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Metronidazole increases intracolonic but not peripheral blood acetaldehyde in chronic ethanol-treated rats
J Tillonen1, S Väkeväinen, V Salaspuro
1Research Unit of Alcohol Diseases, Helsinki University Central Hospital, Finland.
Background:
Metronidazole leads to the overgrowth of aerobic flora in the large intestine by reducing the number of anaerobes. According to our previous studies, this shift may increase intracolonic bacterial acetaldehyde formation if ethanol is present. Metronidazole is also reported to cause disulfiram-like effects after alcohol intake, although the mechanism behind this is obscure. Therefore, the aim was to study the effect of long-term metronidazole and alcohol treatment on intracolonic acetaldehyde levels and to explore the possible role of intestinal bacteria in the metronidazole related disulfiram-like reaction.
Methods:
A total of 32 rats were divided into four groups: controls (n = 6), controls receiving metronidazole (n = 6), ethanol group (n = 10), and ethanol and metronidazole group (n = 10). All rats were pair-fed with the liquid diet for 6-weeks, whereafter blood and intracolonic acetaldehyde levels and liver and colonic mucosal alcohol (ADH) and aldehyde dehydrogenase (ALDH) activities were analyzed.
Results:
The rats receiving ethanol and metronidazole had five times higher intracolonic acetaldehyde levels than the rats receiving only ethanol (431.4 +/- 163.5 microM vs. 84.7 +/- 14.4 microM,p = 0.0035). In contrast, blood acetaldehyde levels were equal. Cecal cultures showed the increased growth of Enterobacteriaceae in the metronidazole groups. Metronidazole had no inhibitory effect on hepatic or colonic mucosal ADH and ALDH activities.
Conclusions:
The increase in intracolonic acetaldehyde after metronidazole treatment is probably due to the replacement of intestinal anaerobes by ADH-containing aerobes. Unlike disulfiram, metronidazole neither inhibits liver ALDH nor increases blood acetaldehyde. Thus, our findings suggested that the mechanism behind metronidazole related disulfiram-like reaction might be located in the gut flora instead of the liver.
Insights
Metronidazole and alcohol increase gut acetaldehyde by altering gut bacteria, not by affecting liver enzymes. This suggests the gut microbiome plays a key role in the disulfiram-like reaction.
Area of Science:
- Microbiology
- Pharmacology
- Gastroenterology
Background:
- Metronidazole alters gut flora, potentially increasing acetaldehyde production with alcohol.
- The mechanism of metronidazole's disulfiram-like effect after alcohol intake is unclear.
Purpose of the Study:
- To investigate the impact of long-term metronidazole and alcohol on intracolonic acetaldehyde.
- To explore the role of intestinal bacteria in metronidazole-induced disulfiram-like reactions.
Main Methods:
- Rats were divided into control, metronidazole, ethanol, and combined ethanol/metronidazole groups.
- Animals received a liquid diet for 6 weeks; blood and intracolonic acetaldehyde levels were measured.
- Liver and colonic mucosal alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activities were analyzed.
Main Results:
- Combined ethanol/metronidazole treatment led to a five-fold increase in intracolonic acetaldehyde compared to ethanol alone.
- Metronidazole groups showed increased Enterobacteriaceae growth in cecal cultures.
- No significant inhibition of hepatic or colonic ADH/ALDH activities by metronidazole was observed.
Conclusions:
- Increased intracolonic acetaldehyde is likely due to aerobic bacteria replacing anaerobes.
- Metronidazole does not inhibit liver ALDH or elevate blood acetaldehyde, unlike disulfiram.
- The gut flora, not the liver, may be the primary site for metronidazole's disulfiram-like reaction mechanism.
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