Importance of Methanogenic Flora in Intestinal Toxicity During 5-Fluorouracil Therapy for Colon Cancer

Rana, SV PhD

Journal of Clinical Gastroenterology:
doi: 10.1097/MCG.0b013e3182702dd6
Author Information

Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

The author declares that she has nothing to disclose.

Reprints: SV Rana, PhD, House No 137, Sector 15-A, Chandigarh 160015, India (e-mail:

Article Outline

To study the association of colonic methane due to methanogenic archae and pH with gastrointestinal symptoms during colorectal cancer (CRC) therapy is an interesting study that focuses on reducing the side effects, namely, gastrointestinal toxicity due to adjuvant 5-fluorouracil (5-FU) chemotherapy.

CRC is the third most common type of cancer in men (663,000 cases, 10.0% of the total number of cancers) and the second most common in women (570,000 cases, 9.4% of the total number of cases) worldwide.1 The incidence rates of CRC vary 10-fold in both sexes worldwide, the highest rates being estimated in Australia/New Zealand and Western Europe and the lowest in Africa (except southern Africa) and south-central Asia.1 About 5% of all colon tumors are represented by hereditary forms, whereas the majority are characterized by sporadic forms. Western diets rich in animal products including fat, cholesterol, and protein were shown to have carcinogenic properties in experimental studies. The composition of the diet not only influences the quality of the gut flora but also helps to establish predictable and competitive relationships between the host bacteria.2,3

New trends in research are changing our understanding of the complex pathways that regulate cancer cell biology, the interactions of tumors with their micro environment, and the mechanisms that normally restrain tumorigenesis. Importantly, researchers are translating these findings into novel approaches toward cancer diagnosis, prognosis, and therapies. Cancer treatment depends on the type of cancer, the stage of the cancer (how much it has spread), age, health status, and additional personal characteristics. There is no single treatment for cancer, and patients often receive a combination of therapies and palliative care. Treatments usually fall into one of the following categories: surgery, radiation, chemotherapy, or gene therapy.

Although surgery remains the mainstay treatment, the role of chemotherapy in CRC has expanded considerably over the past 10 years. At present, the majority of patients receive chemotherapy with 1 or more agents approved for treatment. Combination chemotherapy regimens consist of 5-FU and leucovorin (LV) with oxaliplatin or irinotecan. With the administration of molecular targeted agents (ie, bevacizumab or cetuximab/panitumumab), therapy response rates of 50% to 80% have been achieved, and the median survival time has been prolonged to 20 to 24 months in metastatic CRC patients.4–8

Most people face no serious long-term side effects from chemotherapy. However, on some occasions, chemotherapy can cause permanent changes or damage to the heart, lungs, nerves, kidneys, gastrointestinal tract, and reproductive or other organs. Therefore, the focus of research should also be on methods to cure or modify the side effects associated with chemotherapy and other treatments.

In this study by Holma et al,9 the researchers took into consideration all confounding factors, such as site of resected cancer, type of bowel resection, presence of stoma, chemotherapy regime, hypolactasia, and Lactobacillus GG (LGG) intervention, and performed a multivariate analysis. This study produced some interesting results; it showed that methane producers developed diarrhea less frequently and constipation more frequently compared with methane nonproducers.10 This was similar to a recent study on irritable bowel syndrome in which methane breath excretors were seen to develop diarrhea less frequently compared with nonexcretors.11

Analysis by Furnari et al in 201212 also demonstrated that methane production was strictly associated with constipation. Moreover, after subdividing the study population according to daily stool frequency, they found that mean CH4 excretion seemed to increase in parallel with the reduction in bowel movements. Similar findings were observed by other researchers in patients with constipation–irritable bowel syndrome by using lactulose hydrogen breath test.13 However, many doubts remain as to whether methane is able to produce constipation or is a consequence of intestinal hypomotility. Therefore, this aspect of study by Holma et al9 could be investigated further to find out whether methane production can act as a biomarker for diarrhea due to the dose of 5-FU. Some studies are ongoing in this regard and results would definitely help in ensuring and possibly designing the treatment for it.

Researchers have also indicated that methanogenesis is associated with prolonged colonic transit time.14,15 They report that this could occur by promoting segmental (nonpropagating) contraction or through reduced serotonin levels in the gut, which was investigated by Pimentel et al.16 Serotonin is one of the most abundant molecules in the gastrointestinal tract. It is a paracrine messenger utilized by enterochromaffin cells, which function as sensory transducers. It plays a crucial role in the regulation of several physiological functions, such as motility, secretion, and visceral sensitivity. Besides this well-documented physiological role, increasing evidence supports the concept that 5-HT is directly involved in pathologic mechanisms and in the modulation of immune/inflammatory responses within the gut. The wide range of pathophysiological actions exerted by 5-HT are mediated by several different serotonergic receptor types and subtypes.17

However, the exact mechanism showing the relationship between methanogenesis, colonic transit time, and serotonin levels in case of patients undergoing chemotherapy needs to be known, as this could throw light on the treatment for gastrointestinal symptoms that cancer patients suffer from.

