Finally, both acute and chronic exposure of the small intestine to alcohol can impair the absorption of monosaccharides, several L-amino acid residues and lipids (fatty acids, monoglycerides) as well as some vitamins even in absence of advanced liver disease or pancreatic insufficiency58. The functional interference of ethanol with the physiological absorption of nutrients can contribute to qualitative and quantitative malnutrition frequently observed in alcoholics. Several studies have suggested that the decreased formation of hormone-like substances called prostaglandins might play a role in alcohol-induced mucosal injury (Bode et al. 1996).
- Prolonged intestinal retention also raises concern for synergistic toxicity with substances that share metabolic pathways.
- This phenomenon is likely due to the abundance of Prevotella that promotes propionic acid production as a result of trigger from the PLA MPs 1.
- However, more work is needed to examine possible impacts of intestinal mycobiome changes in these regards.
- There are also other sources of ethanol, such as hygiene products, including daily oral mouthwash use.
- In alcoholics this damage commonly manifests itself as an enlargement (i.e., hypertrophy) of the parotid gland, although the mechanisms leading to this condition are unknown.
Alcohol’s Impact on the Gut and Liver
However, there are interesting differences in the mycobiome of alcoholics compared to non-alcoholic individuals (Figure 2). Each study has noted an increase in the abundance of Candida species, and two have reported an increase in the genus Pichia (Figure 2). Saccharomyces, Penicillium, Epicoccum have all been reported to decrease in the alcoholic GI tract (Yang et al., 2017; Chu et al., 2020; Hartmann et al., 2021; Lang et al., 2020a). Conflicting reports have been obtained for Debaryomyces (Yang et al., 2017; Hartmann et al., 2021; Lang et al., 2020a). These reports raise the possibility that alcoholics could be at greater risk of infection from pathobionts such as Candida spp.
The Gut-Brain Axis in Alcoholism
- It is likely that alcohol directly causes villus contraction with consequent villus tip bleb formation, lymphatic obstruction and exfoliation of the tips of the villi62.
- The area under the salivary ACH curve for one cigarette is thus 58 mg/L/5 min and therefore the cumulative amount for three to five cigarettes ranges from 173 to 288 mg/L/15 min or 25 min/day.
- However, the subsequent conversion of ACH to less harmful substances seems to be very limited due to the lack of active aldehyde dehydrogenase (ALDH) enzymes in both microbial and oropharyngeal mucosal cells.
- This cumulative mitochondrial dysfunction precipitates ATP depletion, exacerbates endoplasmic reticulum (ER) stress, and heightens cellular susceptibility to pro-apoptotic signals.
Key components of the non-immunologic intestinal barrier include an unstirred water layer, mucosal surface hydrophobicity, surface mucous coat, endothelial factors 59, and alcohols role in gastrointestinal tract disorders pmc epithelial factors (most importantly tight junctions). Thus, alcohol can cause gut leakiness by impacting any of these components of intestinal barrier function. Indeed, alcohol affects MUC-2 protein expression 66, which is one of the key components of intestinal mucus layer 67. Other potential means for alcohol to cause gut leakiness is to increase trans-epithelial passage of molecules.
Ethanol Metabolism and Redox Imbalance
Acetaldehyde directly inhibits transcriptional activation activity and DNA binding of PPAR-α 43. Alcohol also indirectly inhibits PPAR-α via CYP2E1-derived oxidative stress, adenosine, the downregulation of adiponectin and zinc deficiency (a common state in patients with alcohol-related liver disease) 30,44. It is the generation of acetaldehyde, a highly reactive protein, which contributes to liver damage.
PET MPs reduce α-diversity indices, such as Observed species and Shannon index, indicating a decline in microbial diversity 29. PS MPs, particularly in meconium microbiota, were negatively related to the Chao1 index 25. This trend of decrease in α-diversity has been previously observed in animal models following exposure to MPs 52, 53. Numerous studies have shown the harmful effects of MPs exposure in tissue cultures and animal models.
