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. Author manuscript; available in PMC: 2024 Jan 1.
Published in final edited form as: Alcohol Clin Exp Res (Hoboken). 2022 Nov 29;47(1):36–44. doi: 10.1111/acer.14979

A critical review of recent knowledge gained on alcohol’s effects on the immunological response in different tissues

Kathryn Crotty 1, Paige Anton 2,3, Leon G Coleman 4, Niya L Morris 1, Sloan A Lewis 5, Derrick R Samuelson 6, Rachel H McMahan 3,7, Phillipp Hartmann 8, Adam Kim 9, Anuradha Ratna 10, Pranoti Mandrekar 11, Todd A Wyatt 12, Mashkoor A Choudhry 13, Elizabeth J Kovacs 3,7,14, Rebecca McCullough 3,2, Samantha M Yeligar 1
PMCID: PMC9974783  NIHMSID: NIHMS1851862  PMID: 36446606

Abstract

Alcohol misuse contributes to dysregulation of immune responses across various tissues and multi-organ dysfunction, which are associated with higher risk of morbidity and mortality in people with alcohol use disorders (AUDs). Organ-specific immune cells, including microglia in the brain, alveolar macrophages in the lungs, and Kupffer cells in the liver, play vital functions in host immune defense through tissue repair and maintaining homeostasis. However, binge-drinking, and chronic alcohol misuse impair these immune cells’ abilities to regulate inflammatory signaling and metabolism, thus contributing towards multi-organ dysfunction. To further complicate these delicate systems, immune cell dysfunction during alcohol misuse is exacerbated by aging and gut barrier leakage. This critical review delves into recent advances made in elucidating the potential mechanisms by which alcohol misuse leads to derangements in host immunity and highlights current gaps in knowledge that may be the focus of future investigations.

Introduction

Alcohol misuse is linked to end-organ injury in the brain, lungs, liver, and gut due, in part, to dysregulated immune responses across these tissues. A status report on alcohol and health conducted by the World Health Organization estimates that alcohol misuse is associated with about 14 percent of total deaths among people ages 20 to 39 (World Health Organization, 2018). In the United States, over fifteen million people are diagnosed with alcohol use disorders (AUDs), and over 95,000 people die per year due to alcohol-related causes (Centers for Disease Control and Prevention, 2020). Additionally, alcohol-related healthcare costs, including emergency room and physician office visits, total more than $249 billion annually in the United States (Bouchery et al., 2011).

The toxic effects of alcohol can directly and negatively impact the immune system, particularly organ-specific immune cells. Overall, the critical functions of immune cells that maintain host defense are impaired as alcohol misuse is associated with non-resolving inflammation and perturbations in cellular metabolism (Gray and Farber, 2022). More co-morbidities, including advanced age, appear to have heightened sensitivity to alcohol and worsened immune cell dysfunction. Despite this knowledge, there are still significant gaps in knowledge related to the specific health impacts of alcohol misuse on host immunity. Accordingly, this critical review delves into recent advances in elucidating potential mechanisms by which alcohol misuse leads to derangements in immunity at the cellular, organ-specific, and organismal level.

The mechanisms involved in alcohol-related organ damage are multifactorial, thus effective therapeutic strategies are limited. In this review, we will outline exciting and novel approaches used to identify mechanisms underlying organ-specific alcohol-associated abnormalities in immune cell signaling. We will additionally highlight areas that are ripe for future investigation regarding current gaps in knowledge.

Alcohol-Associated Neuroinflammation

Alcohol is a direct neurotoxicant, and chronic alcohol misuse leads to neurodegeneration and cognitive dysfunction (de la Monte and Kril, 2014). Persistent neuroimmune activation (i.e., neuroinflammation) facilitates alcohol-induced neurodegeneration through generation of danger associated molecular patterns (DAMPs) and activation of microglia, the resident macrophages of the brain (Crews et al., 2015, Henriques et al., 2018, Coleman et al., 2017). Human alcohol and animal ethanol (EtOH) consumption studies show neuroinflammatory responses to EtOH are mediated via Toll-like receptor (TLR) signaling: post-mortem brain tissue from people with AUD exhibit increased TLR expression compared to healthy controls (Crews et al., 2013), and TLR knock out mice are protected from inductions in pro-inflammatory factor release and neuronal injury after chronic EtOH exposure (Pascual et al., 2011, Alfonso-Loeches et al., 2010). Although these studies indicate mitigating neuroinflammation will protect against alcohol-induced neurotoxicity, the inter- and intracellular factors that facilitate alcohol-induced neuroinflammation have not been fully elucidated.

Despite limited knowledge on alcohol-induced neuroinflammation, newer studies are beginning to define the specific impact of alcohol on innate immunity in the brain. Extracellular vesicles are emerging as key intercellular signaling mediators that carry signaling proteins, mRNAs, and microRNAs (Asquith et al., 2014, Bala et al., 2012), but the role of extracellular vesicles in alcohol-induced neuroimmune activation has not been extensively explored (Coleman, 2022). Recent studies have revealed microglia-derived microvesicles (MVs), extracellular vesicles (0.1–1μm diameter) released from the cell surface of somatic cells, to be pro-inflammatory mediators of neuroimmune signaling in response to EtOH (Coleman et al., 2017, Crenshaw et al., 2019). Activation of microglia leads to augmented release of pro-inflammatory cytokines interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) that amplify neuroinflammation and accelerate alcohol-related neuronal death (Montesinos et al., 2016, Crews et al., 2021).

Using primary organotypic brain slice cultures and sequential ultracentrifugation for MV isolation, studies by Crews et al. demonstrate that MVs drive temporal pro-inflammatory gene production in EtOH challenged animal brain slice (Crews et al., 2021), including TNF-α and IL-1β, concomitant with decreased homeostatic microglia Tmem119, and changes in other microglia-specific genes (i.e., P2RY12, CX3CR1). It was also found that blocking MV secretion using an inhibitor of acid-sphingomyelinase, imipramine, blunted pro-inflammatory activation by EtOH (Crews et al., 2021). Further, microglia depletion with a colony-stimulating factor-1 receptor inhibitor prevented the EtOH-induced production of pro-inflammatory MVs, without diminishing the total number of extracellular vesicles in media. Together, these findings implicate MVs as mediators of neuroimmune signaling in response to EtOH. While these seminal findings identify MVs as critical drivers of neuroinflammation by EtOH, it will be important for future studies to explore the cellular mechanisms underlying EtOH-MV effects as well as the therapeutic potential of blocking EtOH-induced MVs in vivo to reduce AUD-associated neuropathology.

