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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.

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.

Background Effective screening of alcohol use and prevention of alcohol use disorder (AUD) requires the continuous preparation of educated and confident providers across all health professions who will ideally work in close collaboration in their future practices. As one mechanism for achieving this goal, the development and provision of interprofessional education (IPE) training modules for health care students may cultivate beneficial interactions among future health providers early in their formative education. Methods In the present study, we assessed attitudes about alcohol and confidence in screening and AUD prevention in 459 students at our health sciences center. Students represented ten different health professions (audiology, cardiovascular sonography, dental hygiene, dentistry, medicine, nursing, physical therapy, public health, respiratory therapy, and speech language pathology programs). For purposes of this exercise, students were divided into small, professionally diverse teams. Responses to ten survey questions (Likert scale) were collected via a web-based platform. These assessments were collected before and after a case-based exercise that provided information to students on the risks of excessive alcohol use as well as the effective screening and team-based management of individuals susceptible to AUD. Results Wilcoxon signed-rank analyses revealed that the exercise led to significant decreases in stigma toward individuals engaging in at-risk alcohol use. We also discovered significant increases in self-reported knowledge and confidence in personal qualifications needed to initiate brief interventions to reduce alcohol use. Focused analyses of students from individual health programs uncovered unique improvements according to question theme and health profession. Conclusion Our findings demonstrate the utility and effectiveness of single, focused IPE-based exercises to impact personal attitudes and confidence in young health professions learners. While additional longitudinal cohort follow-up studies are needed, these results may translate into more effective and collaborative AUD treatment in future clinical settings.

Cannabis use is frequent in HIV-infected individuals for its appetite stimulation and anti-inflammatory effects. To identify the underlying molecular mechanisms associated with these effects, we simultaneously profiled micro-RNA (miRNA) and mRNA expression in the colon of chronically simian immunodeficiency virus (SIV)-infected rhesus macaques administered either vehicle (VEH/SIV; = 9) or Δ -tetrahydrocannabinol (Δ -THC; THC/SIV; = 8). Pro-inflammatory miR-130a, miR-222, and miR-29b, lipopolysaccharide-responsive miR-146b-5p and SIV-induced miR-190b were significantly upregulated in VEH/SIV rhesus macaques. Compared to VEH/SIV rhesus macaques, 10 miRNAs were significantly upregulated in THC/SIV rhesus macaques, among which miR-204 was confirmed to directly target MMP8, an extracellular matrix-degrading collagenase that was significantly downregulated in THC/SIV rhesus macaques. Moreover, THC/SIV rhesus macaques failed to upregulate pro-inflammatory miR-21, miR-141 and miR-222, and alpha/beta-defensins, suggesting attenuated intestinal inflammation. Further, THC/SIV rhesus macaques showed higher expression of tight junction proteins (occludin, claudin-3), anti-inflammatory , keratin-8 (stress protection), (epithelial proliferation), and anti-HIV . Gomori one-step trichrome staining detected significant collagen deposition (fibrosis) in the paracortex and B cell follicular zones of axillary lymph nodes from all VEH/SIV but not in THC/SIV rhesus macaques, thus demonstrating the ability of Δ -THC to prevent lymph node fibrosis, a serious irreversible consequence of HIV induced chronic inflammation. Furthermore, using flow cytometry, we showed that Δ -THC suppressed intestinal T cell proliferation/activation (Ki67/HLA-DR) and PD-1 expression and increased the percentages of anti-inflammatory CD163 macrophages. Finally, while Δ -THC did not affect the levels of CD4 T cells, it significantly reduced absolute CD8 T cell numbers in peripheral blood at 14 and 150 days post-SIV infection. These translational findings strongly support a role for differential miRNA/gene induction and T cell activation in Δ -THC-mediated suppression of intestinal inflammation in HIV/SIV and potentially other chronic inflammatory diseases of the intestine.

Alcohol exerts significant immunomodulatory effects on innate and adaptive immune responses, impairing host defense against infections. Gut-mucosa-derived dendritic cells (DCs) traffic to mesenteric lymph nodes (MLNs) through mesenteric lymphatic vessels (MLVs), contributing to intestinal antigen homeostasis. Previously, we demonstrated that acute alcohol administration to male rats induces MLV hyperpermeability resulting in perilymphatic adipose tissue (PLAT) inflammation and insulin signaling dysregulation. We hypothesized that alcohol-induced MLV hyperpermeability can lead to DC leakage to PLAT. DCs promote adipose tissue regulatory T cell (Treg) expansion, and this has been proposed as a mechanism underlying age-associated insulin resistance (IR). The aim of this study was to determine whether chronic alcohol consumption promotes DC leakage to PLAT and results in metabolic dysregulation. Male rats received a Lieber–DeCarli liquid diet containing 36% of calories from alcohol for 10 weeks. Time-matched control animals were pair-fed. PLAT, MLNs, and peripheral blood leukocytes (PBLs) were isolated for flow cytometry analyses. PLAT explants were used for determinations of insulin-induced glucose uptake. Chronic alcohol consumption decreased MLN CD4/CD8 ratio and Treg frequency in PBLs. Alcohol increased the frequency of DCs, CD4 T cells, and Tregs in PLAT. Lastly, alcohol decreased insulin-stimulated glucose uptake in PLAT. Collectively, these findings suggest that alcohol-induced immune cell deviation from the gut–MLN pathway is associated with PLAT immunometabolic dysregulation. Whether this immune cell deviation impacts induction of mucosal immunity warrants further investigation.

