EUROPEAN ONE HEALTH-ECOHEALTH WORKSHOP
BRUSSELS, 2016
Commensal Gut Bacteria and Cancer
Theofilos Poutahidis, PhD
Associate Professor
Laboratory of Pathology
Faculty of Health Sciences
School of Veterinary Medicine
Aristotle University of Thessaloniki
Cancer is a multistage process
Cancer initiation and progression
Neoplastic potential
Regression
Evolution
Normal glands
Preneoplastic gland
Preneoplastic lesions are less autonomous in their growth than previously thought
The tumor microenvironment school of thought
Autopsy studies have shown that
focal lesions with neoplastic potential
are commonplace in the human
body
The microenvironment of lesions with
neoplastic potential determines their fate
preneoplasia
The “seed” and the “soil”
Modulating the microenvironment of preneoplastic lesions to prevent cancer
The microenvironment as a part of the… macroenvironment
Major players affecting neoplastic disease progression
Endocrine system
Immune system
Psychological condition
Altering the… “soil” to reduce cancer risk
Aiming at a favorable immune, metabolic and psychological profile
Subclinical Condition Α
Subclinical Condition Β

Immune system
“tone” Α

Immune system
“tone” B
Expanding the macroenvironment notion to include GI flora
Gut bacteria flora exerts systemic effects
Gut bacteria have been reported to affect…
…the 90% of pathology in both humans and experimental animals
Exploiting gut bacteria to reduce cancer risk
Can we exploit gut flora-host signaling to achieve health benefits, including
reducing the risk of developing cancer?
The Lactobacillus reuteri paradigm
Experts think L. reuteri may be an “old friend” according to “hygiene hypothesis”
Beneficial effects of Lactobacillus reuteri in mice (Erdman lab)
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•
•
•
•
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Regulatory T-cells
luxuriant fur
accelerated skin wound healing
resistance to obesity
enhanced reproductive behaviors
increased lifespan
less age-associated atrophic changes in
skeletal muscles
testes
thymus
thyroid glands
(youthful hormonal levels)
upregulation of Tregs and anti-inflammatory cytokines
downregulation of circulating neutrophils and pro-inflammatory cytokines
L. reuteri upregulates host oxytocin
LR in oxytocin-deficient mice
Beneficial effects of LR depend on oxytocin
L. reuteri: A “Psychobiotic”?
Edible L. reuteri suppresses mammary carcinogenesis
L. Reuteri
↑↑↑ Cancer
↓ Cancer
Wild type CD-1 (swiss) mice fed with New Western-type diet, mammary gland preneoplasia
MMTV-neu (HER2) FVB, genetically engineered, mammary carcinoma
Role of gut bacteria-exposed Tregs
Cell transfer mouse models using
1. Helicobacter hepaticus
2. Lactobacillus reuteri
Maternal gut flora dysbiosis increases cancer risk of progeny
wt CD-1 (swiss) mothers fed with New Western-type diet
L. reuteri rescues descendent mice from cancer
Why interested in participating in this workshop ?
Let’ s not meet the opponent (cancer) on his own ground
Look at the bigger picture: Whole organism-Hologenome-Ecosystem
The spirit of One Health-One Medicine-Comparative Medicine
Rudolf Virchow (1821-1902)
Sir William Osler (1849-1919)
Thank you!
The Erdman Lab
http://erdmanlab.us/
Supporting literature- further reading
1. Bissell MJ, Hines WC. Why don’t we get more cancer? A proposed role of themicroenvironment in restraining cancer progression.
Nat Med 2011; 17:320-9.
2. Hanahan D, Weinberg RA. The hallmarks of cancer, Cell 100 (2000) 57–70.
3. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment, Cancer Cell 21
(2012) 309–322.
4. Bissell MJ, Radisky D. Putting tumours in context, Nat. Rev. Cancer 1 (2001) 46–54.
5. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer, Cell 140 (2010) 883–899.