Alcohol Misuse and Advanced Age

Age-related exacerbation of alcohol-induced neurological diseases is a concern considering that binge-drinking is becoming increasingly common among older (>65 years of age) populations (Keyes, 2022a, Keyes, 2022b, Tevik et al., 2019). Advanced age and alcohol use can cause neuroinflammation via microglial activation and pro-inflammatory cytokine production, leading to neurodegeneration (Crews et al., 2015, Henriques et al., 2018). However, the synergistic effects of advanced age and binge alcohol exposure on neuroinflammation and neurodegeneration are not well defined, and there is a current lack of validated animal models to explore age-related susceptibilities to the effects of binge-EOH exposure. Novel rodent models are being developed to accurately reflect alterations in human microglia activation and cytokine production between young and aged alcohol-exposed brain.

Still, the contribution of alcohol misuse to age-related neurodegenerative diseases, such as Alzheimer’s disease and (AD) and AD-Related Dementias has not been fully characterized. The aged brain may be more vulnerable to alcohol-related neuroinflammation and damage due to neuronal “inflamm-aging,” as evidenced by baseline increases in microglia polarization to a pro-inflammatory state and elevated TNF-α and IL-1β production that are further elevated upon exposure to TLR agonists like lipopolysaccharide (LPS) (Franceschi et al., 2000, Frank et al., 2010). These data suggest the aged brain may respond to binge EtOH exposure with greater neuroinflammation and resulting degeneration, yet there is a gap in research defining the specific changes associated with alcohol misuse, neuroinflammation, and advanced age.

To address these gaps knowledge, an animal model was developed to measure changes in EtOH-induced microglia activation and cytokine production between the young and aged brain. Using an intermittent binge EtOH exposure model, aged mice have heightened neuroinflammatory response to EtOH compared to their younger counterparts. Eighteen hours after final exposure TNFα, IL-1β, and IL-6 mRNA levels in aged, EtOH exposed animals were elevated compared to young control and EtOH exposed animals. These data also identify specific differences in EtOH metabolism, like previously published data (Meier and Seitz, 2008): aged animals exhibited significantly higher blood EtOH concentrations (380 mg/dl) compared to young animals (280mg/dL) 30 minutes after final gavage. This induction pattern is like that of aged adults compared to young adults after consuming equal amounts of EtOH (Lucey et al., 1999). These studies suggest that advanced age sensitizes the brain to binge EtOH-related neuroinflammation and that the consequences of these responses on age-related neurodegeneration and cognitive dysfunction should be explored in future studies. This novel model of intermittent binge-EtOH exposure can be used to investigate age-related susceptibility to EtOH-induced microglia activation and associated neuronal injury.

Alcohol-Induced Lung Dysfunction

In contrast to the pro-inflammatory state of the brain chronic alcohol consumption, AUDs profoundly increase the risk of respiratory infections in part due to diminished alveolar macrophage phagocytic capacity (Greenberg et al., 1999) and impaired mucociliary clearance (Price et al., 2019, Wyatt et al., 2004), resulting potential lung damage and acute respiratory distress syndrome (Moss et al., 2003, Baker and Jerrells, 1993). Yet, like alcohol-associated gut barrier dysfunction, inflammasome activation diminishes tight junction protein levels and barrier integrity of the lung epithelium (Burnham et al., 2003, Pelaez et al., 2004, Liang et al., 2012), but the molecular mechanisms leading to these alcohol-induced immune derangements need to be further clarified. We will discuss recent studies that highlight the role of extracellular matrix, bacterial metabolites, and inflammasome activation in regulating immune function in the lung following alcohol use.

In studies of chronic alcohol misuse in humans and mice, alcohol has been shown to impair the ability of alveolar macrophages to phagocytose pathogens (Yeligar et al., 2016a, Baughman and Roselle, 1987, Greenberg et al., 1999, Yeligar et al., 2016b) via increased oxidative stress (Wagner et al., 2012), mitochondrial redox imbalance (Liang et al., 2013) and impaired mitochondrial bioenergetics (Liang et al., 2014). Chronic alcohol drinking is associated with increased susceptibility to infection as well as decreased wound healing and tissue repair capacity (Kumar, 2020, Morris and Yeligar, 2018, Sueblinvong et al., 2014).

Recent studies suggest that alveolar macrophages from alcohol drinking rhesus macaques demonstrate chromatin reorganization and accessibility changes that lead to functional deficits in the macrophages and limit their ability to respond properly to pathogens. A study conducted by Lewis, et al. aimed to uncover the physiological mechanisms by which alcohol disrupts monocyte/macrophage function. One year of chronic alcohol drinking in rhesus macaques results in systematic rewiring of circulating monocytes and splenic macrophages, affecting their ability to respond to bacterial products such as LPS ex vivo (Lewis et al., 2022). Additionally, transcriptional analysis of the response to respiratory syncytial virus (RSV) indicated that while inflammatory, the alcohol exposed macrophage response was lacking in critical antiviral response genes, including interferons (Rhoades et al., 2022, Lewis et al., 2022). Even without a secondary stimulation, alveolar macrophages demonstrated heightened cellular oxidative stress levels (Lewis et al., 2022) and intensified mitochondrial potential. To assess potential mechanisms for these altered functional states with alcohol, single cell level transcriptomics and epigenetics were performed on isolated alveolar macrophages. A new subset of macrophage chromatin reorganization and accessibility changes with alcohol were identified that bolsters the hypothesis that macrophages have limited ability to respond properly to pathogens.

Hyaluronic acid (HA) is an extracellular matrix glycosaminoglycan of variable molecular weight that can function as a pro- or anti-inflammatory signaling molecule. For example, HA synthesis and fragmentation are increased in chronic respiratory diseases and in the bronchoalveolar lavage fluid of ARDS patients (Hallgren et al., 1989), potentially through amplified hyaluronidase activity and oxidant generation during inflammation (Parsons, 2018, Rees et al., 2008). In vitro and in vivo models of EtOH exposure include a murine alveolar macrophage cell line, MH-S cells, treated with 0.08% EtOH for three days or a 12-week EtOH feeding model (20% w/v in drinking water) in C57BL/6J mice (Morris et al., 2021). Preliminary data gathered by the Yeligar lab showed that alcohol or 1000 kD high molecular weight HA treatment diminished mitochondrial bioenergetics measured by an extracellular flux analyzer in vitro. Additionally, alcohol altered HA-binding protein expression in vitro and induced reactive oxygen species in bronchoalveolar lavage fluid in vivo, which was attenuated with pioglitazone (PIO), a synthetic peroxisome proliferator-activated receptor gamma (PPARγ) thiazolidinedione ligand with antioxidant effects (Yeligar et al., 2021). These findings suggest that alcohol alters HA dynamics, and that targeting oxidant stress may improve alveolar macrophage dysfunction. Future studies will continue to explore alterations in HA dynamics resulting in alveolar macrophage immune dysfunction.