Background Effective antiretroviral therapy (ART) in people living with HIV (PLWH) has improved life expectancy and increased risk of age-associated cardiometabolic comorbidities. At-risk alcohol use is more frequent among PLWH and increases the risk of health challenges. PLWH with at-risk alcohol use are more likely to meet criteria for prediabetes/diabetes and this is associated with impaired whole-body glucose-insulin dynamics. Methods The Alcohol & Metabolic Comorbidities in PLWH: Evidence Driven Interventions Study (ALIVE-Ex Study, NCT03299205) is a longitudinal, prospective, interventional study to determine the effects of an aerobic exercise protocol on improving dysglycemia among PLWH with at-risk alcohol use. The intervention is a moderate intensity aerobic exercise protocol implemented 3 days per week for 10 weeks at the Louisiana State University Health Sciences Center-New Orleans. Participants who have a fasting blood glucose level between 94 and 125 mg/dl will be enrolled in the study. Oral glucose tolerance tests, fitness assessments, and skeletal muscle biopsies will be performed pre- and post-exercise intervention. The primary outcome is to determine whether the exercise protocol improves measures of whole-body glucose-insulin dynamics, cardiorespiratory fitness, and skeletal muscle metabolic and bioenergetic function. Secondary outcomes are to determine whether the exercise intervention improves cognitive function and overall quality of life. Results generated will demonstrate the effect of exercise on glycemic measures in PLWH with subclinical dysglycemia and at-risk alcohol use. Conclusions The proposed intervention will also have the potential to be scalable to promote lifestyle changes among PLWH, particularly in underserved communities.

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.Samuelson et al show that alcohol impairs the production/processing of microbial metabolites, specifically tryptophan catabolites, resulting in immune dysregulation and impaired cellular trafficking for optimal host defense. The metabolite, indole, or probiotics making indole metabolites mitigate alcohol-induced susceptibility to Klebsiella-associated pneumonia, and that the mechanisms are partially dependent on AhR.

Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.

Effective antiretroviral therapy (ART) has transitioned HIV to a chronic disease, with more than 50% of people living with HIV (PLWH) being over the age of 50. HIV targets activated CD4+ T cells expressing HIV-specific co-receptors (CCR5 and CXCR4). Previously, we reported that chronic binge alcohol (CBA)-administered male rhesus macaques had a higher percentage of gut CD4+ T cells expressing simian immunodeficiency virus (SIV) co-receptor CXCR4. Evidence also suggests that gonadal hormone loss increased activated peripheral T cells. Further, mitochondrial function is critical for HIV replication and alcohol dysregulates mitochondrial homeostasis. Hence, we tested the hypothesis that CBA and ovariectomy (OVX) increase circulating activated CD4+ T cells expressing SIV co-receptors and dysregulate mitochondrial homeostasis in SIV-infected female rhesus macaques. Results showed that at the study end-point, CBA/SHAM animals had increased peripheral CD4+ T cell SIV co-receptor expression, and a lower CD4+ T cell count compared to CBA/OVX animals. CBA and OVX animals had altered peripheral immune cell gene expression important for maintaining mitochondrial homeostasis. These results provide insights into how at-risk alcohol use could potentially impact viral expression in cellular reservoirs, particularly in SIV-infected ovariectomized rhesus macaques.

Alcohol use and aging are risk factors for falls requiring immobilization and leading to skeletal muscle atrophy. Skeletal muscle regeneration is integral to post-immobilization recovery. This study aimed to elucidate the effects of alcohol and ovarian hormone loss on the expression of genes implicated in muscle regeneration. Three-month-old female rats received an ovariectomy or a sham surgery, consumed an alcohol-containing or control diet for 10 weeks, were subjected to unilateral hind limb immobilization for seven days, and finally were allowed a three (3d)- or 14 (14d)-day recovery. Immobilization decreased the quadriceps weight at 3d and 14d, and alcohol decreased the quadriceps weight at 14d in the nonimmobilized hind limb (NI). At 3d, alcohol decreased gene expression of myoblast determination protein (MyoD) in the immobilized hind limb (IMM) and myocyte enhancer factor (Mef)2C and tumor necrosis factor (TNF)α in NI, and ovariectomy increased MyoD and decreased TNFα expression in NI. At 14d, alcohol increased the gene expression of Mef2C, MyoD, TNFα, and transforming growth factor (TFG)β in IMM and decreased monocyte chemoattractant protein (MCP)1 expression in NI; ovariectomy increased TNFα expression in NI, and alcohol and ovariectomy together increased Mef2C expression in NI. Despite increased TGFβ expression, there was no concomitant alcohol-mediated increase in collagen in IMM at 14d. Overall, these data indicate that alcohol dysregulated the post-immobilization alteration in the expression of genes implicated in regeneration. Whether alcohol-mediated molecular changes correspond with post-immobilization functional alterations remains to be determined.