Review article: inhibition of methanogenic archaea by statins as a targeted management strategy for constipation and related disorders

Abstract

SummaryBackgroundObservational studies show a strong association between delayed intestinal transit and the production of methane. Experimental data suggest a direct inhibitory activity of methane on the colonic and ileal smooth muscle and a possible role for methane as a gasotransmitter. Archaea are the only confirmed biological sources of methane in nature and Methanobrevibacter smithii is the predominant methanogen in the human intestine.AimTo review the biosynthesis and composition of archaeal cell membranes, archaeal methanogenesis and the mechanism of action of statins in this context.MethodsNarrative review of the literature.ResultsStatins can inhibit archaeal cell membrane biosynthesis without affecting bacterial numbers as demonstrated in livestock and humans. This opens the possibility of a therapeutic intervention that targets a specific aetiological factor of constipation while protecting the intestinal microbiome. While it is generally believed that statins inhibit methane production via their effect on cell membrane biosynthesis, mediated by inhibition of the HMG‐CoA reductase, there is accumulating evidence for an alternative or additional mechanism of action where statins inhibit methanogenesis directly. It appears that this other mechanism may predominate when the lactone form of statins, particularly lovastatin lactone, is administered.ConclusionsClinical development appears promising. A phase 2 clinical trial is currently in progress that evaluates the effect of lovastatin lactone on methanogenesis and symptoms in patients with irritable bowel syndrome with constipation. The review concludes with an outlook for the future and subsequent work that needs to be done.

Crystal structure of archaeal HMG‐CoA reductase: insights into structural changes of the C‐terminal helix of the class‐I enzyme

“…The growth rate decreased by 50% in 10-20 nM simvastatin lactone. This concentration was within the range of app K i of simvastatin lactone for the purified enzyme activity measurements in this work but was much lower than the lovastatin (a statin) concentration (4-10 lM) required for 50% inhibition of the methanogenic archaea that inhabit rumen (i.e., Methanobrevibacter) [32,33].…”

Targeting the gut microbiota for the treatment of irritable bowel syndrome

“…By the way, methanogenic bacteria may also be targeted using SYN‐010, a modified release statin . One study demonstrated that 4 weeks of SYN‐010 in IBS patients to reduce methane levels from baseline as well as to improve abdominal pain and stool frequency …”

“…64 One study demonstrated that 4 weeks of SYN-010 in IBS patients to reduce methane levels from baseline as well as to improve abdominal pain and stool frequency. 62 The treatment of IBS symptoms may benefit from certain antibiotics, however, antibiotics may even contribute toward the initial onset of IBS symptoms. There is an association between prior macrolide (P = .036) and tetracycline (P < .025) use within 12 months of a new diagnosis of IBS.…”

Editorial

“…El otro aspecto interesante es la presencia de una línea plana en las pruebas de aliento, explicada también en los ejemplos que se presentan. Esta línea plana puede ser debida a la presencia de bacterias que consumen hidrógeno y, como resultado, las archaeas son incapaces de producir metano, cuyo principal substrato es el hidrógeno 21 . El artículo revisa además la utilidad de las pruebas de aliento en aplicaciones menos conocidas como el vaciamiento gástrico y la DF.…”