6. Faulds MH, Dahlman-Wright K, Metabolic diseases and cancer risk. Curr. Opin. Oncol. 24 (2012) 58–61.
7. Lillberg K, Verkasalo PK, Kaprio J, Teppo L, Helenius H, Koskenvuo M. Stressful life events and risk of breast cancer in 10,808
women: a cohort study, Am. J. Epidemiol. 157 (2003) 415–423.
8. Folkman J, Kalluri R. Cancer without disease. Nature. 2004; 427:787.
9. Lee YK, Mazmanian SK. Has the microbiota played a critical role in the evolution of the adaptive immune system? Science. 2010
Dec 24;330(6012):1768-73.
10. Maynard CL, Elson CO, Hatton RD, Weaver CT. Reciprocal interactions of the intestinal microbiota and immune system. Nature
2012; 489:231-41.
11. Shanahan F. The gut microbiota-a clinical perspective on lessons learned. Nat Rev Gastroenterol Hepatol 2012; 9:609-14.
12. Belkaid, Y., & Hand, T. W. Role of the microbiota in immunity and inflammation. (2014) Cell, 157(1), 121–141.
13. Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view. Cell. 2012
Mar 16;148(6):1258-70.
14. Sommer F, Bäckhed F. The gut microbiota--masters of host development and physiology. Nat Rev Microbiol. 2013 Apr;11(4):22738.
15. Sommer F, Stahlman M, Ilkayeva O, Arnemo JM, Kindberg J, Josefsson J, Newgard CB, Fröbert O, Bäckhed F. The Gut Microbiota
Modulates Energy Metabolism in the Hibernating Brown Bear Ursus arctos. Cell Rep. 2016 Feb 23;14(7):1655-61.
16. Rook GA. Regulation of the immune system by biodiversity from the natural environment: an ecosystem service essential to
health. Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):18360-7.
17. Stilling RM, Dinan TG, Cryan JF. The brain's Geppetto-microbes as puppeteers of neural function and behaviour? J Neurovirol.
2016 Feb;22(1):14-21.
18. Sherwin E, Rea K, Dinan TG, Cryan JF. A gut (microbiome) feeling about the brain. Curr Opin Gastroenterol. 2016 Mar;32(2):96-102
19. Dinan TG, Stanton C, Cryan JF. Psychobiotics: a novel class of psychotropic. Biol Psychiatry. 2013 Nov 15;74(10):720-6.
20. Walter J, Britton RA, Roos S. Host-microbial symbiosis in the vertebrate gastrointestinal tract and the Lactobacillus reuteri
paradigm. Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1:4645-52.
21. Lee HJ, Macbeth AH, Pagani JH, Young WS 3rd. Oxytocin: the great facilitator of life. Prog Neurobiol. 2009 Jun;88(2):127-51.
22. Baribeau DA, Anagnostou E. Oxytocin and vasopressin: linking pituitary neuropeptides and their receptors to social
neurocircuits. Front Neurosci. 2015 Sep 24;9:335.
23. Wang P, Yang HP, Tian S, Wang L, Wang SC, Zhang F, Wang YF. Oxytocin-secreting system: A major part of the neuroendocrine
center regulating immunologic activity. J Neuroimmunol. 2015 Dec 15;289:152-61.
24. Shen H. Neuroscience: The hard science of oxytocin. Nature. 2015 Jun 25;522(7557):410-2.
25. Barengolts E. Oxytocin - an emerging treatment for obesity and dysglycemia: review of randomized controlled trials and cohort
studies. Endocr Pract. 2016 Jul;22(7):885-94.
26. Buffington SA, Di Prisco GV, Auchtung TA, Ajami NJ, Petrosino JF, Costa-Mattioli M.Microbial Reconstitution Reverses Maternal
Diet-Induced Social and Synaptic Deficits in Offspring. Cell. 2016 Jun 16;165(7):1762-75.
Relevant Erdman Lab publications
1. Erdman SE, Poutahidis T, Tomczak M, Rogers AB, Cormier K, Plank B, Horwitz BH, Fox JG. CD4+ CD25+ regulatory T lymphocytes
inhibit microbially induced colon cancer in Rag2-deficient mice. American Journal of Pathology. 2003 Feb, 162(2): 691-702.
