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 (

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
A phenotype (from Greek phainein, 'to show' + typos, 'type') is the composite of an organism's observable characteristics or traits, such as its morphology, development, biochemical or physiological properties, phenology, behavior, and products of behavior (such as a bird's nest). Phenotypes result from the expression of an organism's genes as well as the influence of environmental factors and the interactions between the two.

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
A eukaryote - ew-KARR-ee-ot - is an organism whose cells contain complex structures enclosed within membraines. They have a nucleus, within which the genens. Most contain other membrane bound ogranelles such as mitochondria, chloroplasts and the Gogi apparatus. All largw complex organisms are eukaryotes, and so are unicellular organisms.
Bacterial cells are prokaryotes and do not contain a nucleus.

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
An enterotype is a classification of living organisms based on its bacteriological ecosystem in the gut microbiome. The discovery of three human enterotypes was announced in the April 2011 issue of Nature by Peer Bork and his associates. They found that enterotypes are not dictated by age, gender, body weight, or national divisions

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
Carbohydrates that humans cannot digest without bacterial help include certain starches, fiber, oligosaccharides and sugars that the body failed to digest and absorb[2][10][11] like lactose in the case of lactose intolerance and sugar alcohols, mucus produced by the gut, and proteins.[10] A further result is flatulence, specifically due to the metabolism of oligosaccharides (notably from beans) by many different species.
SCFA - short chain fatty acid

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;
Changing the numbers and species of gut flora can reduce the body's ability to ferment carbohydrates and metabolize bile acids and may cause diarrhea. Carbohydrates that are not broken down may absorb too much water and cause runny stools, or lack of SCFAs produced by gut flora could cause the diarrhea.[11]
A reduction in levels of native bacterial species also disrupts their ability to inhibit the growth of harmful species such as C. difficile and Salmonella kedougou, and these species can get out of hand, though their overgrowth may be incidental and not be the true cause of diarrhea.[2][11][33] Emerging treatment protocols for C. difficile infections involve fecal microbiota transplantation of donor feces. Initial reports of treatment describe success rates of 90%, with few side effects. Efficacy is speculated to result from restoring bacterial balances of bactericides and firmicutes classes of bacteria.[34]
Gut flora composition also changes in severe illnesses, due not only to antibiotic use but also to such factors as ischemia of the gut, failure to eat, and immune compromise. Negative effects from this have led to interest in selective digestive tract decontamination (SDD), a treatment to kill only pathogenic bacteria and allow the re-establishment of healthy ones.[35]

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.)
Abstract
Epidemiology suggests some relationship between the establishment of the gut flora and the risk of developing inflammatory bowel disease. Unrestrained activation of the immune system against commensal bacteria appears to be responsible for the chronicity of these diseases. In animal models, broad-spectrum antibiotics reduce the bacterial load and militate against intestinal inflammation. Several bacterial species found in of the common microflora, including anaerobes, are able to invade the colonic wall when there is dysfunction of the colonic mucosal barrier. Most aerobes provoke focal areas of acute inflammation, but some anaerobes in the predominant flora induce diffuse a fibrogenic transmural response. Current research aims to identify the probiotics that might act against these bacteria. Colonization with specific probiotic strains, including a bacterium genetically engineered to secrete interleukin-10, prevents spontaneous colitis in susceptible mice. Certain lactobacilli exhibit anti-inflammatory properties naturally, i.e. without previous genetic manipulation. Prebiotics may increase colonization by lactobacilli and can prevent mucosal inflammation. Modulation of the gut flora with probiotics may prove useful in the prevention and control of inflammatory bowel diseases.
Best Practice & Research Clinical Gastroenterology
Volume 17, Issue 5 , Pages , October 2003
Role of bacteria in experimental colitis
Francisco Guarner, MD, PhD (Consultant in Gastroenterology) address ,
Juan-R Malagelada, MD, PhD, MRCP (Professor in Medicine and Head of Unit)

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
In adults, Martin argues that the appendix acts as a lymphatic organ. The appendix is experimentally verified as being rich in infection-fighting lymphoid cells, suggesting that it might play a role in the immune system. Zahir suggests that it plays a role in both manufacturing hormones in fetal development as well as functioning to "train" the immune system, exposing the body to antigens so that it can produce antibodies. He notes that doctors in the last decade have stopped removing the appendix during other surgical procedures as a routine precaution, because it can be successfully transplanted into the urinary tract to rebuild a sphincter muscle and reconstruct a functional bladder
Although it was long accepted that the immune tissue, called gut associated lymphoid tissue, surrounding the appendix and elsewhere in the gut carries out a number of important functions, explanations were lacking for the distinctive shape of the appendix and its apparent lack of importance as judged by an absence of side effects following appendectomy.[9]
William Parker, Randy Bollinger, and colleagues at Duke University proposed that the appendix serves as a haven for useful bacteria when illness flushes those bacteria from the rest of the intestines. his proposal is based on a new understanding of how the immune system supports the growth of beneficial intestinal bacteriain combination with many well-known features of the appendix, including its architecture, its location just below the normal one-way flow of food and germs in the large intestine, and its association with copious amounts of immune tissue. Research performed at Winthrop University-Hospital showed that individuals without an appendix were four times more likely to have a recurrence of Clostridium difficile. However, other research showed that there is a significantly greater rate of C. difficile infection among people with an appendix, with more than 80% of the infections occurring among patients with an intact appendix

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”