Alveolar epithelial barrier disruption and subsequent pulmonary leakage are major contributors to ARDS (Liang et al., 2012, Burnham et al., 2003). However, the relationship between inflammasome activation and chronic alcohol-induced lung barrier dysfunction has not previously been examined. NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation diminishes tight junction protein levels and barrier integrity (Gao et al., 2015, Grassme et al., 2014). Also, earlier findings have demonstrated that inflammasome activation is suppressed by activation of PPARγ (Piantadosi and Suliman, 2017, Kane and Drew, 2016). Recent data suggest that chronic alcohol exposure increases inflammasome activation, resulting in barrier impairment in lung epithelial cells and that activation of PPARγ with a synthetic thiazolidinedione ligand reverses these derangements.

An additional study expands on the use of thiazolidinedione ligands in alcohol use lung dysfunction. A mouse alveolar epithelial cell line, MLE-12 cells, was used to examine the role of PPARγ in alcohol-induced alveolar epithelial inflammasome activation and lung barrier dysfunction. MLE-12 cells were treated with 0.08% alcohol for three days followed by treatment with PIO (10 μM) during the final day of alcohol exposure. Preliminary data showing that chronic alcohol increased Nlrp3 mRNA levels and stimulated the expression of the downstream effector proteins IL-1β and IL-18 suggest that chronic Alcohol exposure enhanced inflammasome activation in vitro. Chronic Alcohol exposure also decreased transepithelial electrical resistance and expression of the tight junction proteins claudin-1, occludin, and zonula occludens-1. Treatment of MLE-12 cells with PIO reversed alcohol-induced inflammasome activation and barrier impairment in lung epithelial cells. These findings suggest that therapeutic intervention with PIO may diminish pulmonary barrier disruption in people with a history of AUDs.

Alcohol-Mediated Liver Inflammation and Disease

Acute and chronic alcohol consumption modulates the innate immune system, leading to increased systemic and liver inflammation, and alcohol-associated liver disease (ALD). ALD is characterized by steatosis or fatty liver, steatohepatitis, and fibrosis which can progress to cirrhosis and hepatocellular carcinoma. Chronic insults including alcohol exposure disturb cellular homeostasis and induce heat shock proteins in the endoplasmic reticulum (Mandrekar et al., 2008) and cytoplasm (Muralidharan et al., 2014). Recent studies highlight the pathogenic role of cytosolic heat shock protein 90 and therapeutic potential of its endoplasmic reticulum paralog, glycoprotein 96 (GP96), in liver macrophages during ALD (Choudhury et al., 2020). GP96 is required for the folding, processing, and trafficking of several client proteins including TLRs (Ratna et al., 2021). Further, the role of GP96 has been identified in metabolic diseases and cancer but not in ALD.

Preliminary data from Ratna, et al. suggests that GP96 may be of clinical relevance during Alcohol-induced hepatitis, prominently in liver macrophages. Preliminary evidence suggests the prevention of chronic Alcohol-mediated liver injury, steatosis, and inflammation in a murine myeloid-specific GP96 knock out model (M-GP96KO) (Ratna et al., 2021). Utilizing this model, this same group found higher expression of anti-inflammatory genes and markers of restorative macrophages in livers of M-GP96KO mice compared to WT mice. M-GP96KO mice additionally showed alterations in hepatic lipid homeostasis and endoplasmic reticulum stress. Finally, a cell permeable GP96 specific inhibitor, PU-WS13, and GP96-siRNA markedly decreased pro-inflammatory cytokine production in primary murine macrophages, thus confirming a vital role for GP96 in macrophage activation. These findings highlight a novel and critical role for a liver macrophage endoplasmic reticulum resident chaperone, GP96, in ALD and GP96 targeted inhibition represents a promising therapeutic approach in ALD.

Alcohol-associated hepatitis (AH) is a severe inflammatory disease that can superimpose the spectrum of ALD and leads to significant mortality. In a model of AH, gut-derived LPS acts as an initial signal, and C-type lectin receptor (CTR) upregulation serves as a secondary immune surveillance to detect other gut-derived commensal bacteria, virus, and fungi. CTRs are a family of pattern recognition receptors that sense a diverse array of bacteria, fungi, viruses, and DAMPs (Drouin et al., 2020). However, the role of C-type lectin receptors in modulating myeloid-derived cells, including human peripheral monocytes and murine macrophages during AH, was largely unknown. Research has recently revealed that C-type lectin receptors engage in cell-cell communications between immune effector cells, indicating that modeling signaling dysfunction could supply further targetable pathways for treating AH.

While myeloid cells have low basal CTR expression, it was newly discovered that these genes are robustly induced by TLR signaling in myeloid-derived cells, including human peripheral monocytes and murine macrophages (Kim et al., 2020, Zhou et al., 2016). Using single-cell RNA-seq (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from patients, CTRs were found to be upregulated and sensitized monocytes to a wider array of pathogen-associated molecular patterns (PAMPs) and DAMPs (Kim et al., 2020). Interestingly, CTR genes were clustered together in the genome into a cassette on chromosome 12 called the NK gene receptor complex. Using the scRNA-seq data, CTR genes including Mincle, Dectin-2, and Dectin-3 were discovered to have highly coordinated expression in monocytes. Likewise implicated in AH, Dectin-1 (Yang et al., 2017), was upregulated at baseline in monocytes, while CTRs involved in cell-cell communication between monocytes, NK-cells, and CD8 T-cells were similarly dysregulated. Overall, these findings highlight the need for more studies investigating the role of CTRs and other pattern recognition receptors and their specific role as potential drivers of host immune dysfunction and alcohol-mediated liver damage, particularly as the field embraces an ever-growing appreciation that perturbations in the microbiome and epithelial cell barriers change with chronic alcohol misuse.

Alcohol’s Effects on the Gut and Organ Crosstalk

Alcohol misuse additionally disturb intestinal barriers (Starkel and Schnabl, 2016, Starkel et al., 2018) and the gut microbiota, leading to exacerbated immune responses in humans and mouse models (Sommer et al., 2017, Samuelson et al., 2021). Thus, acute and chronic alcohol consumption and microbial metabolites may modulate the innate immune system, leading to increased systemic and liver inflammation (Maccioni et al., 2021). Chronic alcohol drinking is additionally associated with a heightened incidence of ALD (Shah et al., 2022, Isselbacher and Greenberger, 1964, Lieber, 1966), characterized by steatosis or fatty liver, steatohepatitis, and fibrosis which can progress to cirrhosis and hepatocellular carcinoma (Lieber, 1968). However, study designs are complicated by multi-organ communication, and the lack of adequate models to control for complex variable changes. Herein, we highlight few studies attempting to elucidate the effect of moderate alcohol consumption and aging on the gut-lung and gut-liver axis.

Alcohol and the gut-lung axis

The intestinal microbiota generates many different metabolites which are associated with disease pathogenesis and immune homeostasis (Sommer et al., 2017, Samuelson et al., 2021). Chronic alcohol consumption can change intestinal microbial community structure and functional homeostasis. Intestinal microbiota has been recently highlighted as a major driver of alcohol-induced tissue injury to other organs, including the lungs and liver (Li et al., 2019). Yet, little is known about the role of alcohol-associated dysbiosis on host defense against bacterial pneumonia. The specific effects of alcohol on the intestinal microbiome are still being explored, but together with increased permeability of the intestinal barrier (Bishehsari et al., 2017), gut dysbiosis, and bacterial overgrowth (Hartmann et al., 2019, Yan et al., 2011, Mutlu et al., 2012), new insights into the mechanisms associated with alcohol and the gut have recently been highlighted.

Bacterial species that produce indole derivatives of tryptophan catabolism, which normally exert beneficial effects to the host (Hendrikx and Schnabl, 2019), are lost during chronic alcohol exposure and influence epithelial integrity (Roager and Licht, 2018) in part, via the cytokine IL-22 (Zelante et al., 2013, Hendrikx et al., 2019). Indole derivatives can affect host immunity and defense outside of the gut (Samuelson et al., 2021). Indeed, patients with AUD are more frequently infected with highly virulent respiratory pathogens (e.g., Klebsiella pneumonia) and experience elevated morbidity and mortality (Saitz et al., 1997, Gupta et al., 2020, Jong et al., 1995). These clinical observations have been replicated in rodent models, whereby Alcohol-fed mice have elevated K. pneumoniae lung burden that can be alleviated with oral supplementation of indole (Samuelson et al., 2021). Importantly, the protective effects of indole are exerted via aryl hydrocarbon receptors to improve leukocyte trafficking and killing of K. pneumoniae in the lung while also re-establishing pulmonary and intestinal permeability (Samuelson et al., 2021). Interestingly, indole treatment preferentially improved pulmonary recruitment of NK cells in Alcohol-fed mice. However, if NK cells are required for host defense in indole-treated mice or if indole works directly or indirectly on NK cells remains to be answered. These seminal studies have highlighted that targeting the gut microbiome and their associated metabolites may serve as potential therapeutic targets for alcohol-associated diseases. Further, manipulation of tryptophan catabolism and, therefore, aryl hydrocarbon receptor signaling should be further explored as novel therapeutic approaches for the prevention of alcohol-associated pneumonia.

Alcohol and the gut-liver axis

As previously mentioned, excessive alcohol use and associated gut damage can also influence the pathogenesis ALD (Hartmann et al., 2019, Li et al., 2019). A handful of clinical and animal studies examining dysbiosis of the gut microbiome reveal a dramatic shift in the fecal microbiome in patients with ALD (Ray, 2020, Gao et al., 2020) and animals chronically exposed to alcohol-containing diets (Cheng et al., 2021, Tripathi et al., 2018), characterized by pathobiont expansion, reduced diversity and loss of beneficial microbes (Li et al., 2019). The changes in microbial diversity induced by alcohol can directly cause early organ damage, as demonstrated in fecal transplant studies of donor stool from ALD patients and alcohol-fed rodents into naïve recipients (Llopis et al., 2016). In addition to bacteria, the gut microbiome also consists of archaea, viruses, protits, and fungi, which represent understudied areas in ALD pathogenesis (Perez, 2021, Day and Kumamoto, 2022). Fungi are opportunistic pathogens capable of causing highly lethal blood-borne infections; for example, more than half of individuals with Candida bloodstream infections who also have cirrhosis will succumb to the infection (Bartoletti et al., 2014).

Recent advances have revealed a differential fungal microbiome (i.e., mycobiome) in subjects with progressive and non-progressive ALD, including elevations in genera Candida, Debaryomyces, Pichia, Kluyveromyces, and Issatchenkia, which positively correlate with liver damage markers including caspase-dependent cleavage products of cytokeratin 18 (Hartmann et al., 2021a). Two weeks of alcohol abstinence significantly ameliorated liver disease markers caspase-cleaved and intact cytokeratin 18 (CK18-M65) concentrations and controlled attenuation parameter (CAP) in subjects with AUDs, which was accompanied by significantly lower contributions of the genera Candida, Malassezia, Pichia, Kluyveromyces, Issatchenkia, and the species Candida albicans and Candida zeylanoides. Moreover, anti-C. albicans immunoglobulin G (IgG) and M (IgM) are acutely increased in AUD patients and taper off after two weeks of alcohol abstinence, while the genus Malassezia is elevated in AUD patients with progressive liver disease (Hartmann et al., 2021a, Hartmann et al., 2021b), suggesting mycobiome components may also be additional biomarkers for alcohol misuse. Overall, alcohol abstinence ameliorates liver disease in subjects with AUDs, which is associated with lower intestinal contributions of Candida and Malassezia, and lower serum anti-Candida albicans IgG titers. These data add to the limited number of publications in the field (Lang et al., 2020a, Lang et al., 2020b, Yang et al., 2017), but collectively demonstrate that there is much to be discovered related to the mycobiome and if it is a causal factor for ALD.

Conclusion

Excessive alcohol facilitates multi-organ immune dysfunction, as shown in Figure 1. Overall, there remains much to be discovered regarding the specific health effects of alcohol on people of all ages, but these early studies identify possible links to the exacerbated toxicity and immune response to alcohol. In addition to drinking patterns (e.g., heavy, binge-drinking, chronic), additional host factors, including genetics, sex, co-morbidities, environmental exposures, and age all contribute to alcohol-related organ damage and multi-organ damage (Dunn and Shah, 2016). In fact, individuals over the age of 65 consist of the fastest growing demographic of increasing alcohol consumers in the United States, particularly among female individuals (Peltier et al., 2019, Breslow et al., 2017, Keyes, 2022b). As such, there are significant gaps of knowledge related to specific health impacts of alcohol misuse in subpopulations of people with AUD. Further studies must be done to target especially vulnerable populations, while continuing to investigate mechanisms underlying biological dysfunction in those with AUD.

Figure 1:

Figure 1:

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Alcohol mediated multi-organ immune dysfunction. Excessive alcohol induces neuroinflammation, neurodegeneration and cognitive dysfunction, which is worsened by microglia activation during aging. Pulmonary immunity is compromised by alcohol-induced alterations in bacterial metabolites, hyaluronic acid and inflammasome activation. Gut and liver immunity is diminished, resulting in systematic and localized inflammation and changes in microbial community structure, resulting in intestinal barrier dysfunction. Figure created using BioRender.com.

Acknowledgements

This work was supported in part by grants from: the National Institute on Alcohol Abuse and Alcoholism (F31AA029938) to KMC (ORCID ID: 0000-0002-9461-4032), (R01AA026086) to SMY (ORCID ID: 0000-0001-9309-0233), (R00AA025386, R00AA025386-05S) to RM (ORCID ID: 0000-0001-5341-7326), (R00-AA026336) to DRS (ORCID ID: 0000-0002-5356-1413). (R13AA020768) to EJK/MAC (ORCID ID: 0000-0002-1152-7145), and (R21AA026295) to EJK. Additional support was granted from: the National Institute of General Medical Sciences (T32GM008602) to Randy A. Hall and (R35 GM131831) to EJK (ORCID ID: 000-0002-9459-9928), and from the Department of Veterans Affairs: (I01 BX004335) to EJK, and a Research Career Scientist Award (IK6 BX005962) to TAW. Further, the National Institutes of Health (K12HD85036), University of California San Diego Altman Clinical and Translational Research Institute (ACTRI)/NIH grant (KL2TR001444), and Pinnacle Research Award in Liver Diseases Grant (PNC22-159963) from the American Association for the Study of Liver Diseases Foundation to PH, and (R01AG018859) to EJK. The contents of this report do not represent the views of the Department of Veterans Affairs or the US Government. Finally, we thank Shayaan Kabir for his contribution toward Figure 1.

References

  1. 2018. World Health Organization (WHO). Global Status Report on Alcohol and Health 2018.
  2. 2020. Centers for Disease Control and Prevention (CDC). Alcohol and Public Health: Alcohol-Related Disease Impact (ARDI). Annual Average for United States 2011–2015 Alcohol-Attributable Deaths Due to Excessive Alcohol Use, All Ages. [Online]. Available: https://nccd.cdc.gov/DPH_ARDI/Default/Default.aspx [Accessed]. [Google Scholar]
  3. ALFONSO-LOECHES S, PASCUAL-LUCAS M, BLANCO AM, SANCHEZ-VERA I & GUERRI C 2010. Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. J Neurosci, 30, 8285–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. ASQUITH M, PASALA S, ENGELMANN F, HABERTHUR K, MEYER C, PARK B, GRANT KA & MESSAOUDI I 2014. Chronic ethanol consumption modulates growth factor release, mucosal cytokine production, and microRNA expression in nonhuman primates. Alcohol Clin Exp Res, 38, 980–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. BAKER RC & JERRELLS TR 1993. Recent developments in alcoholism: immunological aspects. Recent Dev Alcohol, 11, 249–71. [PubMed] [Google Scholar]
  6. BALA S, PETRASEK J, MUNDKUR S, CATALANO D, LEVIN I, WARD J, ALAO H, KODYS K & SZABO G 2012. Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases. Hepatology, 56, 1946–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. BARTOLETTI M, GIANNELLA M, CARACENI P, DOMENICALI M, AMBRETTI S, TEDESCHI S, VERUCCHI G, BADIA L, LEWIS RE, BERNARDI M & VIALE P 2014. Epidemiology and outcomes of bloodstream infection in patients with cirrhosis. J Hepatol, 61, 51–8. [DOI] [PubMed] [Google Scholar]
  8. BAUGHMAN RP & ROSELLE GA 1987. Surfactant deficiency with decreased opsonic activity in a guinea pig model of alcoholism. Alcohol Clin Exp Res, 11, 261–4. [DOI] [PubMed] [Google Scholar]
  9. BISHEHSARI F, MAGNO E, SWANSON G, DESAI V, VOIGT RM, FORSYTH CB & KESHAVARZIAN A 2017. Alcohol and Gut-Derived Inflammation. Alcohol Res, 38, 163–171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. BOUCHERY EE, HARWOOD HJ, SACKS JJ, SIMON CJ & BREWER RD 2011. Economic costs of excessive alcohol consumption in the U.S., 2006. Am J Prev Med, 41, 516–24. [DOI] [PubMed] [Google Scholar]
  11. BRESLOW RA, CASTLE IP, CHEN CM & GRAUBARD BI 2017. Trends in Alcohol Consumption Among Older Americans: National Health Interview Surveys, 1997 to 2014. Alcohol Clin Exp Res, 41, 976–986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. BURNHAM EL, BROWN LA, HALLS L & MOSS M 2003. Effects of chronic alcohol abuse on alveolar epithelial barrier function and glutathione homeostasis. Alcohol Clin Exp Res, 27, 1167–72. [DOI] [PubMed] [Google Scholar]
  13. CHENG M, TAN B, WU X, LIAO F, WANG F & HUANG Z 2021. Gut Microbiota Is Involved in Alcohol-Induced Osteoporosis in Young and Old Rats Through Immune Regulation. Front Cell Infect Microbiol, 11, 636231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. CHOUDHURY A, BULLOCK D, LIM A, ARGEMI J, ORNING P, LIEN E, BATALLER R & MANDREKAR P 2020. Inhibition of HSP90 and Activation of HSF1 Diminish Macrophage NLRP3 Inflammasome Activity in Alcohol-Associated Liver Injury. Alcohol Clin Exp Res, 44, 1300–1311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. COLEMAN LG 2022. The emerging world of subcellular biological medicine: extracellular vesicles as novel biomarkers, targets, and therapeutics. Neural Regen Res, 17, 1020–1022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. COLEMAN LG JR., ZOU J & CREWS FT 2017. Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7. J Neuroinflammation, 14, 22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. CRENSHAW BJ, KUMAR S, BELL CR, JONES LB, WILLIAMS SD, SALDANHA SN, JOSHI S, SAHU R, SIMS B & MATTHEWS QL 2019. Alcohol Modulates the Biogenesis and Composition of Microglia-Derived Exosomes. Biology (Basel), 8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. CREWS FT, QIN L, SHEEDY D, VETRENO RP & ZOU J 2013. High mobility group box 1/Toll-like receptor danger signaling increases brain neuroimmune activation in alcohol dependence. Biol Psychiatry, 73, 602–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. CREWS FT, SARKAR DK, QIN L, ZOU J, BOYADJIEVA N & VETRENO RP 2015. Neuroimmune Function and the Consequences of Alcohol Exposure. Alcohol Res, 37, 331–41, 344–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. CREWS FT, ZOU J & COLEMAN LG JR. 2021. Extracellular microvesicles promote microglia-mediated pro-inflammatory responses to ethanol. J Neurosci Res, 99, 1940–1956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. DAY AW & KUMAMOTO CA 2022. Gut Microbiome Dysbiosis in Alcoholism: Consequences for Health and Recovery. Front Cell Infect Microbiol, 12, 840164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. DE LA MONTE SM & KRIL JJ 2014. Human alcohol-related neuropathology. Acta Neuropathol, 127, 71–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. DROUIN M, SAENZ J & CHIFFOLEAU E 2020. C-Type Lectin-Like Receptors: Head or Tail in Cell Death Immunity. Front Immunol, 11, 251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. DUNN W & SHAH VH 2016. Pathogenesis of Alcoholic Liver Disease. Clin Liver Dis, 20, 445–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. FRANCESCHI C, BONAFE M, VALENSIN S, OLIVIERI F, DE LUCA M, OTTAVIANI E & DE BENEDICTIS G 2000. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci, 908, 244–54. [DOI] [PubMed] [Google Scholar]
  26. FRANK MG, BARRIENTOS RM, WATKINS LR & MAIER SF 2010. Aging sensitizes rapidly isolated hippocampal microglia to LPS ex vivo. J Neuroimmunol, 226, 181–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. GAO R, MA Z, HU Y, CHEN J, SHETTY S & FU J 2015. Sirt1 restrains lung inflammasome activation in a murine model of sepsis. Am J Physiol Lung Cell Mol Physiol, 308, L847–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. GAO B, EMAMI A, ZHOU R, LANG S, DUAN Y, WANG Y, JIANG L, LOOMBA R, BRENNER DA, STÄRKEL P & SCHNABL B 2020. Functional Microbial Responses to Alcohol Abstinence in Patients With Alcohol Use Disorder. Frontiers in Physiology, 11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. GRASSME H, CARPINTEIRO A, EDWARDS MJ, GULBINS E & BECKER KA 2014. Regulation of the inflammasome by ceramide in cystic fibrosis lungs. Cell Physiol Biochem, 34, 45–55. [DOI] [PubMed] [Google Scholar]
  30. GRAY JI & FARBER DL 2022. Tissue-Resident Immune Cells in Humans. Annu Rev Immunol, 40, 195–220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. GREENBERG SS, ZHAO X, HUA L, WANG JF, NELSON S & OUYANG J 1999. Ethanol inhibits lung clearance of Pseudomonas aeruginosa by a neutrophil and nitric oxide-dependent mechanism, in vivo. Alcohol Clin Exp Res, 23, 735–44. [PubMed] [Google Scholar]
  32. GUPTA NM, DESHPANDE A & ROTHBERG MB 2020. Pneumonia and alcohol use disorder: Implications for treatment. Cleveland Clinic Journal of Medicine, 87, 493–500. [DOI] [PubMed] [Google Scholar]
  33. HALLGREN R, SAMUELSSON T, LAURENT TC & MODIG J 1989. Accumulation of hyaluronan (hyaluronic acid) in the lung in adult respiratory distress syndrome. Am Rev Respir Dis, 139, 682–7. [DOI] [PubMed] [Google Scholar]
