The human microbiome

1. The human microbiome “The Forgotten Organ”

2. The Forgotten Organ • Within body of healthy adult, microbial cells are estimated to outnumber human cells ten to one (100 trillion microbial cells) • Vast majority of microbial species have not been analyzed, because their growth is dependent upon a specific microenvironment • Human Microbiome Project is studying these communities at different sites on the body, including nasal passages, mouth, skin, GI tract and UG tract ( http://commonfund.nih.gov/hmp/)

3. Interaction of human and our commensural community • We have evolved in the context of complex communities • Microbes play an important part of an organism’s phenotype, beyond just symbiosis • We cannot separate our genes from the context of our microbes

4. Human microbiome • Provide a wide range of metabolic functions that humans lack • Microbes include bacteria, eukaryotes and viruses • DNA based studies to identify and understand the functions of the community

5. Human Microbiome, cont’d • Gut microbiota of humans is dissimilar between individuals • Populations of different countries are similar, with the US having fewer species of gut microbes

6. Gut flora • Consists of microorganisms that live in the digestive tracts • Largest reservoir of human flora • Estimated to have a hundred times as many genes as there are in the human genome • 300 and 1000 different species of bacteria • Fungi and protozoa make up part

7. Escherichia coli, one of the many species of bacteria present in our gut

8. Candida albicans, a fungus that grows as a yeast in the gut

9. Gut flora, cont’d • Commensal (non-harmful) but also mutualistic relationship. • Microbes perform a host of useful functions such as • Fermenting unused energy • Training the immune system • Preventing growth of pathogenic bacteria • Regulating the development of the gut • Producing vitamins, such as biotin and Vit K • Producing hormones to direct the hose to store fats

10. Diet and Gut Flora • Gut micro flora mainly composed of 3 enterotypes, are necessary for the the digestion of carbohydrates, animal proteins, and fats. • They will vary, depending on diet, and as your diet changes, their percentages will change

11. Gut flora in human infants • GI tract of human fetus is sterile • During birth and shortly thereafter, bacteria from the mother and the environment colonize the infant’s gut. • Immediately after vaginal delivery, babies may have bacterial strains derived from the mothers’ feces • Vaginally born infants take up to one month for their intestinal microflora to be well established; caesarian section babies may take 6 months

12. Functions of gut bacteria • Have enzymes that human cells lack for breaking down carbs, turning them into SCFAs • SCFAs increase growth of gut epithelial cells, and may increase growth of lymph tissue • Rats raised in sterile environment have to eat 30% more calories to remain the same weight

13. More functions • Repress microbial growth through the barrier effect • Harmful yeasts and bacteria like Clostridium difficile are unable to grow excessively due to competition from the helpful gut flora • Process of fermentation lowers the pH in colon, preventing proliferation of bad bacteria

14. Functions regarding Immunity • Bacteria promote early development of gut’s mucosal immune system • Stimulate lymph tissue to produce antibodies to pathogens • Immune system recognizes and fights harmful bacteria, but leaves the helpful species alone

15. More immune functions… • Play a role in “toll-like receptors” molecules that help repair damage due to injury, like radiation • Allow gut ability to discriminate between pathogenic and helpful bacteria • Activate inflammatory cytokines • Create oral tolerance, which help IS be less sensitive to antigen once its been ingested.

16. Help to prevent allergies • Children who have allergies have more harmful species of of bacteria, and lower helpful species • Since helpful gut flora stimulate the IS and train it to respond properly to antigens, lack of these bacteria leads to an inadequately trained IS.

17. Prevent IBS • Some bacteria can prevent inflammation • Disease linked to good hygiene in children, lack of breast feeding, consumption of large amounts of sucrose and animal fat and use of antibiotics in early life. • Inversely linked with poor sanitation in early years of life and consumption of fruits, veggies, and unprocessed foods.

18. Effects of antibiotics • Can alter the numbers of gut bacteria, which can reduce ability to digest • Can cause diarrhea by irritating the bowel directly, changing the levels of gut flora, and allowing pathogenic bacteria to grow • Creates antibiotic resistant bacteria in gut • Probiotics rely on a few strains of good bacteria;

19. Role in disease • Bacteria in digestive tract have pathogenic and health promoting roles • Can produce toxins and carcinogens • Bacteria have been related to sepsis and colon cancer, IBD, Crohn’s, Ulcerative Colitis • Balance is critical: harmful if numbers are too high or too low

20. Gut bacteria may affect arteries • Different mixes of gut microbes help determine whether people will have heart attacks or strokes brought on by plaque • HT disease patients carry fewer microbes that make anti-inflammatory and anti-oxidant compounds and more inflammation-producing bacteria (Dec 4 Nature Communications/Science News 1/12/2013,p 24))

21. Obesity • Obese mice lacking leptin have distinct gut flora population • Microbe colonies are different between obese and lean humans • Different species of flora have different energy reabsorbing potential…could lead to an increase in weight despite decrease in food

22. Role in disease, cont’d • Some bacteria are associated with tumor growth and others prevent tumors • Helpful bacteria can be harmful if they get outside of intestinal tract • Increased gut lining permeability can occur in “leaky gut syndrome”, or cirrhosis

23. Leaky Gut Syndrome • Means increased intestinal wall permeability • Just now being investigated; not recognized as a diagnosis • Hypothesized to be caused by increased permeability of the gut wall resulting from toxins, poor diet, parasites, infection or medications • Leaky gut allows toxins, microbes, indigested food, waste to leak through gut • Could cause immune reactions (rheumatoid arthritis, lupus, asthma, Type I diabeties, etc.)

24. T helper 17 cells • Recently discovered to play role in inflammatory process • Important anti-microbial barrier • Excessive amounts hypothesized to play role in autoimmune diseases such as MS, psoriasis, Type I diabetes, rheumatoid arthritis, Crohn’s • Autism spectrum disorders being investigated • Specific bacteria direct their differentiation in the mucosa of the gut

25. How does body differentiate good and bad • SI function of sorter, teaching IS to separate self from non-self • Oral tolerance:gut flora train innate IS to recognize self • If not “self” IL-12 in Peyer’s Patches inducing inflammation

26. Appendix • Immune tissue and antibodies are concentrated • Houses large numbers of bacteria in biofilms that offer services to our gut • Serves as an incubator, allowing for regeneration • When severe illness wipes out good bacteria, appendix can regenerate

27. Appendix, cont;d • Appendix in developed countries is infrequently challenged by pathogens and appendicitis is more common • In developing countries, humans get very sick from intestinal parasites • Perhaps appendix, through its role of replenishing the gut, is being kept healthy

28. Because nearly 70% of the immune system is localized to the digestive tract, a state of controlled physiologic inflammation,along with environmental contact with commensal bacteria, is essential for proper development of the immune system.

29. Fecal Transplants • Transplanting fecal matter directly into gut of someone suffering from a number of intestinal illnesses, including various inflammatory diseases, C Diff overpopulation, etc,has shown great promise • Still in experimental stage.

30. Bacteriophage • A virus that infects and replicates within bacteria, killing them. • Phages are all over - in soil, sea water, intestines, etc. • Use for over 90 years in the Eastern Europe against bacterial infections • Possible therapy against multi-drug resistant strains of bacteria.

31. Electron micrograph of phages attached to bacterial cell

32. Resources • “Integrative Gastroenterology”, by Gerard E. Mullin • “The Wild Life of our Bodies: Predators, Parasites, and Partners That Shape Who We Are Today”, by Rob Dunn • Ted.com “Meet Your Microbes” Jonathan Eisen, 2012”