Alcohol Feeding in Mice Promotes Colonic Hyperpermeability and Changes in Colonic Organoid Stem Cell Fate

Forsyth, Christopher B.; Shaikh, Maliha; Bishehsari, Faraz; Swanson, Garth; Voigt, Robin M.; Dodiya, Hemraj B.; Wilkinson, Peter; Samelco, Beata; Song, Shuqun; Keshavarzian, Ali

doi:10.1111/acer.13519

Cited by 31 publications

(34 citation statements)

References 55 publications

(84 reference statements)

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“…There is growing evidence indicating that alcohol abuse alters intestinal permeability to toxic substances, although the direct mechanisms are not completely understood. A recent study showed that mice fed an alcohol‐containing diet exhibited decreased apical junctional proteins leading to colonic hyper‐permeability (Forsyth et al ., ). Inflammation may exacerbate barrier dysfunction in a synergistic manner.…”

Section: Discussionmentioning

confidence: 97%

Alcohol binge disrupts the rat intestinal barrier: the partial protective role of oleoylethanolamide

Antón

Rodríguez-González

Ballesta

et al. 2018

British J Pharmacology

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The authors contributed equally to this work. BACKGROUND AND PURPOSEChronic alcohol consumption alters the gut-brain axis, but little is known about alcohol binge episodes on the functioning of the intestinal barrier. We investigated the influence of ethanol binges on bacterial translocation, gut inflammation and immunity, and tight junction (TJ) structure and the ability of the biolipid oleoylethanolamide (OEA) to prevent ethanol binge-induced intestinal barrier dysfunction. EXPERIMENTAL APPROACHOEA was injected i.p. before repeated ethanol administration by oral gavage. Plasma, spleen, liver and mesenteric lymph nodes (MLN) were collected in sterile conditions for determination of bacterial load. Immune/inflammatory parameters, TJ proteins and apoptotic markers were determined in colonic tissue by RT-PCR and Western blotting. TJ ultrastructure was examined by transmission electron microscopy. KEY RESULTSEthanol binges induced bacterial translocation to the MLN (mainly) and spleen. Colonic tissues showed signs of inflammation, and activation of innate (Toll-like receptor-4) and adaptive (IgA) immune systems and TJ proteins (occludin and claudin-3) were decreased after ethanol binges. Pretreatment with OEA reduced intestinal inflammation and immune activation and partially preserved the TJ structure affected by alcohol binges but had no effect on alcohol-induced apoptosis. Ultrastructural analyses of colonic TJs revealed dilated TJs in all ethanol groups, with less electron-dense material in non-pretreated rats. The protective effects of i.p. OEA did not reduce bacterial translocation to the MLN. However, intragastric OEA administration significantly reduced plasma LPS levels and bacterial translocation to the MLN. CONCLUSION AND IMPLICATIONSOEA-based pharmacotherapies could potentially be useful to treat disorders characterized by intestinal barrier dysfunction, including alcohol abuse.

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Section: Discussionmentioning

confidence: 97%

Alcohol binge disrupts the rat intestinal barrier: the partial protective role of oleoylethanolamide

Antón

Rodríguez-González

Ballesta

et al. 2018

British J Pharmacology

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“…Loss of Wnt signaling in these cells results in loss of secretory lineage epithelial cells and loss of epithelial and crypt structure . Disruption of the Wnt/Notch signaling balance in the ISC results in abnormal changes in stem cell fate ratios and loss of intestinal barrier function (leaky gut) . Targeted loss of Lgr5 results in loss of crypt ISCs and loss of intestinal epithelial renewal .…”

Section: Wnt Signaling In Aging Intestinementioning

confidence: 99%

“…104 Disruption of the Wnt/Notch signaling balance in the ISC results in abnormal changes in stem cell fate ratios and loss of intestinal barrier function (leaky gut). 105,106 Targeted loss of Lgr5 results in loss of crypt ISCs and loss of intestinal epithelial renewal. 98 Inhibiting Wnt signaling in adult mice with an inducible Wnt antagonist, DKK1, blocks proliferation within crypts and results in crypt loss.…”

Section: Wnt Signaling In Aging Intestinementioning

confidence: 99%

Wnt signaling in bone, kidney, intestine, and adipose tissue and interorgan interaction in aging

