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Microbiome

A new dimension in Medicine

Israel De Alba, MD MPH

Clinical Professor

AIM

• To look at ordinary things from a different perspective….to jump start curiosity

• Reason to have lunch……

We know so much about the human body, yet we know so little

The unexplained is the path to truth

• Recent stories that prove that medicine is an unfinished product

– Appendix

– The interstitium

– Microbiome

Appendix: what is if for?

• 2012 study: individuals without an appendix were 4X more likely to have a recurrence of Clostridium difficile colitis

• Important role in immune system, particularly as lymphatic tissue is known

to stimulate the growth of certain types of beneficial gut bacteria.

• Colorectal cancer incidence was 14% higher in the appendectomy patients

• Functions: repopulate intestinal flora, mediate immune tolerance to favorable bacteria

A new organ?

New Organ!?!?

Role

• Reservoir and transportation system for nutrients and solutes distributing among organs, cells, and capillaries

• Way for signaling molecules communicating between cells, and for antigens and cytokines participating in immune regulation.

• Spread of infectious agents, cancer (melanoma)

New Organ!?!?

or·gan ˈôrɡən/ Part of an organism that is typically self-contained and has a specific vital function, such as the heart or liver in humans. Interstitium: layer of fluid-filled compartments strung together in a web of collagen and a flexible protein called elastin. NYU: been hidden in plain sight because of the way tissue is studied.

The discovery of the microbiome has changed how we see ourselves, very much like when we discovered that

the Earth was not the center of the universe.

Microbiome 101

• Microbiome is the genetic material of all the microbes, e.g. bacteria, fungi, protozoa and viruses

• Co-evolved for millennia, involved in: – digestion and nutrition – detoxification and body defense – maturation of the host immune system – disease mediation

• Microbiome can be found throughout the human body, ranging from the skin to the

gut, and to previously considered as sterile environments such as the blood in circulation

• Over 10,000 microbial species have been shown to occupy various parts of the human body

Microbiome 101

• “Normal” gut microbiota in healthy persons include such pathogenic strains as E. coli and Enterococci – but as of yet, there is no clear distinction of which are the good versus the bad bacteria

• The gut microbiome of Americans and most other Westernized, industrialized populations is less diverse and dominated by different bacterial species than that of people from rural, less developed populations.

• Diet plays a role, but a general shift away from natural environments with little exposure to soil, animals, and other environmental microbes seems to be impacting the gut microbiome in potentially detrimental ways.

• Many new links of known conditions to the microbiome

• Human cells in humans are outnumbered 10 to 1

• Human genes are outnumbered 100 to 1

• All microbes together weigh as much as 4 pounds, about the same as the human brain

Microbiome: huge, diverse, dynamic

Microbiome: huge, diverse, dynamic

Role of Microbiota

• Although microbial genomes are much smaller than that of the host, the microbiota has a potentially greater metabolic capability in total

• Metabolic activities are carried out jointly, with contributions from both microbes and the host.

• Signaling between the host and indigenous microbiota can alter the structure and function of both partners in this symbiosis.

Mechanisms

• Metabolic activities: catabolism, bioconversion of complex molecules, synthesis of a wide range of compounds that can have effects on both the microbiota and the host.

• Microbial metabolism can affect the bioavailability of certain oral drugs, as has been shown for the cardiac glycoside digoxin, digoxin, etc

• Indigenous microbiota can modify epithelial responses and systemic responses, such as the development and activity of the immune system. Potential role in autoimmune conditions, inflammatory bowel disease, etc.

Mechanisms

• A final global function that has been attributed to the indigenous microbiota is that of colonization resistance, where the presence of the microbiota protects the host from colonization by and disease from potentially pathogenic microbes

• Gut bacteria are involved in manufacturing neurotransmitters such as serotonin, enzymes and vitamins like vitamin K and are involved with immune and metabolic functions.

• Trophic Control of epithelial cell proliferation and differentiation; development and homoeostasis of the immune system

• Protective Protection against pathogens (the barrier effect)

What does it mean to be human?

• Most of the cells in our body are not human

• Most of the genes in our body are not human

• The microbiome is integrated in our molecular signaling, metabolism, gene expression, behavior, etc. Some of our gears are not ours.

