By Jordan Haworth, Clinical GI Physiologist
Methane production in the gut is associated with functional bowel disease such as constipation and bloating, as well as obesity and reduced weight loss following bariatric surgery.(1-3) Detecting methane in breath is a safe and non-invasive means of identifying those with excessive methane production. However, treating patients with excessive methane is typically not as straight forward.
In the gut, methane is produced almost exclusively by archaea, namely Methanobrevibacter smithii. These microorganisms are similar in size to bacteria although their cell wall structure is different. The bacterial cell wall is made of peptidoglycan, or murein, which has beta 1-4 glycosidic bonds, whereas the archaea have a cell wall made of pseudomurein, which has beta 1-3 glycosidic bonds. This means archaea are not susceptible to many antibiotics that target peptidoglycan synthesis, such as penicillin derivatives or cephalosporins.(4)
Rifaximin is a minimally absorbed antibiotic that acts locally in the gut. It is effective in treating small intestinal bacterial overgrowth (SIBO) and irritable bowel syndrome (IBS) without constipation, but has a poor efficacy in patients with constipation-predominant IBS (IBS-C).(5) Methane production is associated with IBS-C and one study found that neomycin improves constipation in this group.(6) However, when rifaximin and neomycin were combined, there was a far superior response in methane-positive IBS-C patients compared to neomycin alone; a greater reduction in constipation, straining and bloating scores at 4 weeks following therapy.(7) Subjects with eradication of breath methane to <3ppm after treatment reported greater improvement in symptom scores than those whose methane remained present. A combination of neomycin (500 mg twice daily) and rifaximin (550 mg three times daily) was used.
Figure 1: Constipation severity (A) and bloating severity (B) by week in neomycin vs rifaximin/neomycin groups.(7)
Whilst antibiotics may wipe out bacterial gut microbiota, statins could potentially be a more specific therapeutic option. Statins are some of the most commonly prescribed medications used to lower cholesterol, and the biosynthesis of cholesterol in humans is the same enzyme used for the biosynthesis of the cell membrane in archaea.(8) Previous studies have shown that statins, specifically HMG-CoA reductase inhibitors such as lovastatin, inhibit methanogenic archaea growth without affecting bacterial numbers.(9)
Lovastatin is a secondary fungal metabolite that can be found in oyster mushrooms and red yeast rice. It mostly converted to hydroxyacid in the stomach and absorbed, which effectively lowers cholesterol but is ineffective at inhibiting methane production. Alternatively, in the intestinal tract it is converted to the prodrug lactone form of lovastatin, which is highly effective at inhibiting methanogen growth. Thus, a modified form of lovastatin has been developed to release in the duodenum and the ileocecal region – the two most common sites of M smithii in the GI tract.(10) Currently an ongoing trial of this product, SYN-010, is underway in IBS-C patients with anticipation of results published by 2020.
Over the counter medications such as laxatives can alleviate constipation but do not directly treat methane. One herbal supplement called Atrantil was shown to be around 80% effective in reducing symptoms of bloating, constipation and abdominal discomfort in patients with IBS-C.(11) However, the open label study did not measure methane levels before or after treatment. Atrantil contains a natural mixture of peppermint, quebracho and conker tree extract with no side-effects reported during the study.
There are many commercially available probiotics, but there is also a lack of published evidence for their benefits. In fact, recent studies have suggested that probiotics do not benefit everyone and can have negative consequences, such as brain fog, gas and bloating, especially in patients with SIBO.(12) Another recent study found that probiotic users had significantly more methane-positive lactulose breath tests (but not hydrogen-positive) and produced more methane overall.(13) However, there is one probiotic strain, Lactobacillus reuteri, which has been shown to reduce symptoms of chronic constipation and reduce levels of methane in breath.(14) They gave subjects one probiotic capsule (Reuflor) 30 minutes after eating twice per day for 4 weeks.
Several medications and supplements may cause constipation, including iron. Our latest research here at the Functional Gut Clinic has suggested that iron is utilised by methanogenic archaea in the gut.(15) This leads to a greater production of methane on lactulose breath test, and the degree of methane production is associated with greater severity of constipation in IBS-C.(16) When prescribing or taking iron, it may be useful to perform a lactulose breath test to identify methane as a potential cause of iron-induced constipation.