Chen

Xie

Shu

et al. 2018

Annals of the New York Academy of Sciences

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Over the last two decades, it has become increasingly apparent that Wnt signaling plays a critical role in development and adult tissue homeostasis in multiple organs and in the pathogenesis of many diseases. In particular, a crucial role for Wnt signaling in bone development and bone tissue homeostasis has been well recognized. Numerous genome-wide association studies confirmed the importance of Wnt signaling in controlling bone mass. Moreover, ample evidence suggests that Wnt signaling is essential for kidney, intestine, and adipose tissue development and homeostasis. Recent emerging evidence demonstrates that Wnt signaling may play a fundamental role in the aging process of those organs. New discoveries show that bone is not only the major reservoir for calcium and phosphate storage, but also the largest organ with multiple functions, including mineral and energy metabolism. The interactions among bone, kidney, intestine, and adipose tissue are controlled and regulated by several endocrine signals, including FGF23, klotho, sclerostin, osteocalcin, vitamin D, and leptin. Since the aging process is characterized by structural and functional decline in almost all tissues and organs, understanding the Wnt signaling-related interactions among bone, kidney, intestine, and adipose tissue in aging may shed light on the pathogenesis of age-related diseases.

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“…On the other hand, mice on Lieber-DeCarli (LD) which is an isocaloric liquid diet, go through a similar ramping phase from 0% to 3.395% EtOH (w/v) 21 . To explore chronic alcohol effects, duration of exposure to LD diet is also variable between 25 days to 8 weeks, with an average around one month [22][23][24][25][26][27][28][29] . This model was created to "enhance" the mice ALD phenotype to be similar to the human ALD patient phenotype and to avoid confounding effects of differences in caloric content of oral intake of alcohol consumption.…”

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confidence: 99%

Restricted immunological and cellular pathways are shared by murine models of chronic alcohol consumption

Vogle

Qian

Zhu

et al. 2020

Sci Rep

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Murine models of chronic alcohol consumption are frequently used to investigate alcoholic liver injury and define new therapeutic targets. Lieber-DeCarli diet (LD) and Meadows-Cook diet (MC) are the most accepted models of chronic alcohol consumption. It is unclear how similar these models are at the cellular, immunologic, and transcriptome levels. We investigated the common and specific pathways of LD and MC models. Livers from LD and MC mice were subjected to histologic changes, hepatic leukocyte population, hepatic transcripts level related to leukocyte recruitment, and hepatic RNA-seq analysis. Cross-species comparison was performed using the alcoholic liver disease (ALD) transcriptomic public dataset. Despite LD mice have increased liver injury and steatosis by alcohol exposure, the number of CD45 + cells were reduced. Opposite, MC mice have an increased number of monocytes/liver by alcohol. The pattern of chemokine gradient, adhesion molecules, and cytokine transcripts is highly specific for each model, not shared with advanced human alcoholic liver disease. Moreover, hepatic RNA-seq revealed a limited and restricted number of shared genes differentially changed by alcohol exposure in these 2 models. Thus, mechanisms involved in alcohol tissue injury are model-dependent at multiple levels and raise the consideration of significant pathophysiological diversity of human alcoholic liver injury. Murine models are frequently used to investigate new pathophysiological pathways of human diseases and many new treatment trials for alcoholic liver disease (ALD) are based on preclinical testing provided by murine models. ALD in humans is the result of a complex interaction between the alcoholic effects on gut microbiota, intestinal cells, immune system, and the hepatic microenvironment 1,2. Based on an extensive body of literature, alcohol increases the intestinal permeability and subsequent systemic translocation of bacterial products, e.g. LPS 1,3,4. Stimulation of Toll-like receptors (TLR) by bacterial products results in immune cell activation related to hepatic alcohol metabolic process that has a deleterious effect on the liver, resulting in histological features of ALD: steatosis, innate immune infiltrate with predominance of neutrophils and monocytes, and histological signs of hepatocyte dysfunction (Mallory hyaline formation, ballooning hepatocyte) 3,5-7. ALD includes a spectrum of histological and clinical entities: steatosis, steatohepatitis, and alcoholic hepatitis 8,9. In time, chronic liver injury with a dysregulated innate immune response results in alcohol-induced progressive hepatic fibrogenesis, liver cirrhosis and end-stage liver disease 10. Based on this classical paradigm, few trials have been attempted to control an exacerbated innate immune response or to improve hepatocyte function. Besides steroids that may be beneficial for only subsets of patients with alcoholic hepatitis 11 , no other treatments have proven consistent survival benefit 12. Moreover, treatment of anti-TNFα in alcoholic hepati...

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Alcohol Feeding in Mice Promotes Colonic Hyperpermeability and Changes in Colonic Organoid Stem Cell Fate

Cited by 31 publications

References 55 publications

Alcohol binge disrupts the rat intestinal barrier: the partial protective role of oleoylethanolamide

Alcohol binge disrupts the rat intestinal barrier: the partial protective role of oleoylethanolamide

Wnt signaling in bone, kidney, intestine, and adipose tissue and interorgan interaction in aging

Restricted immunological and cellular pathways are shared by murine models of chronic alcohol consumption

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