• The immune system definition of “self” involves not only human cells but bacteria, fungi, viruses and other “bugs” that are recognized as part of us.

• Humans are not organisms but ecological communities

Humans are not organisms but ecological communities

[From mitochondria and bacterial genes to IBS and depression]

Bugs are not passengers but part of the engine

The discovery of the microbiome has changed how we see ourselves, very much like when we discovered that the Earth

was not the center of the universe.

The masterpiece of God’s creation is part bacteria

The microbiome has also chanced our relationship to bacteria

Germ Theory

• Proposed by Girolamo Fracastoro in 1546

• Miasma: cholera and Black Death were caused by a noxious form of "bad air" emanating from rotting organic matter

• Quickly led to the identification of the actual organisms that cause many diseases

• Viruses were discovered in the 1890s.

• Pasteur discovered the pathology of the puerperal fever and the pyogenic vibrio in the blood, and suggested using boric acid to kill these microorganisms

• Era of sanitation: bacteria, viruses and other were “the enemy”

• The role of “extreme” hygiene, antibiotics in disease.

Koch's postulates

• The bacteria must be present in every case of the disease.

• The bacteria must be isolated from the host with the disease and grown in pure culture.

• The specific disease must be reproduced when a pure culture of the bacteria is inoculated into a healthy susceptible host.

Microbiota in human disease

Obesity

C. Diff

• C. diff incidence increasing

• Role of probiotics

• Role of stool transplant

IBD

• The microbiome itself is thought to be pathogenic and in predisposed hosts contributes to the development of the dysregulated inflammatory response

• Patients with a diagnosis of Crohn’s disease known to carry the NOD2 mutation have an increased population of mucosa-adherent bacteria, in particular Escherichia coli.

• Positive correlation between Crohn’s disease and Pasteurellacae (Haemophilus sp.), Veillonella parvula, Neisseriacaea corrodens, and Fusobacteriaceae nucleatum

• Fusobacteriaceae nucleatum (which has been implicated in promoting a microenvironment beneficial toward progression of colorectal carcinoma

Fatty Liver

• The underlying pathogenesis of NAFLD/NASH remains unclear; however, alterations in gut microbiota are thought to be a major contributor in its development

• Metabolism by colonic bacteria produces volatile organic compounds that may have deleterious effects on the liver

Cardiovascular disease

• High levels of TMAO (trimethylamine

oxide) in blood increase risk of major adverse cardiovascular events

• TMAO in the blood increases after consuming foods containing carnitine (eggs, red meat)

• Gut bacteria (e.g. species

of Acinetobacter) in the human microbiome convert dietary carnitine to TMAO

• TMAO alters cholesterol metabolism in the intestines, in the liver, and in artery walls.

• Balsamic vinegars, red wines, and some cold-pressed extra virgin olive oils and grape seed oils decrease TMAO

Gut microbiota and possible molecular pathways linked to cardiovascular and

cardiometabolic diseases.

W.H. Wilson Tang et al. Circ Res. 2017;120:1183-1196

Copyright © American Heart Association, Inc. All rights reserved.

Others

• Studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic bacteria or antibiotic drugs suggest a role for the gut microbiota in the regulation of anxiety, mood, cognition and pain

• Acne • Antibiotic-associated diarrhea • Asthma/allergies • Autism • Autoimmune diseases • Cancer: GI tract, prostate • Dental cavities • Depression and anxiety • Diabetes • Eczema • Gastric ulcers • Hardening of the arteries • Inflammatory bowel diseases • Malnutrition • Obesity

Therapeutic Interventions

Love…..bugs are the best medicine!.......??

• Fecal transplantation

• Prebiotics and probiotics

• Antibiotics

• Phage therapy

Potential Interventions

• Potential therapeutic intervention through manipulation of microbiome

• Preventive medicine intervention by early identification of “abnormal” microbiome profile

• Diagnosis potential by analysis of symptoms and microbiome profile

What does it mean to be human?

• Most of the cells in our body are not human

• Most of the genes in our body are not human

• The microbiome is integrated in our molecular signaling, metabolism, gene expression, behavior, etc. Some of our vital gears are not ours.

• The immune system definition of “self” involves not only human cells but bacteria, fungi, viruses and other “bugs” that are recognized as part of us.

• Humans are not organisms but ecological communities