The Forgotten Organ: Why Our Guts Biome is Reversing the ‘Germ Theory’ Domination of Medicine, and Why its Relevant For NCDs.

Are we organisms or living ecosystems?Michael Ash DO, ND, BSc, RNTDisorders of ‘supraorganism’ function underlie the aetiology of many modern non-communicable diseases

GOOD BAD

“the only good bug is

a dead bug”

Petrof EO, Claud EC, Gloor GB, Allen-Vercoe E. Microbial ecosystems therapeutics: a new paradigm in medicine? Benef Microbes. 2013 Mar 1;4(1):53-65

A more holistic understanding of what constitutes gut health

will ultimately guide future approaches to correcting gut

dysbiosis and the answer surely lies in the consideration of the

entire microbial ecosystem rather than its individual

components.

"a relationship of non-acute non-infectious host-microorganism interaction that adversely affects the human host.“ …A. Vasquez

The

Knowledge

SHIFT

..much of the research on infectious diseases continues to be dominated by reductionist approaches; one variable is altered while all others are assumed to

hold constant. Microbiologists tend to view the

microbe as the key variable in disease and treat the host as a constant. Immunologists generally see the

microbe as a constant and the host response as the variable

Casadevall A, Pirofski LA. Microbiology: Ditch the term pathogen. Nature. 2014 Dec 11;516(7530):165-6

This term should take in not just microbes, but the wider 'exposome' and recent discoveries in infection and immunity research

A term is needed that encompasses sequences from the environment — intrinsic or extrinsic — that impart pathogenic or benign information to eukaryotic immune receptors.

‘PERCEPTOGEN’ (microbial or environmental) to cover protein sequences that affect the body's range of reactions after perception by its immune receptors.

Altmann D, Boyton R. Nomenclature: Replace 'pathogens' with 'perceptogens'. Nature. 2015 Feb 5;518(7537):35

Louis Pasteur1861

Robert KochPostulates

1875

1667 Antoni van LeeuwenhoekMotile microorganisms

Elie Metchnikoff 1908LAB

Turnbaugh 2007Metagenomics 16S rDNA

Pro bioticsPre biotics

Faecal Transplants

Carl BensussanImmune Maturation

Inflammation

Germ Theory CommensalsPathobionts

> 75% Die from NCD

Infectious medicine

1% of Bacteria cause human

diseasemillions a year still

die from them

Tolerance & Health

The healthy IM cannot be defined as an absolute entity anymore, but it needs to be reconsidered as a dynamic factor, with its own degree of ability to change over time preserving the individual homeostasis through the human lifespan and in response to a changing environment.

Candela M, Biagi E, Turroni S, Maccaferri S, Figini P, Brigidi P. Dynamic efficiency of the human intestinal microbiota. Crit Rev Microbiol. 2015 Jun;41(2):165-71

Humans are eco systems

Over the past 50 years, humans have changed ecosystems more rapidly and extensively than in any comparable period of time in human history, largely to meet rapidly growing demands for food, fresh water, timber, fibre, and fuel. This has resulted in a substantial and largely irreversible loss in the diversity of life on Earth

50

Moya A, Ferrer M. Functional Redundancy-Induced Stability of Gut Microbiota Subjected to Disturbance. Trends Microbiol. 2016 May;24(5):402-13.

Gut microbial community development is an example of ecological succession, starting when the embryonic

intestinal organ is developing in the uterus. We can apply Waddington's notion of an epigenetic landscape,

and consider the ecological dynamics of the gut microbiota in a similar way to the development of any

other human organ presenting phenotypic changes from ontogeny until death.

