The Microbiome and Cancer: Should we ever prescribe bacteria? Gregory A. Plotnikoff, MD, MTS, FACP

Transcription

1 The Microbiome and Cancer: Should we ever prescribe bacteria? Gregory A. Plotnikoff, MD, MTS, FACP

2 2011 SIO Conference: Like 15th century explorers describing the outline of a new continent, HMP researchers employed a new technological strategy to define, for the first time, the normal microbial makeup of the human body. The New Frontier Francis S. Collins, M.D., Ph.D.

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5 Genes Responsible for Human Survival Human genome: approx 22,000 proteincoding genes Human microbiome: approx 8 million unique protein-coding genes Key point: we harbor 360 times more bacterial genes than human genes

6 Enabled Disease-Specific Studies Now that we understand what the normal human microbiome looks like, we should be able to understand how changes in the microbiome are associated with, or even cause, illnesses. Barbara Methé, Ph.D.

7 Normal Microbial Variation We now have a very good idea of what is normal for a healthy Western population and are beginning to learn how changes in the microbiome correlate with physiology and disease. Defined James M. Anderson, MD, PhD

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10 Figure 1. Variability within the 16S rrna gene. Andersson AF, Lindberg M, Jakobsson H, Bäckhed F, et al. (2008) Comparative Analysis of Human Gut Microbiota by Barcoded Pyrosequencing. PLoS ONE 3(7): e2836. doi: /journal.pone

11 Key Finding It appears that bacteria can pinch hit for each other. It matters whether the metabolic function is present, not which microbial species provides it. Curtis Huttenhower, Ph.D.

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13 The Human Microbiome: Our Second Genome Annual Review of Genomics and Human Genetics. 2012; 13: Elizabeth A. Grice and Julia A. Segre Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health,

14 Microbial Interaction with Hosts We have co-evolved and share a symbiotic relationship Microbial signaling affects host metabolic, neurological, inflammatory, immunologic and host-defense functions The nature of host responses also shapes microbiome populations and metabolism Muegge et al., 2011; Vijay-Kumar et al., 2010.

15 Microbiome and Oncology Direct effects (H. pylori) Hyperinsulinism Obesity Inflammation (via metabolic endotoxemia, elevated serum LPS) Hyperestrogenism (via β-glucuronidase) Cancer cell proliferation (via low SCFAs) Anxiety Depression GI distress Immune function C. diff risk (via competitive exclusion) Intestinal wall integrity/bacterial translocation (neutropenic fever, sepsis)

16 Microbiome and Oncology Direct effects (H. pylori) Hyperinsulinism Obesity Inflammation (via metabolic endotoxemia, elevated serum LPS) Hyperestrogenism (via β-glucuronidase) Cancer cell proliferation (via low SCFAs) Anxiety Depression GI distress Immune function C. diff risk (via competitive exclusion) Intestinal wall integrity/bacterial translocation (neutropenic fever, sepsis)

17 Microbiome and Oncology Direct effects (H. pylori) Hyperinsulinism Obesity Inflammation (via metabolic endotoxemia, elevated serum LPS) Hyperestrogenism (via β-glucuronidase) Cancer cell proliferation (via low SCFAs) Anxiety Depression GI distress Immune function C. diff risk (via competitive exclusion) Intestinal wall integrity/bacterial translocation (neutropenic fever, sepsis)

18 Microbiome and Oncology Direct effects (H. pylori) Hyperinsulinism Obesity Inflammation (via metabolic endotoxemia, elevated serum LPS) Hyperestrogenism (via β-glucuronidase) Cancer cell proliferation (via low SCFAs) Anxiety Depression GI distress Immune function C. diff risk (via competitive exclusion) Intestinal wall integrity/bacterial translocation (neutropenic fever, sepsis)

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20 Schematic representation of the multiple consequences of the cross-talk between the probiotic bacteria and the intestinal mucosa. Corthésy B et al. J. Nutr. 2007;137:781S-790S 2007 by American Society for Nutrition

21 David Kerr, Clinical Development of Gene Therapy for Colorectal Cancer, Nature Reviews Cancer. 2003; 3:

22 Microbiome s Contribution to CRC? 2 bile salt transformations Bacterial beta-glucuronidases Production of hydrogen sulfide Production of aglycones Production of aromatic amines Generation of acetaldehyde Generation of reactive oxygen species Desulfuration of bile acids

23 Key Point Numerous toxic and genotoxic host metabolites exist that can lead to mutations by binding specific cell surface receptors and affecting intracellular signal transduction.

24 Microbiome Changes Fusobacterium predominate more in CRC Decreased numbers of: Faecalibacterium Ruminococcus Lachnospiraceae Peptostreptococcacae Enterobacteriaceae Decreased butyrate production

25 Bacterial Biotransformation 1 7-α-dehydroxylation of cholic acid and chenodeoxylcholic acid to produce deoxycholic acid and lithocholic acid. Carcinogens produced in increased amounts via dysbiotic intestinal ecology. Measurable and modifiable.

26 Bernstein C et al. Arch Toxicol. 2011; 85(8):

27 Probiotics may offer benefits in GI tumor tx Beneficial autophagy: Kim Y et al. Lett Appl Microbiol Aug;51(2): Cell-bound exopolysaccharide from probiotic bacteria induces autophagic cell death of tumour cells. Antiproliferative: Lee do K et al. BMC Cancer. 2008;8:310. Anti-proliferative effects of Bifidobacterium adolescentis SPM0212 extract on human colon cancer cell lines. Promotes apoptosis: Borowicki A et al. Nutr Cancer. 2011;63(1): Fermented wheat aleurone enriched with probiotic strains LGG and Bb12 modulates markers of tumor progression in human colon cells. Inhibits cell differentiation: Linsalata M et al. Curr Pharm Des. 2010;16(7): Lactobacillus rhamnosus GG influences polyamine metabolism in HGC-27 gastric cancer cell line: a strategy toward nutritional approach to chemoprevention of gastric cancer. Enhances 5-FU: Baldwin C et al. Nutr Cancer. 2010;62(3): Probiotic Lactobacillus acidophilus and L. casei mix sensitize colorectal tumoral cells to 5-fluorouracilinduced apoptosis.