  34. HARTMANN P, CHU H, DUAN Y & SCHNABL B 2019. Gut microbiota in liver disease: too much is harmful, nothing at all is not helpful either. Am J Physiol Gastrointest Liver Physiol, 316, G563–G573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. HARTMANN P, LANG S, ZENG S, DUAN Y, ZHANG X, WANG Y, BONDAREVA M, KRUGLOV A, FOUTS DE, STARKEL P & SCHNABL B 2021a. Dynamic Changes of the Fungal Microbiome in Alcohol Use Disorder. Front Physiol, 12, 699253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. HARTMANN P, LANG S, ZENG S, DUAN Y, ZHANG X, WANG Y, BONDAREVA M, KRUGLOV A, FOUTS DE, STÄRKEL P & SCHNABL B 2021b. Dynamic Changes of the Fungal Microbiome in Alcohol Use Disorder. Front Physiol, 12, 699253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. HENDRIKX T & SCHNABL B 2019. Indoles: metabolites produced by intestinal bacteria capable of controlling liver disease manifestation. Journal of Internal Medicine, 286, 32–40. [DOI] [PubMed] [Google Scholar]
  38. HENDRIKX T, DUAN Y, WANG Y, OH J-H, ALEXANDER LM, HUANG W, STÄRKEL P, HO SB, GAO B, FIEHN O, EMOND P, SOKOL H, VAN PIJKEREN J-P & SCHNABL B 2019. Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice. Gut, 68, 1504–1515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. HENRIQUES JF, PORTUGAL CC, CANEDO T, RELVAS JB, SUMMAVIELLE T & SOCODATO R 2018. Microglia and alcohol meet at the crossroads: Microglia as critical modulators of alcohol neurotoxicity. Toxicol Lett, 283, 21–31. [DOI] [PubMed] [Google Scholar]
  40. ISSELBACHER KJ & GREENBERGER NJ 1964. Metabolic Effects of Alcohol on the Liver. N Engl J Med, 270, 403–10 CONCL. [DOI] [PubMed] [Google Scholar]
  41. JONG GM, HSIUE TR, CHEN CR, CHANG HY & CHEN CW 1995. Rapidly fatal outcome of bacteremic Klebsiella pneumoniae pneumonia in alcoholics. Chest, 107, 214–7. [DOI] [PubMed] [Google Scholar]
  42. KANE CJ & DREW PD 2016. Inflammatory responses to alcohol in the CNS: nuclear receptors as potential therapeutics for alcohol-induced neuropathologies. J Leukoc Biol, 100, 951–959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. KEYES KM 2022a. Age, Period, and Cohort Effects in Alcohol Use in the United States in the 20th and 21st Centuries: Implications for the Coming Decades. Alcohol Res, 42, 02. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. KEYES KM 2022b. Alcohol use in older adult US population: trends, causes and consequences. Alcohol. [DOI] [PubMed] [Google Scholar]
  45. KIM A, BELLAR A, MCMULLEN MR, LI X. & NAGY LE 2020. Functionally Diverse Inflammatory Responses in Peripheral and Liver Monocytes in Alcohol-Associated Hepatitis. Hepatol Commun, 4, 1459–1476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. KUMAR V 2020. Pulmonary Innate Immune Response Determines the Outcome of Inflammation During Pneumonia and Sepsis-Associated Acute Lung Injury. Front Immunol, 11, 1722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. LANG S, DUAN Y, LIU J, TORRALBA MG, KUELBS C, VENTURA-COTS M, ABRALDES JG, BOSQUES-PADILLA F, VERNA EC, BROWN RS JR., VARGAS V, ALTAMIRANO J, CABALLERIA J, SHAWCROSS D, LUCEY MR, LOUVET A, MATHURIN P, GARCIA-TSAO G, HO SB, TU XM, BATALLER R, STARKEL P, FOUTS DE & SCHNABL B 2020a. Intestinal Fungal Dysbiosis and Systemic Immune Response to Fungi in Patients With Alcoholic Hepatitis. Hepatology, 71, 522–538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. LANG S, FAIRFIED B, GAO B, DUAN Y, ZHANG X, FOUTS DE & SCHNABL B 2020b. Changes in the fecal bacterial microbiota associated with disease severity in alcoholic hepatitis patients. Gut Microbes, 12, 1785251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. LEWIS SA, DORATT B, SURESHCHANDRA S, PAN T, GONZALES SW, SHEN W, GRANT KA & MESSAOUDI I 2022. Profiling of extracellular vesicle-bound miRNA to identify candidate biomarkers of chronic alcohol drinking in nonhuman primates. Alcohol Clin Exp Res, 46, 221–231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. LI F, MCCLAIN CJ & FENG W 2019. Microbiome dysbiosis and alcoholic liver disease (). Liver Res, 3, 218–226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. LIANG Y, YELIGAR SM & BROWN LA 2012. Chronic-alcohol-abuse-induced oxidative stress in the development of acute respiratory distress syndrome. ScientificWorldJournal, 2012, 740308. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. LIANG Y, HARRIS FL, JONES DP & BROWN LAS 2013. Alcohol induces mitochondrial redox imbalance in alveolar macrophages. Free Radic Biol Med, 65, 1427–1434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. LIANG Y, HARRIS FL & BROWN LA 2014. Alcohol induced mitochondrial oxidative stress and alveolar macrophage dysfunction. Biomed Res Int, 2014, 371593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. LIEBER CS 1966. Hepatic and metabolic effects of alcohol. Gastroenterology, 50, 119–33. [PubMed] [Google Scholar]
  55. LIEBER CS 1968. Fatty liver, cirrhosis, and metabolic effects related to problem drinking. Psychiatr Res Rep Am Psychiatr Assoc, 24, 119–31. [PubMed] [Google Scholar]
  56. LLOPIS M, CASSARD AM, WRZOSEK L, BOSCHAT L, BRUNEAU A, FERRERE G, PUCHOIS V, MARTIN JC, LEPAGE P, LE ROY T, LEFEVRE L, LANGELIER B, CAILLEUX F, GONZALEZ-CASTRO AM, RABOT S, GAUDIN F, AGOSTINI H, PREVOT S, BERREBI D, CIOCAN D, JOUSSE C, NAVEAU S, GERARD P & PERLEMUTER G 2016. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease. Gut, 65, 830–9. [DOI] [PubMed] [Google Scholar]
  57. LUCEY MR, HILL EM, YOUNG JP, DEMO-DANANBERG L & BERESFORD T 1999. The influences of age and gender on blood ethanol concentrations in healthy humans. Journal of Studies on Alcohol, 60, 103–110. [DOI] [PubMed] [Google Scholar]
  58. MACCIONI L, LECLERCQ IA, SCHNABL B & STARKEL P 2021. Host Factors in Dysregulation of the Gut Barrier Function during Alcohol-Associated Liver Disease. Int J Mol Sci, 22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. MANDREKAR P, CATALANO D, JELIAZKOVA V & KODYS K 2008. Alcohol exposure regulates heat shock transcription factor binding and heat shock proteins 70 and 90 in monocytes and macrophages: implication for TNF‐α regulation. Journal of leukocyte biology, 84, 1335–1345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. MEIER P & SEITZ HK 2008. Age, alcohol metabolism and liver disease. Current Opinion in Clinical Nutrition & Metabolic Care, 11, 21–26. [DOI] [PubMed] [Google Scholar]
  61. MONTESINOS J, ALFONSO-LOECHES S & GUERRI C 2016. Impact of the Innate Immune Response in the Actions of Ethanol on the Central Nervous System. Alcohol Clin Exp Res, 40, 2260–2270. [DOI] [PubMed] [Google Scholar]
  62. MORRIS NL & YELIGAR SM 2018. Role of HIF-1alpha in Alcohol-Mediated Multiple Organ Dysfunction. Biomolecules, 8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. MORRIS NL, HARRIS FL, BROWN LAS & YELIGAR SM 2021. Alcohol induces mitochondrial derangements in alveolar macrophages by upregulating NADPH oxidase 4. Alcohol, 90, 27–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. MOSS M, PARSONS PE, STEINBERG KP, HUDSON LD, GUIDOT DM, BURNHAM EL, EATON S & COTSONIS GA 2003. Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock. Crit Care Med, 31, 869–77. [DOI] [PubMed] [Google Scholar]