2. Erdman SE, Rao VP, Poutahidis T, Ihrig MM, Ge Z, Feng Y, Tomczak M, Rogers AB, Horwitz BH, Fox JG. CD4+CD25+ regulatory
lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice. Cancer Research. 2003 Sep 15, 63(18): 6042-50.
3. Rao VP, Poutahidis T, Ge Z, Nambiar PR, Boussahmain C, Wang YY, Horwitz BH, Fox JG, Erdman SE. Innate immune inflammatory
response against enteric bacteria Helicobacter hepaticus induces mammary adenocarcinoma in mice. Cancer Research. 2006 Aug
1;66(15):7395-400.
4. Rao VP, Poutahidis T, Fox JG, Erdman SE. Breast cancer: should gastrointestinal bacteria be on our radar screen? Cancer Research.
2007 Feb 1;67(3):847-50.
5. Poutahidis T, Haigis KM, Rao VP, Nambiar PR, Taylor CL, Ge Z, Watanabe K, Davidson A, Horwitz BH, Fox JG, Erdman SE. Cytokinemediated rapid reversal of epithelial invasion in a mouse model of microbially-induced colon carcinoma. Carcinogenesis. 2007
Dec;28(12):2614-23
6. Erdman SE, Rao VP, Poutahidis T, Rogers AB, Taylor CL, Jackson EA, Ge Z,. Lee CW, Schauer DB, Wogan GN, Tannenbaum SR, Fox
JG. Nitric oxide and TNF-α trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus-infected, Rag2-deficient
mice. Proceedings of the National Academy of Sciences of the United States of America. 2009 Jan 27;106(4):1027-32.
7. Erdman SE, Rao VP, Olipitz W, Taylor CL, Jackson EA, Levkovich T, Lee CW, Horwitz BH, Fox JG, Ge Z, Poutahidis T. Unifying roles for
regulatory T cells and inflammation in cancer. International Journal of Cancer. 2010 Apr 1;126(7):1651-65.
8. Erdman SE, Poutahidis T. Cancer inflammation and regulatory T cells. International Journal of Cancer. 2010 Aug 15;127(4):768-79.
9. Levkovich T, Poutahidis T, Smillie C, Varian BJ, Ibrahim YM, Lakritz JR, Alm EJ, Erdman SE. Probiotic bacteria induce a 'glow of
health'. PLoS One. 2013;8(1):e53867.
10. Poutahidis T, Kleinewietfeld M, Smillie C, Levkovich T, Perrotta A, Bhela S, Varian BJ, Ibrahim YM, Lakritz JR , Kearney SM,
Chatzigiagkos A, Hafler DA, Alm EJ, Erdman SE. Microbial reprogramming inhibits Western diet-associated obesity. PLoS One.
2013 8(7): e68596.
11. Poutahidis T, Cappelle K, Levkovich T, Lee CW, Doulberis M, Ge Z, Fox JG, Horwitz BH, Erdman SE. Pathogenic intestinal
bacteria trigger prostate cancer via systemic activation of immune cells in mice. PLoS One. 2013 8(8): e73933
12. Poutahidis T , Kearney SM, Levkovich T, Qi P, Varian BJ, Lakritz JR, Ibrahim YM, Chatzigiagkos A, Alm EJ, Erdman SE. Microbial
symbionts accelerate wound healing by an oxytocin-dependent mechanism. PLoS One. 2013 Oct 30;8(10):e78898.
13. Poutahidis T, Springer A, Levkovich T, Qi P, Varian BJ, Lakritz JR, Ibrahim, YM Chatzigiagkos A, Alm EJ, Erdman SE. Probiotic
microbes increase serum testosterone levels and testicular size in mice. PLoS One. 2014 Jan 2;9(1):e84877
14. Poutahidis T, Erdman SE. Probiotic ‘glow of health’: more than skin deep. Beneficial Microbes. 2014 Jun 1;5(2):109-19.