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29 In Obesity, the Microbiome is associated with: phylum-level changes in the microbiota, reduced bacterial diversity, and, altered representation of bacterial genes and metabolic pathways

30 Microbiome Exchange Means Phylogenetic Change Vijay-Kumar M et al. Science. 2010; 328 (5975): Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Turnbaugh PJ. Et al. Cell Host Microbe. 2008; 3(4): Dietinduced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Turnbaugh PJ. Nature. 2006;444(7122): An obesityassociated gut microbiome with increased capacity for energy harvest.

31 Heat map of the Spearman r correlations between the gut bacteria significantly modified by the prebiotic treatment and anthropometric/biological parameters. Dewulf E M et al. Gut doi: /gutjnl Copyright BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

32 Collinsella aerofaciens and Hippurate significantly augmented with prebiotics, has been associated with a low risk of colon cancer correlated with higher urinary levels of hippurate, a gut-derived metabolite commonly associated with a healthy phenotype. one of the main discriminant metabolites explaining the difference in urine metabolic profiles between lean and obese or diabetic individuals. Thus, increased levels of Collinsella and urinary hippurate could be considered as a beneficial effect associated with ITF fermentation.

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34 Bacterial Biotransformation 2 Bacterial β-glucuronidase deconjugation of congjugated estrogen metabolites in the intestinal tract. β-glucuronidase produced in increased amounts with dysbiotic intestinal ecology. Measurable and modifiable.

35 Plottel CS, Blaser MJ. The microbiome and malignancy. Cell Host Microbe. 2011; 10(4):

36 Metabolism and DNA Adducts of Estrogens Cavalieri E L et al. PNAS 1997;94: by National Academy of Sciences

37 Estrogen Metabolism and Increased Risk of Cancer The catechol estrogen-3,4-quinones (CE-3,4-Q) can react with DNA to form depurinating adducts. These adducts constitute >99% of total DNA adducts formed. These adducts are released from DNA to generate apurinic sites. Error-prone base excision repair of this damage may lead to the mutations that can initiate breast, prostate and other types of cancer. Cavalieri E. et al. Biochim Biophys Acta Aug;1766(1): Cavalieri E, Rogan EG. J Steroid Biochem Mol Biol Jul;125(3-5):

38 Estrogen Metabolism, Cancer and the Microbiome Key point 1: depurinating adducts of estrogens are endogenous tumor initiators. Key point 2: Enterohepatic recirculation of estrogens increases levels of these depurinating adducts. Key point 3: Increased intestinal bacterial β- glucuronidase results in greater reabsorption and enterohepatic recirculation of unconjugated free estrogens.

39 Restoration and Maintenance of a Healthy Estrobolome Can measure beta-glucoronidase activity Can measure estrone metabolites Can modify estrobolome functional activity Potential Areas of Interest: A) estrogen-driven malignancy risk reduction (Type I endometrial cancer, ER positive breast cancer, and some ovarian cancers). B) estrogen-driven malignancy risk identification C) rebalancing species with β-glucuronidase and β-glucuronide activities

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41 The Microbiome and Cancer: Should we ever prescribe bacteria? Gregory A. Plotnikoff, MD, MTS, FACP

42 Research Challenges 1 or more strains Multiple species Physiological state of cultures at production Age of cultures Dose (CFU/ml)

43 Research Opportunities Β-glucuronidase and estrogen metabolism 2 Bile acids and GI cancers SCFA production and insulinism/obesity Microbiome resilience to perturbations (dietary change, antibiotics, surgery, radiation and chemotherapy)

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45 R X : Prebiotics Non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the intestines and thus improve host health. These ingredients are neither hydrolyzed nor absorbed in the upper GI. International Scientific Association for Probiotics and Prebiotics

46 Fiber is a Nutrient Increases mineral absorption Stimulates beneficial microbes Reduces survival of pathogenic bacteria Supports proper immune function Treats constipation

47 Not All Fiber is a Prebiotic Inulin FOS GOS Soya-oligosaccharides Xylo-oligosaccharides Pyrodextrins Note: most Americans only get 15 grams of fiber today with the top two sources being potatoes and white bread.

48 Prebiotic Foods Artichokes, asparagus, bananas, chicory root, dandelion greens, raw garlic, Jerusalem artichoke, jicama, leek, onion, wheat, rye. Fermented vegetables Fermented dairy Fibrous foods or fiber supplements

49 Key Point Dietary intake of diverse plant fibers promotes microbiome diversification, improves gene richness and improves risk phenotypes.

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52 Conjugative pathways for estrone and 17β-estradiol. Oxford University Press Raftogianis R et al. J Natl Cancer Inst Monogr 2000;2000:

53 Estrone E1 Phase I and Phase II Hepatic Metabolism CYP1A1 2-OH-E1 COMT 2-MeOE1 CYP3A4 16-α-OH-E1 CYP1B1 4-OH-E1 COMT 4-MeOE1 Phase II: methylation via COMT, glucuronidation, or sulfation

54 Key Finding Relative abundance of metabolic and functional pathways are more stable than organismal abundances.

55 Source: