioning of physiologic processes commonly undermined by aging. We used a previously validated 34-item frailty index (FI34) to identify changes in gut microbiota community structure associated with biological age of community-dwelling adults. Stool 16S rRNA cDNA libraries from 85 subjects ranging in age (43-79) and FI34 score (0-0.365) were deep sequenced, denoised, and clustered using DADA2. Subject biological age but not chronological age correlated with a decrease in stool microbial diversity. Specific microbial genera were differentially abundant in the lower, middle, and upper 33rd percentiles of biological age. Using Sparse Inverse Covariance Estimation for Ecological Association and Statistical Inference (SPIEC-EASI) and Weighted Gene Co-Expression Network Analysis (WGCNA), we identified modules of coabundant microbial genera that distinguished biological from chronological aging. A biological age-associated module composed of Eggerthella, Ruminococcus, and Coprobacillus genera was robust to correction for subject age, sex, body mass index, antibiotic usage, and other confounders. Subject FI34 score positively correlated with the abundance of this module, which exhibited a distinct inferred metagenome as predicted by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). We conclude that increasing biological age in community-dwelling adults is associated with gastrointestinal dysbiosis., (© The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Walnuts are rich in omega-3 fatty acids, phytochemicals and antioxidants making them unique compared to other foods. Consuming walnuts has been associated with health benefits including a reduced risk of heart disease and cancer. Dysbiosis of the gut microbiome has been linked to several chronic diseases. One potential mechanism by which walnuts may exert their health benefit is through modifying the gut microbiome. This study identified the changes in the gut microbial communities that occur following the inclusion of walnuts in the diet. Male Fischer 344 rats (n=20) were randomly assigned to one of two diets for as long as 10 weeks: (1) walnut (W), and (2) replacement (R) in which the fat, fiber, and protein in walnuts were matched with corn oil, protein casein, and a cellulose fiber source. Intestinal samples were collected from the descending colon, the DNA isolated, and the V3-V4 hypervariable region of 16S rRNA gene deep sequenced on an Illumina MiSeq for characterization of the gut microbiota. Body weight and food intake did not differ significantly between the two diet groups. The diet groups had distinct microbial communities with animals consuming walnuts displaying significantly greater species diversity. Walnuts increased the abundance of Firmicutes and reduced the abundance of Bacteriodetes. Walnuts enriched the microbiota for probiotic-type bacteria including Lactobacillus, Ruminococcaceae, and Roseburia while significantly reducing Bacteroides and Anaerotruncus. The class Alphaproteobacteria was also reduced. Walnut consumption altered the gut microbial community suggesting a new mechanism by which walnuts may confer their beneficial health effects., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic alcohol consumption perturbs the normal intestinal microbial communities (dysbiosis). To investigate the relationship between alcohol-mediated dysbiosis and pulmonary host defense we developed a fecal adoptive transfer model, which allows us to investigate the impact of alcohol-induced gut dysbiosis on host immune response to an infectious challenge at a distal organ, independent of prevailing alcohol use. Male C57BL/6 mice were treated with a cocktail of antibiotics (ampicillin, gentamicin, neomycin, vancomycin, and metronidazole) via daily gavage for two weeks. A separate group of animals was fed a chronic alcohol (or isocaloric dextrose pair-fed controls) liquid diet for 10 days. Microbiota-depleted mice were recolonized with intestinal microbiota from alcohol-fed or pair-fed (control) animals. Following recolonization groups of mice were sacrificed prior to and 48 hrs. post respiratory infection with Klebsiella pneumoniae. Klebsiella lung burden, lung immunology and inflammation, as well as intestinal immunology, inflammation, and barrier damage were examined. Results showed that alcohol-associated susceptibility to K. pneumoniae is, in part, mediated by gut dysbiosis, as alcohol-naïve animals recolonized with a microbiota isolated from alcohol-fed mice had an increased respiratory burden of K. pneumoniae compared to mice recolonized with a control microbiota. The increased susceptibility in alcohol-dysbiosis recolonized animals was associated with an increase in pulmonary inflammatory cytokines, and a decrease in the number of CD4+ and CD8+ T-cells in the lung following Klebsiella infection but an increase in T-cell counts in the intestinal tract following Klebsiella infection, suggesting intestinal T-cell sequestration as a factor in impaired lung host defense. Mice recolonized with an alcohol-dysbiotic microbiota also had increased intestinal damage as measured by increased levels of serum intestinal fatty acid binding protein. Collectively, these results suggest that alterations in the intestinal immune response as a consequence of alcohol-induced dysbiosis contribute to increased host susceptibility to Klebsiella pneumonia.