Gut Microbes: Potential targets in the prevention and treatment of IBD Neelendu Dey, MD Instructor Division of Gastroenterology
Disclosure The following are my disclosures. Potential conflicts of interest have been resolved. Research Support / Grants Stock/Equity Consulting / Employment Speakers Bureau / Honoraria Other None None None None None
The probiotics industry is worth $20-30 billion
197 clinical trials are currently investigating the role of probiotics in a variety of conditions http://clinicaltrials.gov (results of search for probiotics on 11/2/12, Open Studies only)
Number of Publications Number of Publications on Gut Microbes in IBD (1983-2012) 250 200 150 100 50 0 Year From web resource at URL:http://dan.corlan.net/medline-trend.html. Alexandru Dan Corlan. Medline trend: automated yearly statistics of PubMed results for any query, 2004.
Patients, physicians, and scientists are all interested in gut microbes why?
Why study gut microbes in IBD? Potential clinical benefits Inform prognosis and thus guide therapy Improved understanding of pathogenesis Rationale Critical in training the immune system Gut microbes > human cells (10-fold) 1 Microbial genes > human genes (>100-fold) Influences digestion and metabolism, produces vitamins, defends from pathogens 1 Bäckhed et al. Science 2005; 307: 1915-20.
Concept #1: THE DATA BEHIND PROBIOTICS IS NOT STRONG (ONE EXCEPTION: POUCHITIS)
The National Institutes of Health says we re not there yet Our understanding of probiotics is a work in progress. Although probiotic products are marketed for many different uses, scientific evidence supporting specific uses is still limited, and the FDA has not approved any health claims for probiotics. From the NIH National Center for Complementary and Alternative Medicine (NCCAM) website: http://nccam.nih.gov/health/probiotics/introduction.htm
Primum non nocere Available evidence does not suggest increased risk of adverse events 1 Existing studies primarily examined Lactobacillus +/- Bifidobacterium Case reports of fungemia (ICU patients) 2,3 Data on long-term safety limited 1. Safety of Probiotics Used to Reduce Risk and Prevent or Treat Disease, Structured Abstract. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/tp/probiotictp.htm 2. Stefanatou E, Kompoti M, Paridou A, et al. Probiotic sepsis due to Saccharomyces fungaemia in a critically ill burn patient. Mycoses 2011;54:e643 646. 3. Thygesen JB, Glerup H, Tarp B. Saccharomyces boulardii fungemia caused by treatment with a probioticum. BMJ Case Rep 2012;2012.
Concept #2: ANTIBODIES TO MICROBES ARE SEEN IN CROHN S DISEASE
Immune responses in Crohn s disease ASCA OmpC CBir1 I2 panca In Crohn s patients, antibodies against microbes occur in greater frequency than in UC or healthy patients.
Antibody sum and surgery Probability of non-progressive CD 1.00 0.75 0.50 0.25 Antibody sum=0 (n=189) Antibody sum=1 (n=243) Antibody sum=2 (n=174) Antibody sum=3 (n=47) 0.00 0 25 50 75 100 125 150 175 Time to surgery (months) p<0.0001 Dubinsky et al, Gastroenterology 2007; 132: A-17 (No. 82)
The antibody ASCA predicts Crohn s disease Retrospective analysis stored soldiers sera 10/32 Crohn s patients ASCA+ before symptoms (versus 0/95 controls) Mean interval from ASCA+ to diagnosis = 38 months Israeli E, Grotto I, Gilburd B, et al. Anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inflammatory bowel disease. Gut 2005;54:1232 6.
Concept #3: GUT MICROBIAL COMMUNITIES ARE ALTERED IN IBD (ESPECIALLY IN CROHN S DISEASE )
Dysbiosis is seen in many IBD patients St. Louis, MO Chicago, IL Columbia, MO Rockford, IL St. Louis, MO 0 300 125 300 Chicago, IL 300 0 400 90 Columbia, MO 125 400 0 400 Rockford, IL 300 90 400 0 Frank et al. PNAS 2007; 104(34): 13780-5.
Percentage of total microbes Gut microbial differences in IBD Frank et al. PNAS 2007; 104(34): 13780-5.
Dysbiosis varies with distribution of disease (ileal versus colonic) Willing et al. Gastroenterology 2010; 139(6):1844-54.
Treatment, environment, and disease subtype affect gut microbes Morgan et al. Genome Biology 2012; 13(9):R79.
Disease phenotype and genotype associated with dysbiosis in IBD Frank et al. IBD 2011; 17:179-184.
Concept #4: GUT MICROBES CAN BE BENEFICIAL OR HARMFUL (OFTEN DEPENDING ON CONTEXT)
Protection from gut injury is dependent on gut microbes Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, et al. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118:229 241.
Faecalibacterium prausnitzii = an anti-inflammatory bacterium? P = 0.03 (n = 8) (n = 13) Sokol et al. PNAS 2008; 105(43):16731-6.
Segmented filamentous bacteria induce intestinal Th17 Cells in mice Ivanov et al. Cell 2009; 139(3):485-98.
Concept #5: RIGHT TIME, RIGHT PLACE: TIMELY MICROBIAL EXPOSURES ARE IMPORTANT FOR IMMUNITY
Gut microbes train the immune system early in life SPF = specific pathogen free; GF = germ-free. GF/n = colonized pregnant GF female mice just prior to delivery; GF/a = colonized mice at 5 weeks of age. Sacrifice or oxazolone challenge performed at 8-9 weeks of age. Olszak T et al. (2012) Microbial Exposure During Early Life Has Persistent Effects on Natural Killer T Cell Function. Science.
Gut microbes induce anti-inflammatory immune cells in the colon Colonization at 2 weeks, sacrifice or DSS at 8 weeks Atarashi K et al. (2011) Induction of Colonic Regulatory T Cells by Indigenous Clostridium Species. Science 331:337-341.
Summary The data behind probiotics is not strong Antibodies to microbes are seen in Crohn s disease Gut microbial communities are altered in IBD (especially in Crohn s disease) Gut microbes can be beneficial or harmful (often depending on context) Microbial exposures are important for immunity
Acknowledgements Thanks to the CCFA for inviting me! Thanks to you all for attending this talk!