Dietary changes are often favourable in patients with positive hydrogen and methane breath tests. Typically, increasing fibre intake is recommended in the presence of constipation. However, a review found that increasing dietary fibre consumption does not improve IBS symptoms.(17)
A low FODMAP diet may alleviate symptoms in patients with IBS-C.(18) FODMAPs (Fermentable Oligo-, Di-, Mono-saccharides and Polyols) are short-chain carbohydrates found mostly in plant-based foods like fruits, vegetables, grains and nuts. These are fermented by bacteria in the gut to produce hydrogen gas, which is then used to form methane by methanogens. Reducing the level of bacterial fermentation through a low FODMAP diet may, in theory, reduce the availability of hydrogen that can be converted into methane by methanogenic archaea. Although, studies have shown that a low FODMAP diet did not change the number of methanogens nor reduce breath methane levels.(19,20)
Kiwifruits are low FODMAP and consuming just two kiwis per day for 4 weeks was shown to increase the number of weekly defecations in IBS-C subjects.(21) In addition, kiwifruits are not associated with colonic fermentation on hydrogen and methane breath testing.(22)
Faecal microbiota transplantation (FMT) is a novel treatment which targets the gut microbiome. FMT appears to be efficacious and safe for the treatment of recurrent Clostridium difficile infection (CDI). Although, one female with chronic CDI received FMT from a healthy donor and whilst the CDI was cured, she developed severe bloating and constipation. A follow up breath test found that the healthy donor had methane but was asymptomatic.(23) Many studies have shown the benefits of FMT in patients with chronic constipation,(24,25) although no study to date has looked at reducing methane or the number of methanogens with FMT.
Despite several different ways to approach treatment of excessive methane production, a follow up breath test is necessary to predict the response to treatment. It appears that the most favourable responses are seen when there is an eradication of methane <10ppm on hydrogen and methane breath testing.
- Kunkel D, Basseri RJ, Makhani MD, Chong K, Chang C, Pimentel M. Methane on breath testing is associated with constipation: a systematic review and meta-analysis. Digestive Diseases and Sciences. 2011; 56: 1612-1618.
- Basseri RJ, Basseri B, Pimentel M, Chong K, Youdim A, Low K, Hwang L, Soffer E, Chang C, Mathur R. Intestinal methane production in obese individuals is associated with a higher body mass index. Gastroenterology & Hepatology. 2012; 8: 22-28.
- Mathur R, Mundi MS, Chua KS, Lorentz PA, Barlow GM, Lin E, Burch M, Youdim A, Pimentel M. Intestinal methane production is associated with decreased weight loss following bariatric surgery. Obesity Research & Clinical Practice. 2016; 10: 728-733.
- Khelaifia S, Drancourt M. Susceptibility of archaea to antimicrobial agents: applications to clinical microbiology. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2012; 18: 841-848.
- Pimentel M, Lembo A, Chey WD, Zakko S, Ringel Y, Yu J, Mareya SM, Shaw AL, Bortey E, Forbes WP. Rifaximin Therapy for Patients with Irritable Bowel Syndrome without Constipation. New England Journal of Medicine. 2011; 364: 22-32.
- Pimentel M, Chatterjee S, Chow EJ, Park S, Kong Y. Neomycin improves constipation-predominant irritable bowel syndrome in a fashion that is dependent on the presence of methane gas: subanalysis of a double-blind randomized controlled study. Digestive Diseases and Sciences. 2006; 51: 1297-1301.
- Pimentel M, Chang C, Chua KS, Mirocha J, DiBaise J, Rao S, Amichai M. Antibiotic Treatment of Constipation-Predominant Irritable Bowel Syndrome. Digestive Diseases and Sciences. 2014; 59: 1278-1285.
- Jain S, Caforio A, Driessen AJ. Biosynthesis of archaeal membrane ether lipids. Frontiers in Microbiology. 2014; 5: 641.
- Marsh E. Lovastatin Lactone Inhibits Methane Production in Human Stool Homogenates. 2016.
