Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway

Abstract

Discuss this article AbstractMethane produced by the methanoarchaeon ( Methanobrevibacter smithii M. ) has been linked to constipation, irritable bowel syndrome with smithii constipation (IBS-C), and obesity. Lovastatin, which demonstrates a cholesterol-lowering effect by the inhibition of HMG-CoA reductase, may also have an anti-methanogenesis effect through direct inhibition of enzymes in the archaeal methanogenesis pathway. We conducted protein-ligand docking experiments to evaluate this possibility. Results are consistent with recent clinical findings. METHODS: F420-dependent methylenetetrahydromethanopterin dehydrogenase ( ), a key methanogenesis enzyme with a known sequence mtd but no tertiary protein structural information, was modeled for two different methanogenic archaea: and . Once protein M. smithii Methanopyrus kandleri models were developed, ligand-binding sites were identified. Multiple ligands and their respective protonation, isomeric and tautomeric representations were docked into each site, including F420-coenzyme (natural ligand), lactone and β-hydroxyacid forms of lovastatin and simvastatin, and other co-complexed ligands found in related crystal structures. RESULTS: 1) Generally, for each modeled site the lactone form of the statins had more favorable site interactions compared to F420; 2) The statin lactone forms generally had the most favorable docking scores, even relative to the native template PDB ligands; and 3) The statin β-hydroxyacid forms had less favorable docking scores, typically scoring in the middle with some of the F420 tautomeric forms. Consistent with these computational results were those from a recent phase II clinical trial ( ) with a proprietary, NCT02495623 modified-release lovastatin-lactone (SYN-010) in patients with IBS-C, which showed a reduction in symptoms and breath methane levels, compared to placebo.

Small Intestinal Bacterial Overgrowth in Children: A State-Of-The-Art Review

“…Finally, there is some evidence to suggest that certain statins may have a role in depleting Methanobrevibacter spp., thereby offering a novel therapy for methane-specific SIBO (149, 150). In line with this, a modified-release formulation of lovastatin, termed SYN-010, has been created to deliver the drug in a biphasic manner during transit, thereby avoiding considerable degradation and absorption in the upper gastrointestinal tract (151).…”

Targeting the gut microbiota for the treatment of irritable bowel syndrome

“…63 By the way, methanogenic bacteria may also be targeted using SYN-010, a modified release statin. 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.…”

Gut Microbiota-Based Therapies for Irritable Bowel Syndrome

“…Several IBS therapeutics have been developed that target the gut microbiota or the secondary consequences of alterations in the gut microbiota ( Table 1 ). 14 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 One of the most well-studied treatments for IBS is the non-absorbable antibiotic rifaximin. Rifaximin is currently available in 47 countries; it has been available in Italy since 1987 and in the United States since 2004.…”

“…SYN-010 is a nonabsorbable derivative of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin lactone; this modified-release statin formulation is thought to decrease methane production by blocking cell membrane biosynthesis of M. smithii , a predominant methane producer in the GI tract. 53 , 66 , 76 In a phase 2 study, 62 patients with IBS-C and elevated breath methane levels were treated with 4 weeks of SYN-010 21 mg, SYN-010 42 mg, or placebo once daily. 76 After 1 week, only the higher dose of SYN-010 significantly reduced methane levels from baseline ( P =0.047; primary endpoint).…”