Several lines of evidence suggest that use of LGG reduces diarrhea during chemotherapy.18–21 Measurements of the intestinal microflora show that LGG adheres to the intestinal wall during healthy periods and during episodes of diarrhea. In addition, LGG improves the microflora balance and normalizes fecal enzyme and short-chain fatty acid levels. However, in the study by Holma et al,9 diarrhea was reduced only in the case of methane nonproducers by using LGG. This could be because of differences in the cause of diarrhea or in adhesion, colonization, metabolism, or effect of LGG between producers and nonproducers of CH4; however, this remains incompletely clarified. Therefore, further lines of evidence are required to know the exact mechanism of how LGG reduces diarrhea only in nonmethane producers and whether it reduces diarrhea in patients undergoing chemotherapy only.

Furthermore, many studies link methanogenesis to constipation and suggest that the reduction of methane production is a potential means to treat constipation.11,14,15,22 In this issue, Holma et al9 have suggested that methanogenesis promotion could be a tool in treatment of diarrhea due to adjuvant 5-FU. However, the patient’s methane production status could be an important factor in determining the 5-FU dose.

The study was well planned and conducted, providing important knowledge and evidence to the concept of association of methanogenic archae and fecal pH with gastrointestinal symptoms during CRC chemotherapy using 5-FU. However, some limitations need to be investigated further, as significant results were not obtained:

* When patients were administered different treatments with LGG, LGG+guar gum (fiber) and were compared with controls who were given no supplements

* With respect to the relation between methane production and LGG intervention

* With respect to fecal pH in different chemotherapy regimens.

At present, the explanation of a correlation between colon cancer and CH4 excretion is still unknown. We do not know whether the methanogenic flora predates the tumor or is derived from the tumor. However, an imbalance between gas metabolism and abnormal CH4 production has been considered in the pathogenesis of several intestinal disorders, including colon cancer.

Back to Top | Article Outline


1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–2917
2. McGarr SE, Ridlon JM, Hylemon PB. Diet anaerobic bacterial metabolism, and colon cancer: a review of the literature. J Clin Gastroenterol. 2005;39:98–109
3. Nystrom M, Mutanen M. Diet and epigenetics in colon cancer. World J Gastroenterol. 2009;15:257–263
4. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229–237
5. Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25:1670–1676
6. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–2019
7. Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–1417
8. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–671
9. Holma R, Korpela R, Sairanen U, et al. Colonic methane production modifies gastrointestinal toxicity associated with adjuvant 5-fluorouracil chemotherapy for colorectal cancer. J Clin Gastroenterol. 2013;47:45–51
10. Cen P, Ajani JA. Medical treatment for advanced gastroesophageal adenocarcinoma. Curr Opin Gastroenterol. 2007;23:631–635
11. Makhani M, Yang J, Mirocha J, et al. Factor analysis demonstrates a symptom cluster related to methane and non-methane production in irritable bowel syndrome. J Clin Gastroenterol. 2011;45:40–44
12. Furnari M, Savarino E, Bruzzone L, et al. Reassessment of the role of methane production between irritable bowel syndrome and functional constipation. J Gastrointest Liver Dis. 2012;21:157–163
13. Pimentel M, Mayer AG, Park S, et al. Methane production during lactulose breath test is associated with gastrointestinal disease presentation. Dig Dis Sci. 2003;48:86–92
14. Levitt MD, Furne JK, Kuskowski M, et al. Stability of human methanogenic flora over 35 years and a review of insights obtained from breath methane measurements. Clin Gastroenterol Hepatol. 2006;4:123–129
15. Attaluri A, Jackson M, Valestin J, et al. Methanogenic flora is associated with altered colonic transit but not stool characteristics in constipation without IBS. Am J Gastroenterol. 2010;105:1407–1411
16. Pimentel M, Kong Y, Park S. IBS subjects with methane on lactulose breath test has lower postprandial serotonin levels than subjects with hydrogen. Dig Dis Sci. 2004;49:84–87
17. Cirillo C, Vanden BP, Tack J. Role of serotonin in gastrointestinal physiology and pathology. Minerva Endocrinol. 2011;36:311–324
18. Osterlund P, Ruotsalainen T, Korpela R, et al. Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. Br J Cancer. 2007;97:1028–1034
19. Basu S, Chatterjee M, Ganguly S, et al. Effect of Lactobacillus rhamnosus GG in persistent diarrhea in Indian children: a randomized controlled trial. J Clin Gastroenterol. 2007;41:756–760
20. Guarino A, Vecchio AL, Canani RB. Probiotics as prevention and treatment for diarrhea. Curr Opin Gastroenterol. 2009;25:18–23
21. D’Souza AL, Rajkumar C, Cooke J, et al. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. BMJ. 2002;324:1361–1366
22. Morken MH, Berstad AE, Nysaeter G, et al. Intestinal gas in plain abdominal radiographs does not correlate with symptoms after lactulose challenge. Eur J Gastroenterol Hepatol. 2007;19:589–593
© 2013 Lippincott Williams & Wilkins, Inc.