15. Lakritz JR, Poutahidis T, Levkovich T, Varian BJ, Ibrahim YM, Chatzigiagkos A, Alm EJ, Erdman SE. Beneficial bacteria stimulate
host immune cells to counteract dietary and genetic predisposition to breast cancer. International Journal of Cancer. 2014
Aug 1;135(3):529-40.
16. Poutahidis T, Erdman SE. Gut microbiota and the paradox of cancer immunotherapy. 2014 Frontiers in Immunology 2014 Apr
7;5:157.
17. 50.Poutahidis T, Erdman SE. Microbiome and the tumor macro-environment. Oncoimmunology. 2014 March; 3, e28271
(Invited Commentary)
18. Levkovich T, Poutahidis T, Cappelle K, Smith MB, Perrotta A, Alm EJ, Erdman SE. 'Hygienic' lymphocytes convey increased
cancer risk. Journal of Analytical Oncology 2014;3(3):113-21.
19. Varian BJ, Poutahidis T, Levkovich T, Ibrahim YM, Lakritz JR, Chatzigiagkos A, Scherer-Hoock A, Alm EJ, Erdman SE. Beneficial
Bacteria Stimulate Youthful Thyroid Gland Activity. Journal of Obesity and Weight Loss Therapy 2014;4 (220).
20. Ibrahim YM, Kearney SM, Levkovich T, Springer A, Mirabal S, Poutahidis T, Varian BJ, Lakritz JR, Alm EJ, Erdman SE. Maternal
Gut Microbes Control Offspring Sex and Survival. Journal of Probiotics and Health. 2014;2:120.
21. Doulberis M, Angelopoulou K, Kaldrymidou E, Tsingotjidou A, Abas Z, Erdman SE, Poutahidis T. Cholera-toxin suppresses
carcinogenesis in a mouse model of inflammation-driven sporadic colon cancer. Carcinogenesis. 2015;36(2):280-90.
22. Poutahidis T, Varian BJ, Levkovich T, Lakritz JR, Mirabal S, Kwok C, Ibrahim YM, Kearney SM, Chatzigiagkos A, Alm EJ, Erdman
SE. Dietary microbes modulate transgenerational cancer risk. Cancer Research. 2015 Apr 1;75(7):1197-204.
23. Lakritz JR, Poutahidis T, Mirabal S, Varian BJ, Levkovich T, Ibrahim YM, Ward JM, Teng EC, Fisher B, Parry N, Lesage S, Alberg N,
Gourishetti S, Fox JG, Ge Z, Erdman SE. Gut bacteria require neutrophils to promote mammary tumorigenesis. Oncotarget.
2015 Apr 20;6(11):9387-96.
24. Erdman SE, Poutahidis T. Gut bacteria and cancer. Biochimica et Biophysica Acta Reviews on Cancer. 2015 Jun 4; 1856:86-90.
25. Poutahidis T, Angelopoulou K, Erdman SE. Old enemies meet new friends for colon cancer prevention. OncoImmunology.
2015, 4 (10), 3 p.
26. Varian BJ, Goureshetti S, Poutahidis T, Lakritz JR, Levkovich T, Kwok C, Teliousis K, Ibrahim YM, Mirabal S, Erdman SE. Beneficial
bacteria inhibit cachexia. Oncotarget. 2016 Mar 15;7(11):11803-16.
27. Bernard BJ, Levkovich T, Poutahidis T, Ibrahim YM, Perrotta A, Alm EJ and Erdman SE. Beneficial Dog Bacteria Up-Regulate Oxytocin
and Lower Risk of Obesity. Journal of Probiotics and Health. 2016; 4:149.
28. Poutahidis T, Erdman SE. Commensal bacteria modulate the tumor microenvironment. Cancer Letters. 2016 Sep 28;380(1):356-8.
29. Erdman SE, Poutahidis T. Microbes and Oxytocin: Benefits for Host Physiology and Behavior. Volume 131. In: International Review
of Neurobiology: Gut Microbiome and Behavior. Eds JF Cryan, G Clarke. Elsevier-Academic Press. In Press.