Stability/Resistance, Resilience, Functional Redundancy, & Dysbiosis of gut microbiotas are exemplified in Waddington's epigenetic landscape

Microbiome Phytobiome

The microbiota should be considered as just another component of the human epigenetic landscape. Thus, health is also a reflection of the diversity and composition of gut microbiota and its metabolic status

The phytobiome should be considered as just another component of the human epigenetic landscape. Thus, health is also a reflection of the diversity and composition of soil microbiota and its metabolic status

PolyphenolsAHR LigandsMineralsVitamins

Night Soil Soil Life

“The Nation that destroys its soils destroys itself” – Franklin D Roosevelt

Zhernakova A, et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science. 2016 Apr 29;352(6285):565-9

Are they asking the

right questions?

the set of observable characteristics of an individual resulting from the interaction of its genotype with the environment.

MetabolomicsSystems level Dx

Deep sequencing of the gut microbiomes of 1135 participants from a Dutch population-based cohort shows relations between the microbiome and 126 exogenous and intrinsic host factors, including 31 intrinsic factors, 12 diseases, 19 drug groups, 4 smoking categories, and 60 dietary factors.

It is becoming increasingly apparent that our diet, gut microbiota and health are

inextricably linked. We must be conscious that, when we make dietary interventions,

we affect the growth of trillions of bacteria.

Chu DM, Aagaard KM. Microbiome: Eating for trillions. Nature. 2016 Apr 21;532(7599):316-7.

DiversityComposition

FunctionPathobionts

High DiversityRedundancyStability Diversity

Faecalibacteriumprausnitzii

Key Stone Compensatory SCFA Production

Diet, Xenobiotics

Loss of ResilienceFunction

Immune,Metabolomic

Regulation

Increase in Enterobacteriacea

Host

IgA Coating

Eubiosis

Dysbiosis

Microbiota Influencing Factors

ExternalDietDrugsMode of BirthEnvironmentGeography

InternalInflammationGenesDefensinsMicrobe-MicrobeMetabolites

mic

rob

iota

Human metabolic phenotypes, and multiple disease processes, are highly dependent on gut-microbial activity.

……depends on the ability of the microbiota to react and return to the pre-disturbed state, that is, one in which the microbiota is considered stable. This notion of Stability, however, must be considered from both the standpoint of Composition (Diversity), Redundancy and Function.

Resolution of Dysbiosis

Pathologies or More

The concept of the mammalian ‘supraorganism’, with the gut microbiota

collectively acting as a major virtual organ that augments host metabolism and

physiology, has resulted in a paradigm shift in understanding human biology and

medicine

Holmes E, Li JV, Marchesi JR, Nicholson JK. Gut microbiota composition and activity in relation to host metabolic phenotype and disease risk. Cell Metab. 2012 Nov 7;16(5):559-64

‘Metabotypes’ vary extensively between individuals and populations, and result from the complex interplay between host

genes, lifestyle, diet and gut microbes.

Complex CHo(MAC)

Phytonutrients

Refined CHoPhytonutrients

Beneficial OrganismsPathobiontsPathogens

Beneficial OrganismsPathobiontsPathogens

Gut Bacterial Diversity

Post Prandial Glucose

Response

T2D Risk

Microbiota-Accessible Carbohydrates

Vanamala JK, Knight R, Spector TD. Can Your Microbiome Tell You What to Eat? Cell Metab. 2015 Dec 1;22(6):960-1.

Demonstrate that the gut microbiota can be used to predict individualised blood glucose responses to particular foods, which differ between individuals.

> Polyp

hen

olic co

nten

t

Bottom-up approaches emphasising microbiota-derived metabolites -Metabolomics data can complement data derived from standard taxonomic approaches (e.g. 16S sequencing).

Moya A, Ferrer M. Functional Redundancy-Induced Stability of Gut Microbiota Subjected to Disturbance. Trends Microbiol. 2016 May;24(5):402-13.

Engaging patients to change behaviour will be easier if we give them more of what they want…….

“

That means effective, early, functional assessments/interventions (nutrition and lifestyle) with less reliance on historical notions of the absence of disease being the arbiter of health….

‘Better health’ rather than more health services.

Pharmaco/nutri-metabonomic approaches

Thank you for your attention