scholarly journals Essential Role of IFN-γ in Regulating Gut Antimicrobial Peptides and Microbiota to Protect Against Alcohol-Induced Bacterial Translocation and Hepatic Inflammation in Mice

2021 ◽  
Vol 11 ◽  
Author(s):  
Ruichao Yue ◽  
Xiaoyuan Wei ◽  
Jiangchao Zhao ◽  
Zhanxiang Zhou ◽  
Wei Zhong
Keyword(s):  
Gut Microbiota ◽  
Antimicrobial Peptides ◽  
Bacterial Translocation ◽  
Treatment Time ◽  
Alcohol Exposure ◽  
Feeding Time ◽  
Chronic Alcohol ◽  
Hepatic Inflammation ◽  
Stat Signaling ◽  
Ifn Γ

The mechanisms by which alcohol provokes bacterial translocation in the development of alcoholic liver disease (ALD) remain incompletely defined. Our previous study demonstrates that impaired gut epithelial antimicrobial defense is critically involved in the pathogenesis of ALD. The study was set to determine the mechanisms of how alcohol inhibits the antimicrobial ability of intestinal epithelial cells (IECs) and to explore possible solutions to this issue. C57BL/6J mice were fed either alcohol or isocaloric dextrin liquid diet for 8 weeks, and intestinal IFN-γ-signal transducer and activator of transcription (STAT) signaling was analyzed. We found that chronic alcohol exposure led to a significant reduction in intestinal IFN-γ levels compared to a control; the protein levels of phosphorylated STAT1 (p-STAT1) and p-STAT3 were both declined by alcohol. We then tested the effects of IFN-γ-STAT signaling on regulating antimicrobial peptides (AMPs), gut microbiota, and disease progression of ALD in a mouse model of chronic alcohol feeding, time-course acute IFN-γ treatment, and in vivo and in vitro IEC-specific STAT1 or STAT3 knockout mouse models, respectively. Administration of IFN-γ activated intestinal STAT1 and STAT3, upregulated the expression of Reg3 and α-defensins, orchestrated gut microbiota, and reversed alcohol-induced intestinal ZO-1 disruption and systemic endotoxin elevation as well as hepatic inflammation. Meanwhile, acute IFN-γ treatment time-dependently induced AMP expression and α-defensin activation. We then dissected the roles of STAT1 and STAT3 in this progress. Lack of IEC-specific STAT3 inhibited IFN-γ-induced expression of Reg3 and α-defensins and hindered activation of α-defensins via inactivating matrix metallopeptidase 7 (MMP7), whereas lack of IEC-specific STAT1 impaired IFN-γ-stimulated expression of α-defensins and the IEC marker, sodium-hydrogen exchanger 3. Lastly, we found that interleukin (IL)-18, a known IFN-γ inducer, was also reduced by alcohol in mice. IL-18 treatment to alcohol-fed mice normalized gut IFN-γ levels and ameliorated organ damages in both the intestine and liver. Taken together, the study reveals that IFN-γ is critically involved in the regulation of AMPs through regulation of STAT1 and STAT3; impaired IFN-γ-STAT signaling provides an explanation for alcohol-induced gut antimicrobial dysfunction and microbial dysbiosis. Therefore, IFN-γ remains a promising host defense-enhancing cytokine with unexplored clinical potential in ALD therapy.

Chronic alcohol exposure induced gut microbiota dysbiosis and its correlations with neuropsychic behaviors and brain BDNF/Gabra1 changes in mice

BioFactors ◽  
2018 ◽  
Vol 45 (2) ◽  
pp. 187-199 ◽  
Author(s):  
Zheng Xu ◽  
Can Wang ◽  
Xiaoguang Dong ◽  
Tao Hu ◽  
Lingling Wang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Alcohol Exposure ◽  
Chronic Alcohol ◽  
Chronic Alcohol Exposure ◽  
Gut Microbiota Dysbiosis

scholarly journals Effect of chronic alcohol exposure on gut vitamin B7 uptake: Involvement of epigenetic mechanisms and effect of alcohol metabolites

2021 ◽  
Author(s):  
Kalidas Ramamoorthy ◽  
Subrata Sabui ◽  
Padmanabhan Srinivasan ◽  
Saleh Al-Juburi ◽  
Quang Pham ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Ethyl Oleate ◽  
Alcohol Exposure ◽  
Chronic Alcoholism ◽  
Inhibitory Effect ◽  
Epigenetic Mechanisms ◽  
Epigenetic Alterations ◽  
Chronic Alcohol ◽  
Ethyl Palmitate ◽  
Chronic Alcohol Exposure

Vitamin B7 (biotin) is essential from normal health and its deficiency/sub-optimal levels occur in a variety of conditions including chronic alcoholism. Mammals, including humans, obtain biotin from diet and gut-microbiota via absorption along the intestinal tract. The absorption process is carrier-mediated and involves the sodium-dependent multivitamin transporter (SMVT; SLC5A6). We have previously shown that chronic alcohol exposure significantly inhibits intestinal/colonic biotin uptake via suppression of Slc5a6 transcription in animal and cell line models.. However, little is known about the transcriptional/epigenetic factors that mediate this suppression. Additionally, the effect of alcohol metabolites (generated via alcohol metabolism by gut microbiota and host tissues) on biotin uptake is still unknown. In order to address these questions, we first demonstrated that chronic alcohol exposure inhibits small intestinal and colonic biotin uptake and SMVT expression in human differentiated enteroid and colonoid monolayers. We then showed that chronic alcohol exposures of both, Caco-2 cells and mice, are associated with a significant suppression in expression of the nuclear factor KLF-4 (needed for Slc5a6 promoter activity), as well as with epigenetic alterations (histone modifications). We also found that chronic exposure of NCM460 human colonic epithelial cells as well as human differentiated colonoid monolayers, to alcohol metabolites (acetaldehyde, ethyl palmitate, ethyl oleate) significantly inhibited biotin uptake and SMVT expression. These findings shed light onto the molecular/epigenetic mechanisms that mediate the inhibitory effect of chronic alcohol exposure on intestinal biotin uptake. They further show that alcohol metabolites are also capable of inhibiting biotin uptake in the gut.