- Hubert S, Chadwick A, Wacher V, Coughlin O, Kokai-Kun J, Bristol A. Development of a Modified-Release Formulation of Lovastatin Targeted to Intestinal Methanogens Implicated in Irritable Bowel Syndrome With Constipation. Journal of Pharmaceutical Sciences. 2018; 107: 662-671.
- Brown K, Scott-Hoy B, Jennings LW. Response of irritable bowel syndrome with constipation patients administered a combined quebracho/conker tree/M. balsamea Willd extract. World J Gastrointest Pharmacol Ther. 2016; 7: 463-468.
- Rao SSC, Rehman A, Yu S, Andino NMd. Brain fogginess, gas and bloating: a link between SIBO, probiotics and metabolic acidosis. Clin Transl Gastroenterol. 2018; 9: 162-162.
- Mitten E, Goldin A, Hanifi J, Chan WW. Recent Probiotic Use Is Independently Associated With Methane-Positive Breath Test for Small Intestinal Bacterial Overgrowth: 1151. American Journal of Gastroenterology. 2018;113:S660.
- Ojetti V, Petruzziello C, Migneco A, Gnarra M, Gasbarrini A, Franceschi F. Effect of Lactobacillus reuteri (DSM 17938) on methane production in patients affected by functional constipation: a retrospective study. European review for medical and pharmacological sciences. 2017;21:1702-1708.
- Smith S, Haworth J, Treadway S, Hobson A. Su1635 – Oral Iron Supplementation, Microbiome Related Methanogenesis and Constipation – a Novel Model to Explain and Age Old Problem. Gastroenterology. 2019;156:S-592.
- Chatterjee S, Park S, Low K, Kong Y, Pimentel M. The degree of breath methane production in IBS correlates with the severity of constipation. The American journal of gastroenterology. 2007;102:837-841.
- Ford AC, Talley NJ, Spiegel BMR, Foxx-Orenstein AE, Schiller L, Quigley EMM, Moayyedi P. Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis. BMJ. 2008;337:a2313.
- Halmos EP, Power VA, Shepherd SJ, Gibson PR, Muir JG. A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology. 2014;146:67-75.e65.
- Sloan TJ, Jalanka J, Major GAD, Krishnasamy S, Pritchard S, Abdelrazig S, Korpela K, Singh G, Mulvenna C, Hoad CL, et al. A low FODMAP diet is associated with changes in the microbiota and reduction in breath hydrogen but not colonic volume in healthy subjects. PLoS One. 2018;13:e0201410-e0201410.
- Ong DK, Mitchell SB, Barrett JS, Shepherd SJ, Irving PM, Biesiekierski JR, Smith S, Gibson PR, Muir JG. Manipulation of dietary short chain carbohydrates alters the pattern of gas production and genesis of symptoms in irritable bowel syndrome. Journal of Gastroenterology and Hepatology. 2010;25:1366-1373.
- Chang CC, Lin YT, Lu YT, Liu YS, Liu JF. Kiwifruit improves bowel function in patients with irritable bowel syndrome with constipation. Asia Pacific journal of clinical nutrition. 2010;19:451-457.
- Chen AGY, Offereins MSL, Mulder CJ, Frampton CM, Gearry RB. A Pilot Study of the Effect of Green Kiwifruit on Human Intestinal Fermentation Measured by Hydrogen and Methane Breath Testing. Journal of Medicinal Food. 2018;21:1295-1298.
- Chang BW, Rezaie A. Irritable Bowel Syndrome-Like Symptoms Following Fecal Microbiota Transplantation: A Possible Donor-Dependent Complication. The American journal of gastroenterology. 2017;112:186-187.
- Tian H, Ge X, Nie Y, Yang L, Ding C, McFarland LV, Zhang X, Chen Q, Gong J, Li N. Fecal microbiota transplantation in patients with slow-transit constipation: A randomized, clinical trial. PLoS One. 2017;12:e0171308-e0171308.
- Ge X, Tian H, Ding C, Gu L, Wei Y, Gong J, Zhu W, Li N, Li J. Fecal Microbiota Transplantation in Combination with Soluble Dietary Fiber for Treatment of Slow Transit Constipation: A Pilot Study. Archives of medical research. 2016;47:236-242.