Precision Medicine Approaches Targeting the Intestinal Microbiome
Faecalibacterium prausnitzii is not the only bacterium hypothesized to have a protective role in the alcoholic GI tract. In protecting intestinal barrier integrity in the alcoholic GI tract and maintaining functional glycan metabolism (Seo et al., 2020). Flagellin from Roseburia increased the intestinal barrier integrity in an alcoholic mouse model.
Ethanol metabolism by CYP2E1 in enterocytes generates significant quantities of reactive oxygen species (ROS), including superoxide and hydrogen peroxide. These ROS are produced in proximity to mitochondrial membranes, where they compromise membrane potential, disrupt ATP synthesis, and trigger mitochondrial permeability transition (MPT) 43. Such disruptions promote cytochrome c release and caspase activation, initiating apoptosis in the gut epithelium 44. These effects are exacerbated by ethanol-induced mitochondrial fragmentation and oxidative phosphorylation impairment.
In parallel, host mitochondrial pathways shape the microbial niche through mechanisms involving NAD+ availability, reactive oxygen species, and antimicrobial peptide production. Ethanol-driven inhibition of NAD+ biosynthesis disrupts sirtuin activity and impairs mitochondrial protein acetylation homeostasis, leading to redox collapse and altered innate immune surveillance. Emerging studies suggest that NAD+ restoration strategies may indirectly remodel microbiota by altering host-derived metabolic signals and epithelial redox status 80. Emerging data support the role of dietary polyphenols, such as resveratrol, quercetin, and curcumin, in modulating intestinal immunity. These compounds activate Nrf2 signaling, inhibit NF-κB, and enhance tight junction integrity, offering a multifaceted approach to redox and immune restoration. Polyphenol metabolites generated by gut bacteria may exert localized effects at the epithelial interface.
Links to NCBI Databases
Inflammasome activation is driven by both mitochondrial ROS and cytosolic NAD+ depletion, linking redox imbalance to immune dysfunction 73. These responses are interconnected with intestinal cell death pathways, autophagy impairment, and metabolic reprogramming. Although the term “intestinal drinking” remains conceptual, it reflects a reproducible physiological pattern with implications for alcohol pharmacokinetics and toxicity.
Alcohol-induced damage to the mucosal lining of the esophagus also increases the risk of esophageal cancer. In the stomach, alcohol interferes with gastric acid secretion and with the activity of the muscles surrounding the stomach. Similarly, alcohol may impair the muscle movement in the small and large intestines, contributing to the diarrhea frequently observed in alcoholics. Moreover, alcohol inhibits the absorption of nutrients in the small intestine and increases the transport of toxins across the intestinal walls, effects that may contribute to the development of alcohol-related damage to the liver and other organs. One of the advantages of the breath tests, namely their non-invasive character, is simultaneously one of the weaknesses of these tests. The pathways through which the test meal is metabolized, within the liver and the colon, is not completely understood.
Hepatocyte cell death occurs through several mechanisms including apoptosis, pyroptosis, necrosis and necroptosis 48. Apoptosis is induced by direct alcohol-mediated hepatotoxicity, the induction of oxidative stress, the inhibition of survival genes (C-met) and the induction of pro-apoptotic signalling molecules (TNF-α and Fas ligand) 49. Necrosis, cell swelling and membrane rupture can also occur via a programmed pathway known as necroptosis, while pyroptosis is a programmed cell death dependent on caspase-1. The mode of cell death is likely to be influenced by the disease state, with apoptosis predominating in early alcohol-related liver disease but inflammasome activation driving pyroptosis and propagating liver injury in alcoholic hepatitis 50. The alcohol dehydrogenase pathway is efficient in metabolising alcohol in small quantities, but in chronic alcohol exposure, the pathway becomes saturated and there is significant induction of CYP2E1 32. ROS bind to proteins, changing their structural and functional properties, and may act as neoantigens.