  65. MURALIDHARAN S, AMBADE A, FULHAM MA, DESHPANDE J, CATALANO D & MANDREKAR P 2014. Moderate alcohol induces stress proteins HSF1 and hsp70 and inhibits proinflammatory cytokines resulting in endotoxin tolerance. The Journal of Immunology, 193, 1975–1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. MUTLU EA, GILLEVET PM, RANGWALA H, SIKAROODI M, NAQVI A, ENGEN PA, KWASNY M, LAU CK & KESHAVARZIAN A 2012. Colonic microbiome is altered in alcoholism. Am J Physiol Gastrointest Liver Physiol, 302, G966–78. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. PARSONS BJ 2018. Free radical studies of components of the extracellular matrix: contributions to protection of biomolecules and biomaterials from sterilizing doses of ionizing radiation. Cell Tissue Bank, 19, 201–213. [DOI] [PubMed] [Google Scholar]
  68. PASCUAL M, BALINO P, ALFONSO-LOECHES S, ARAGON CM & GUERRI C 2011. Impact of TLR4 on behavioral and cognitive dysfunctions associated with alcohol-induced neuroinflammatory damage. Brain Behav Immun, 25 Suppl 1, S80–91. [DOI] [PubMed] [Google Scholar]
  69. PELAEZ A, BECHARA RI, JOSHI PC, BROWN LA & GUIDOT DM 2004. Granulocyte/macrophage colony-stimulating factor treatment improves alveolar epithelial barrier function in alcoholic rat lung. Am J Physiol Lung Cell Mol Physiol, 286, L106–11. [DOI] [PubMed] [Google Scholar]
  70. PELTIER MR, VERPLAETSE TL, MINEUR YS, PETRAKIS IL, COSGROVE KP, PICCIOTTO MR & MCKEE SA 2019. Sex differences in stress-related alcohol use. Neurobiol Stress, 10, 100149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. PEREZ JC 2021. Fungi of the human gut microbiota: Roles and significance. Int J Med Microbiol, 311, 151490. [DOI] [PubMed] [Google Scholar]
  72. PIANTADOSI CA & SULIMAN HB 2017. Mitochondrial Dysfunction in Lung Pathogenesis. Annu Rev Physiol, 79, 495–515. [DOI] [PubMed] [Google Scholar]
  73. PRICE ME, GERALD CL, PAVLIK JA, SCHLICHTE SL, ZIMMERMAN MC, DEVASURE JM, WYATT TA & SISSON JH 2019. Loss of cAMP-dependent stimulation of isolated cilia motility by alcohol exposure is oxidant-dependent. Alcohol, 80, 91–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. RATNA A, LIM A, LI Z, ARGEMI J, BATALLER R, CHIOSIS G & MANDREKAR P 2021. Myeloid Endoplasmic Reticulum Resident Chaperone GP96 Facilitates Inflammation and Steatosis in Alcohol-Associated Liver Disease. Hepatol Commun, 5, 1165–1182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. RAY K 2020. Manipulating the gut microbiota to combat alcoholic hepatitis. Nature Reviews Gastroenterology & Hepatology, 17, 3–3. [DOI] [PubMed] [Google Scholar]
  76. REES MD, KENNETT EC, WHITELOCK JM & DAVIES MJ 2008. Oxidative damage to extracellular matrix and its role in human pathologies. Free Radic Biol Med, 44, 1973–2001. [DOI] [PubMed] [Google Scholar]
  77. RHOADES NS, DAVIES M, LEWIS SA, CINCO IR, KOHAMA SG, BERMUDEZ LE, WINTHROP KL, FUSS C, MATTISON JA, SPINDEL ER & MESSAOUDI I 2022. Functional, transcriptional, and microbial shifts associated with healthy pulmonary aging in rhesus macaques. Cell Rep, 39, 110725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. ROAGER HM & LICHT TR 2018. Microbial tryptophan catabolites in health and disease. Nat Commun, 9, 3294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. SAITZ R, GHALI WA & MOSKOWITZ MA 1997. The impact of alcohol-related diagnoses on pneumonia outcomes. Arch Intern Med, 157, 1446–52. [PubMed] [Google Scholar]
  80. SAMUELSON DR, GU M, SHELLITO JE, MOLINA PE, TAYLOR CM, LUO M & WELSH DA 2021. Pulmonary immune cell trafficking promotes host defense against alcohol associated Klebsiella pneumonia. Communications Biology, 4, 997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. SHAH NJ, ROYER A & JOHN S 2022. Alcoholic Hepatitis. StatPearls. Treasure Island (FL). [PubMed] [Google Scholar]
  82. SOMMER F, ANDERSON JM, BHARTI R, RAES J & ROSENSTIEL P 2017. The resilience of the intestinal microbiota influences health and disease. Nat Rev Microbiol, 15, 630–638. [DOI] [PubMed] [Google Scholar]
  83. STARKEL P & SCHNABL B 2016. Bidirectional Communication between Liver and Gut during Alcoholic Liver Disease. Semin Liver Dis, 36, 331–339. [DOI] [PubMed] [Google Scholar]
  84. STARKEL P, LECLERCQ S, DE TIMARY P & SCHNABL B 2018. Intestinal dysbiosis and permeability: the yin and yang in alcohol dependence and alcoholic liver disease. Clin Sci (Lond), 132, 199–212. [DOI] [PubMed] [Google Scholar]
  85. SUEBLINVONG V, KERCHBERGER VE, SAGHAFI R, MILLS ST, FAN X & GUIDOT DM 2014. Chronic alcohol ingestion primes the lung for bleomycin-induced fibrosis in mice. Alcohol Clin Exp Res, 38, 336–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. TEVIK K, SELBAEK G, ENGEDAL K, SEIM A, KROKSTAD S & HELVIK AS 2019. Mortality in older adults with frequent alcohol consumption and use of drugs with addiction potential - The Nord Trondelag Health Study 2006–2008 (HUNT3), Norway, a population-based study. PLoS One, 14, e0214813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. TRIPATHI A, DEBELIUS J, BRENNER DA, KARIN M, LOOMBA R, SCHNABL B & KNIGHT R 2018. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol, 15, 397–411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. WAGNER MC, YELIGAR SM, BROWN LA & MICHAEL HART C 2012. PPAR gamma ligands regulate NADPH oxidase, eNOS, and barrier function in the lung following chronic alcohol ingestion. Alcohol Clin Exp Res, 36, 197–206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. WYATT TA, GENTRY-NIELSEN MJ, PAVLIK JA & SISSON JH 2004. Desensitization of PKA-stimulated ciliary beat frequency in an ethanol-fed rat model of cigarette smoke exposure. Alcohol Clin Exp Res, 28, 998–1004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. YAN AW, FOUTS DE, BRANDL J, STARKEL P, TORRALBA M, SCHOTT E, TSUKAMOTO H, NELSON KE, BRENNER DA & SCHNABL B 2011. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology, 53, 96–105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. YELIGAR SM, CHEN MM, KOVACS EJ, SISSON JH, BURNHAM EL & BROWN LA 2016a. Alcohol and lung injury and immunity. Alcohol, 55, 51–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. YELIGAR SM, MEHTA AJ, HARRIS FL, BROWN LA & HART CM 2016b. Peroxisome Proliferator-Activated Receptor gamma Regulates Chronic Alcohol-Induced Alveolar Macrophage Dysfunction. Am J Respir Cell Mol Biol, 55, 35–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. YELIGAR SM, MEHTA AJ, HARRIS FL, BROWN LAS & HART CM 2021. Pioglitazone Reverses Alcohol-Induced Alveolar Macrophage Phagocytic Dysfunction. J Immunol. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. ZELANTE T, IANNITTI RG, CUNHA C, DE LUCA A, GIOVANNINI G, PIERACCINI G, ZECCHI R, D’ANGELO C, MASSI-BENEDETTI C, FALLARINO F, CARVALHO A, PUCCETTI P & ROMANI L 2013. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity, 39, 372–85. [DOI] [PubMed] [Google Scholar]
  95. ZHOU H, YU M, ZHAO J, MARTIN BN, ROYCHOWDHURY S, MCMULLEN MR, WANG E, FOX PL, YAMASAKI S, NAGY LE & LI X. 2016. IRAKM-Mincle axis links cell death to inflammation: Pathophysiological implications for chronic alcoholic liver disease. Hepatology, 64, 1978–1993. [DOI] [PMC free article] [PubMed] [Google Scholar]

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