Monday, 15 June 2015

Diarrhea resets the gut microbiome

I read this recent paper with interest: Gut microbial succession follows acute secretory diarrhea in humans (published in mBio, 19 May 2015) 1. This study used current techniques (i.e. 16s rRNA and metagenomic sequencing) to measure the recovery of the gut microbiota following acute diarrhea caused by Vibrio cholerae (Cholera) and enterotoxigenic E. coli (ETEC). Recovery of the gut microbiota took 30 days, 4 major stages/steps were identified, and these were explained by ecological theory and metagenomics 1, as described below:
  1. Initially diarrhea dramatically lowers the levels of all commensal microbes (estimated decline 100-100,000 fold) and allows the normally almost anoxic bowel environment to accumulate oxygen.
  2. Oxygen-tolerant facultative bacteria (e.g. E. coli, Streptococcus and Enterococcus) are first to re-establish themselves and consume the oxygen via aerobic respiration.
  3.  Mid-stage obligate anaerobes (i.e. Bacteroides) make a comeback; this may be driven by lower oxygen levels and accumulation of mucus and carbohydrates.
  4. Finally there is a shift toward a normal microbiota dominated by other obligate anaerobes (i.e. Prevotella and Roseburia); the decrease in facultative bacteria and Bacteroides likely involves bacteriophage predation and competition for carbohydrates/resources 1.
Perhaps not surprisingly these stages above resemble those characterising the early development of the infant microbiota. Facultative microbes are first to colonise and consume the oxygen 2. Then the combination of an anoxic environment and the introduction of solid foods (weaning) supports the growth of obligate anaerobes and progression toward an adult anaerobic gut microbiota 3. Therefore severe diarrhea may basically set you back toward an infant-like microbiota! Also what the paper did not consider is the possible role the appendix may play in re-inoculating the bowel with commensal microbiota after diarrhea, to accelerate its recovery. There is actually some initial basic evidence to suggest this may be the evolutionary function of the appendix 4,5.

This research has some broader parallels. Many chronic gut conditions start after an infection/diarrhea (e.g. IBD and post-infectious IBS-D). Both inflammation and diarrhea can shape intestinal redox and consequently the gut microbiota. Gut inflammation triggers an increased intestinal permeability (leaky gut) and influx of immune proteins and water which promotes diarrhea and aids pathogen removal 6,7; although also removes much of the gut microbiota as above. Chronic diarrhea and elevated oxygen may account for a loss of beneficial obligate anaerobes in conditions like inflammatory bowel disease (IBD) 8. Furthermore inflammation also releases reactive oxygen and nitrogen species (RONS) which can favour blooms in facultative Enterobacteriaceae, which may account for their increased abundance in many gut conditions (e.g. IBD, IBS, AIDS and infections) 9. Many pathogenic Enterobacteriaceae (e.g. Salmonella) are themselves capable of triggering inflammation, which is thought to represent an evolutionary mechanism favouring their growth and passage to another host 10. Lastly, all this research may also have some relevance to ME/CFS, considering there are elevated levels of facultative Streptococci and Enterococci 11,12 and immune responses to Proteobacteria/Enterobacteriaceae 13.

I think this research also has basic implications for how one treats gut dysbiosis resulting from diarrhea/inflammation-type disturbances. A diet high in indigestible carbohydrates (resistant starch and fibre) might promote late-stage recovery of the beneficial obligate anaerobes and their saccharolytic/fermenting metabolism. The resulting production of short-chain fatty acids (SCFAs) will lower the colonic pH and inhibit enteric pathogens and Enterobacteriaceae 3. Similarly consumption of plant polyphenols will inhibit pathogens and promote the growth of beneficial bacteria. Accordingly diets with a low plant-to-animal food ratio decrease beneficial bacteria while promoting overgrowth of potentially troublesome Proteobacteria/Enterobacteriaceae, as reviewed recently 3.

Different probiotics might also help different stages of microbiota recovery. For instance most probiotics on the market contain the facultative anaerobes Lactobacilli and Bifidobacteria, since they can be easily cultured commercially. Perhaps these could help by lowering inflammatory Enterobacteriaceae and promoting re-establishment of the obligate anaerobes? Perhaps next-generation probiotics themselves containing beneficial obligate anaerobes and butyrate-producing bacteria will be even more effective? Finally there are various oxygen-based colon cleansing products on the market, with unfounded claims about supporting beneficial gut bacteria. Might they actually induce a similar gut dysbiosis as diarrhea and inflammation?

References
1.         Begum, Y., Qadri, F., Larocque, R. C. & Turnbaugh, J. Gut Microbial Succession Follows Acute Secretory Diarrhea in Humans. MBio 6, 1–14 (2015).
2.         Circu, M. L. & Aw, T. Y. Redox biology of the intestine. Free Radic. Res. 45, 1245–66 (2011).
3.         Simpson, H. L. & Campbell, B. J. Review article: dietary fibre-microbiota interactions. Aliment. Pharmacol. Ther. n/a–n/a (2015). doi:10.1111/apt.13248
4.         Randal Bollinger, R., Barbas, A. S., Bush, E. L., Lin, S. S. & Parker, W. Biofilms in the large bowel suggest an apparent function of the human vermiform appendix. J. Theor. Biol. 249, 826–31 (2007).
5.         Guinane, C. M. et al. Microbial composition of human appendices from patients following appendectomy. MBio 4, (2013).
6.         McDermott, J. R. et al. Mast cells disrupt epithelial barrier function during enteric nematode infection. Proc. Natl. Acad. Sci. U. S. A. 100, 7761–6 (2003).
7.         Tang, Y. et al. Epithelial NF-kappaB enhances transmucosal fluid movement by altering tight junction protein composition after T cell activation. Am. J. Pathol. 176, 158–67 (2010).
8.         Rigottier-Gois, L. Dysbiosis in inflammatory bowel diseases: the oxygen hypothesis. ISME J. 7, 1256–61 (2013).
9.         Winter, S. E. & Bäumler, A. J. Why related bacterial species bloom simultaneously in the gut: Principles underlying the ‘like will to like’ concept. Cell. Microbiol. 16, 179–184 (2014).
10.       Winter, S. E., Lopez, C. a & Bäumler, A. J. The dynamics of gut-associated microbial communities during inflammation. EMBO Rep. 14, 319–27 (2013).
11.       Sheedy, J. R. et al. Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome. In Vivo 23, 621–8 (2009).
12.       Frémont, M., Coomans, D., Massart, S. & De Meirleir, K. High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients. Anaerobe 22, 50–6 (2013).
13.       Maes, M., Leunis, J.-C., Geffard, M. & Berk, M. Evidence for the existence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with and without abdominal discomfort (irritable bowel) syndrome. Neuro Endocrinol. Lett. 35, 445–453 (2014).

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