The human microbiome

“The Forgotten Organ”

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 microenvironmentHuman 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/)

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

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

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

Gut flora

Consists of microorganisms that live in the digestive tractsLargest reservoir of human floraEstimated to have a hundred times as many genes as there are in the human genome300 and 1000 different species of bacteriaFungi and protozoa make up part

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

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

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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 systemPreventing growth of pathogenic bacteriaRegulating the development of the gutProducing vitamins, such as biotin and Vit KProducing hormones to direct the hose to store fats

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

Gut flora in human infants

GI tract of human fetus is sterileDuring 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’ fecesVaginally born infants take up to one month for their intestinal microflora to be well established; caesarian section babies may take 6 months

Functions of gut bacteria

Have enzymes that human cells lack for breaking down carbs, turning them into SCFAsSCFAs increase growth of gut epithelial cells, and may increase growth of lymph tissueRats raised in sterile environment have to eat 30% more calories to remain the same weight

More functions

Repress microbial growth through the barrier effectHarmful 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

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

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.

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.

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.

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;

Role in disease

Bacteria in digestive tract have pathogenic and health promoting rolesCan produce toxins and carcinogensBacteria have been related to sepsis and colon cancer, IBD, Crohn’s, Ulcerative ColitisBalance is critical: harmful if numbers are too high or too low

Gut bacteria may affect arteries

Different mixes of gut microbes help determine whether people will have heart attacks or strokes brought on by plaqueHT 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))

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

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

Leaky Gut Syndrome

Means increased intestinal wall permeabilityJust now being investigated; not recognized as a diagnosisHypothesized to be caused by increased permeability of the gut wall resulting from toxins, poor diet, parasites, infection or medicationsLeaky gut allows toxins, microbes, indigested food, waste to leak through gutCould cause immune reactions (rheumatoid arthritis, lupus, asthma, Type I diabeties, etc.)

T helper 17 cells

Recently discovered to play role in inflammatory processImportant anti-microbial barrier Excessive amounts hypothesized to play role in autoimmune diseases such as MS, psoriasis, Type I diabetes, rheumatoid arthritis, Crohn’sAutism spectrum disorders being investigatedSpecific bacteria direct their differentiation in the mucosa of the gut

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

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

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

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.

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.

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.

Electron micrograph of phages attached to bacterial cell

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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”