Lactulose MoA

Q: What are the 3 mechanisms by which lactulose improves hepatic encephalopathy?

Answer: 

Although lactulose use is usually synonymous with a simple cathartic intervention to 'flush out' colonic bacteria, its mechanism of action (MoA) is relatively more complex:

1. The conversion of Lactulose to lactic acid results in acidification of the gut lumen. This favors the conversion of NH4+ + to NH3 and the passage of NH3 from tissues into the lumen.

2. Gut acidification inhibits ammoniagenic coliform bacteria, leading to increased levels of nonammoniagenic lactobacilli.

3. Lactulose also works as a cathartic, reducing colonic bacterial load.

Also, in contrast to conventional belief, lactulose does not significantly alter colonic water content; rather, its effect is due to stimulation of motility (reference # 2)

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References:

1. Bloom PP, Tapper EB. Lactulose in cirrhosis: Current understanding of efficacy, mechanism, and practical considerations. Hepatol Commun. 2023 Oct 12;7(11):e0295. doi: 10.1097/HC9.0000000000000295. PMID: 37820287; PMCID: PMC10578757.

2. Gunn D, Yeldho C, Hoad C, Menys A, Gowland P, Marciani L, Spiller R. Mechanisms underlying the laxative effect of lactulose: A randomized placebo-controlled trial showing increased small bowel water and motility unaltered by the 5-HT3 receptor antagonist, ondansetron. Neurogastroenterol Motil. 2024 Apr;36(4):e14754. doi: 10.1111/nmo.14754. Epub 2024 Feb 5. PMID: 38316636.