What is endogenous production of alcohol and how does it affect the human body?

Endogenous Production of Alcohol

Endogenous alcohol production refers to the fermentation of dietary carbohydrates into ethanol by microorganisms residing in the gastrointestinal tract, a process that occurs at low levels in nearly all individuals but can become pathological when excessive, leading to measurable blood alcohol levels and systemic toxicity without external alcohol consumption. 1, 2

Mechanisms of Endogenous Ethanol Production

Normal Physiological Production

• The gut microbiome produces ethanol as a metabolic byproduct in nearly all individuals through fermentation of dietary carbohydrates 2
• More than half of the variance in the plasma metabolome can be explained by gut microbiome activity, with ethanol being a major microbial metabolite 2
• Under normal circumstances, the liver's capacity to metabolize this endogenously produced ethanol prevents accumulation to pathological levels 2

Pathological Overproduction

When gut homeostasis is disrupted, certain microorganisms can proliferate and produce excessive amounts of ethanol that surpass the liver's metabolic capacity. 2

The primary causative organisms include:

Fungal species:

• Saccharomyces cerevisiae (most commonly reported) 1, 3
• Candida species (C. albicans, C. glabrata, C. kefyr, C. parapsilosis, C. intermedia) 1, 4, 3
• Pichia species 3

Bacterial species:

• Klebsiella pneumoniae (most common bacterial cause) 1, 3
• Escherichia coli 3
• Species from Lachnospiraceae and Clostridiaceae families 3
• Lactobacillales order members 3
• Bifidobacterium genus 3

Predisposing Factors

• Prolonged antibiotic exposure is the most consistently reported risk factor, as antibiotics alter gut microbiome composition and allow fungal overgrowth 1, 5
• Short bowel syndrome creates conditions favorable for microbial fermentation 4
• Disruption of normal gut barrier function 6

Effects on the Human Body

Metabolic and Hepatic Effects

Endogenous ethanol production contributes to liver disease through the same metabolic pathways as exogenous alcohol consumption. 7

Hepatic Steatosis Development

Ethanol metabolism leads to four primary pathogenic mechanisms:

1. Increased NADH production from alcohol oxidation, favoring fatty acid and triglyceride synthesis while inhibiting mitochondrial β-oxidation 7, 8

2. Enhanced hepatic influx of free fatty acids from adipose tissue and chylomicrons from intestinal mucosa 7, 8

3. AMPK pathway suppression by ethanol, resulting in increased lipogenesis through SREBP1c activation and decreased lipolysis through PPARα suppression 7, 8

4. Acetaldehyde-induced organelle damage to mitochondria and microtubules, causing decreased NADH oxidation and VLDL accumulation 7, 8

Inflammatory Liver Injury

Ethanol is metabolized to acetaldehyde through three enzymatic pathways: alcohol dehydrogenase (ADH) in the cytosol, cytochrome P450 (particularly CYP2E1) in microsomes, and catalase in peroxisomes. 7

The toxic effects of acetaldehyde include:

• Direct hepatocyte injury through binding to proteins and DNA, altering their function and creating autoantigens that activate immune responses 7, 8
• Oxidative stress generation through mitochondrial damage and impaired glutathione function, leading to apoptosis 7, 8
• Lipid peroxidation with DNA adduct formation 7
• Decreased mitochondrial glutathione and S-adenosyl-L-methionine (SAMe) levels, sensitizing hepatocytes to injury 7, 8

Pro-inflammatory Cascade

Alcohol metabolites and reactive oxygen species (ROS) stimulate multiple inflammatory signaling pathways including NF-κB, STAT-JAK, and JNK, inducing production of TNF-α, IL-17, CXC chemokines, and osteopontin. 7

Gut-Liver Axis Disruption

A critical mechanism linking endogenous alcohol to systemic disease involves increased intestinal permeability. 6

