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

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.

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Effects of Chronic Alcohol Exposure on Kainate Receptor-Mediated Neurotransmission in the Hippocampus

10.21236/ada412906 ◽

2002 ◽

Author(s):

C. F. Valenzuela ◽

Daniel D. Savage ◽

Jeff. L. Weiner

Keyword(s):

Alcohol Exposure ◽

Kainate Receptor ◽

Chronic Alcohol ◽

Chronic Alcohol Exposure

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Effects of Chronic Alcohol Exposure on Kainate Receptor-Mediated Neurotransmission in the Hippocampus

10.21236/ada434072 ◽

2004 ◽

Author(s):

C. F. Valenzuela

Keyword(s):

Alcohol Exposure ◽

Kainate Receptor ◽

Chronic Alcohol ◽

Chronic Alcohol Exposure

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CB1R Promotes Chronic Alcohol-Induced Neuronal Necroptosis in Mice Prefrontal Cortex

Alcohol and Alcoholism ◽

10.1093/alcalc/agaa135 ◽

2020 ◽

Author(s):

Lin Ye ◽

Shuhao Li ◽

Xiaochen Liu ◽

Dingang Zhang ◽

Liliang Li ◽

...

Keyword(s):

Prefrontal Cortex ◽

Protein Level ◽

Cannabinoid Receptors ◽

Alcohol Exposure ◽

Global Burden ◽

Dependent Manner ◽

Chronic Alcohol ◽

Inverse Agonists ◽

Alcohol Vapor ◽

Chronic Alcohol Exposure

Abstract Aims Alcohol abuse induces multiple neuropathology and causes global burden to human health. Prefrontal cortex (PFC) is one of the most susceptible regions to alcohol-induced neuropathology. However, precise mechanisms underlying these effects on PFC remain to be elucidated. Herein, we investigated whether RIP1/RIP3/MLKL-mediated necroptosis was involved in the alcohol-induced PFC injury, and explored the effect that cannabinoid receptors (CBRs) exerted on the neurotoxicity of alcohol. Methods In this study, dynamic development of neuronal necroptosis in the PFC region was monitored after 95% (v/v) alcohol vapor administration for 15 and 30 days, respectively. Selective CBRs agonists or inverse agonists were pretreated according to the experimental design. All the PFC tissues were isolated and further examined by biochemical and histopathological analyses. Results It was found that chronic alcohol exposure increased the protein level of MLKL and also the phosphorylated levels of RIP1, RIP3 and MLKL in a time-dependent manner, all of which indicated the activation of necroptosis signaling. Particularly, compared to astrocytes, neurons from the PFC showed more prototypical necrotic morphology in response to alcohol insults. In parallel, an increased protein level of CB1R was also found after 15 and 30 days alcohol exposure. Administration of specific inverse agonists of CB1R (AM251 and AM281), but not its agonists or CB2R modulators, significantly alleviated the RIP1/RIP3/MLKL-mediated neuronal necroptosis. Conclusion We reported the involvement of RIP1/RIP3/MLKL-mediated necroptosis in alcohol-induced PFC neurotoxicity, and identified CB1R as a critical regulator of neuronal necroptosis that enhanced our understanding of alcohol-induced neuropathology in the PFC.

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Chronic alcohol exposure inhibits biotin uptake by pancreatic acinar cells: possible involvement of epigenetic mechanisms

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00278.2014 ◽

2014 ◽

Vol 307 (9) ◽

pp. G941-G949 ◽

Cited By ~ 8

Author(s):

Padmanabhan Srinivasan ◽

Rubina Kapadia ◽

Arundhati Biswas ◽

Hamid M. Said

Keyword(s):

Transgenic Mice ◽

Chronic Exposure ◽

Methylation Status ◽

Acinar Cells ◽

Alcohol Exposure ◽

Significant Inhibition ◽

Pancreatic Acinar Cells ◽

Chronic Alcohol ◽

Wild Type ◽

Chronic Alcohol Exposure

Chronic exposure to alcohol affects different physiological aspects of pancreatic acinar cells (PAC), but its effect on the uptake process of biotin is not known. We addressed this issue using mouse-derived pancreatic acinar 266-6 cells chronically exposed to alcohol and wild-type and transgenic mice (carrying the human SLC5A6 5′-promoter) fed alcohol chronically. First we established that biotin uptake by PAC is Na+ dependent and carrier mediated and involves sodium-dependent multivitamin transporter (SMVT). Chronic exposure of 266-6 cells to alcohol led to a significant inhibition in biotin uptake, expression of SMVT protein, and mRNA as well as in the activity of the SLC5A6 promoter. Similarly, chronic alcohol feeding of wild-type and transgenic mice carrying the SLC5A6 promoter led to a significant inhibition in biotin uptake by PAC, as well as in the expression of SMVT protein and mRNA and the activity of the SLC5A6 promoters expressed in the transgenic mice. We also found that chronic alcohol feeding of mice is associated with a significant increase in the methylation status of CpG islands predicted to be in the mouse Slc5a6 promoters and a decrease in the level of expression of transcription factor KLF-4, which plays an important role in regulating SLC5A6 promoter activity. These results demonstrate, for the first time, that chronic alcohol exposure negatively impacts biotin uptake in PAC and that this effect is exerted (at least in part) at the level of transcription of the SLC5A6 gene and may involve epigenetic/molecular mechanisms.

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