scholarly journals Alcohol dependence promotes systemic IFN-γ and IL-17 responses in mice

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0239246
Author(s):  
Kayla Frank ◽  
Shawn Abeynaike ◽  
Rana Nikzad ◽  
Reesha R. Patel ◽  
Amanda J. Roberts ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Dependence ◽  
Inflammatory Responses ◽  
Alcohol Exposure ◽  
Cell Types ◽  
Ethanol Vapor ◽  
Chronic Alcohol ◽  
Multiparametric Flow Cytometry ◽  
Chronic Alcohol Exposure ◽  
Ifn Γ

Alcohol use disorder (AUD) is a chronic relapsing disorder characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences. AUD is associated with a variety of physiological changes and is a substantial risk factor for numerous diseases. We aimed to characterize systemic alterations in immune responses using a well-established mouse model of chronic intermittent alcohol exposure to induce alcohol dependence. We exposed mice to chronic intermittent ethanol vapor for 4 weeks and analyzed the expression of cytokines IFN-γ, IL-4, IL-10, IL-12 and IL-17 by different immune cells in the blood, spleen and liver of alcohol dependent and non-dependent control mice through multiparametric flow cytometry. We found increases in IFN-γ and IL-17 expression in a cell type- and organ-specific manner. Often, B cells and neutrophils were primary contributors to increased IFN-γ and IL-17 levels while other cell types played a secondary role. We conclude that chronic alcohol exposure promotes systemic pro-inflammatory IFN-γ and IL-17 responses in mice. These responses are likely important in the development of alcohol-related diseases, but further characterization is necessary to understand the initiation and effects of systemic inflammatory responses to chronic alcohol exposure.

scholarly journals Alcohol dependence promotes systemic IFN-γ and IL-17 responses in mice

2020 ◽  
Author(s):  
Kayla Frank ◽  
Shawn Abeynaike ◽  
Rana Nikzad ◽  
Reesha R. Patel ◽  
Amanda J. Roberts ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Dependence ◽  
Inflammatory Responses ◽  
Alcohol Exposure ◽  
Cell Types ◽  
Ethanol Vapor ◽  
Chronic Alcohol ◽  
Multiparametric Flow Cytometry ◽  
Chronic Alcohol Exposure ◽  
Ifn Γ

AbstractAlcohol use disorder (AUD) is a chronic relapsing disorder characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences. AUD is associated with a variety of physiological changes and is a substantial risk factor for numerous diseases. We aimed to characterize systemic alterations in immune responses using a mouse model of chronic intermittent alcohol exposure to induce alcohol dependence. We exposed mice to chronic intermittent ethanol vapor for 4 weeks and used multiparametric flow cytometry to analyze the expression of cytokines IFN-γ, IL-4, IL-10, IL-12 and IL-17 by different immune cells in the blood, spleen and liver of alcohol dependent and non-dependent control mice. We found increases in IFN-γ and IL-17 expression in a cell type- and organ-specific manner. Often, B cells and neutrophils are primary contributors to increased IFN-γ and IL-17 levels while other cell types play a secondary role. We conclude that chronic alcohol exposure promotes systemic pro-inflammatory IFN-γ and IL-17 responses in mice. These responses are likely important in the development of alcohol-related diseases, but further characterization is necessary to understand the initiation and effects of systemic inflammatory responses to chronic alcohol exposure.

scholarly journals Obesity-Induced Dysbiosis Exacerbates IFN-γ Production and Pulmonary Inflammation in the Mycobacterium tuberculosis Infection

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1732
Author(s):  
Sandra Patricia Palma Albornoz ◽  
Thais Fernanda de Campos Fraga-Silva ◽  
Ana Flávia Gembre ◽  
Rômulo Silva de Oliveira ◽  
Fernanda Mesquita de Souza ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Gut Microbiota ◽  
Inflammatory Diseases ◽  
Pulmonary Inflammation ◽  
Host Susceptibility ◽  
Chronic Infections ◽  
Mycobacterium Tuberculosis Infection ◽  
Pulmonary Damage ◽  
Ifn Γ

The microbiota of the gut–lung axis affects local and far-reaching immune responses and might also trigger chronic and inflammatory diseases. We hypothesized that gut dysbiosis induced by obesity, which coexists in countries with a high tuberculosis burden, aggravates the host susceptibility and the pulmonary damage tolerance. To assess our hypothesis, we used a model of high-fat diet (HFD)-induced obesity, followed by infection of C57BL/6 mice with Mycobacterium tuberculosis. We showed that obesity increased the susceptibility, the pulmonary inflammation and IFN-γ levels in M. tuberculosis-infected mice. During the comorbidity obesity and tuberculosis, there is an increase of Bacteroidetes and Firmicutes in the lungs, and an increase of Firmicutes and butyrate in the feces. Depletion of gut microbiota by antibiotic treatment in the obese infected mice reduced the frequencies of CD4+IFN-γ+IL-17− cells and IFN-γ levels in the lungs, associated with an increase of Lactobacillus. Our findings reinforce the role of the gut–lung axis in chronic infections and suggest that the gut microbiota modulation may be a potential host-directed therapy as an adjuvant to treat TB in the context of IFN-γ-mediated immunopathology.

Sign in / Sign up

Export Citation Format

Share Document