• Alcohol abuse disrupts normal intestinal microbiota and increases gut barrier permeability 7, 6
• Bacterial endotoxins (lipopolysaccharides) enter circulation at elevated levels 7, 6
• These endotoxins trigger inflammatory reactions in Kupffer cells via the CD14/toll-like receptor 4 (TLR4) pathway 7, 6
• Gut barrier dysfunction represents an early event in the pathogenesis of alcohol-related liver disease 6

Fibrosis and Cirrhosis Progression

Chronic exposure to endogenous ethanol can lead to progressive liver fibrosis through hepatic stellate cell (HSC) activation. 7, 8

Mechanisms include:

• Direct HSC activation by acetaldehyde, the main collagen-producing cells in injured liver 7
• Paracrine activation through damaged hepatocytes, activated Kupffer cells, and infiltrating polymorphonuclear leukocytes 7
• Release of fibrogenic mediators including TGF-β1, PDGF, leptin, angiotensin II, IL-8, TNF-α, and ROS 7
• ROS-mediated stimulation of pro-fibrogenic intracellular signaling pathways (ERK, PI3K/Akt, JNK) in HSCs 7
• Up-regulation of TIMP-1 and decreased metalloproteinase activity, promoting collagen accumulation 7

Clinical Manifestations: Auto-Brewery Syndrome

When endogenous ethanol production becomes excessive, patients develop auto-brewery syndrome (also called gut fermentation syndrome), presenting with signs of alcohol intoxication despite denying alcohol consumption. 1, 5

Clinical features include:

• Measurable blood ethanol concentrations (documented cases show levels of 15 mmol/L or higher) 4
• Symptoms of alcohol intoxication following carbohydrate-rich meals 1, 5, 4
• Severe impact on patients' wellbeing with potential social and legal consequences 1
• Association with metabolic dysfunction-associated steatotic liver disease (formerly NAFLD) 2

Carcinogenic Effects

While the provided evidence focuses on exogenous alcohol consumption, the carcinogenic mechanisms apply equally to endogenous ethanol production. 7

• Both ethanol and acetaldehyde are classified as carcinogenic to humans by IARC 7
• Carcinogenic effects involve DNA and protein damage, oxidative stress, inhibition of DNA repair, increased cell proliferation, nutritional malabsorption, and changes in DNA methylation 7
• There is no safe level of ethanol exposure for cancer prevention 7

Clinical Implications and Management Considerations

Diagnosis

Auto-brewery syndrome should be considered in any patient presenting with manifestations of alcohol toxicity who denies alcohol ingestion. 5

Diagnostic approach includes:

• Standardized carbohydrate challenge test with blood ethanol measurement 5
• Upper and lower endoscopy to obtain intestinal secretions for fungal and bacterial culture 5
• Speciation of organisms and antimicrobial sensitivity testing 5

Treatment Strategies

Current evidence-based treatments for pathological endogenous ethanol production include:

1. Antimicrobial therapy: Antifungal medications (for fungal overgrowth) or antibiotics (for bacterial overgrowth) based on culture results 1, 5

2. Dietary modification: Carbohydrate-free or low-carbohydrate diet during initial treatment phase (typically 6 weeks) 1, 5, 4

3. Probiotics: Both single-strain and multi-strain bacterial probiotics for competitive inhibition of pathogenic organism growth 1, 5

   • Probiotics have shown benefits in improving gut barrier function, reducing endotoxemia, and reducing TLR4 activation 6

4. Emerging therapies: Fecal microbiota transplantation may have a potential role, though evidence is limited 1

Important Caveats

• The condition is rare but likely underdiagnosed in clinical practice 1, 5
• Most reported cases had prior antibiotic exposure, highlighting the importance of antibiotic stewardship 1, 5
• Carbohydrate rechallenge should be performed before reintroducing carbohydrates into the diet to confirm resolution 5
• In short bowel syndrome patients, endogenous ethanol fermentation should be added to the differential diagnosis list alongside D-lactic acidosis 4