The Gut Hypothesis of Acute Illness:

A Subjective History in Five Acts

John C. Marshall MD FRCSCCICM Annual Meeting

Sydney, Australia May 26, 2017

University of TorontoSt. Michael’s Hospital

Dora Mavor Moore

1888 - 1979

Prologue:

The emergence of multicellular organisms

Act 1: The Ancient Mediterranean

Ebers Papyrus1550 BCEUkhedu

AsclepionOf Kos

Hippocrates 460-370 BCE

Act 2 19th Century Europe

Louis Pasteur1822 - 1895

Eli Metchnikoff1845 - 1916

“When faecal matter is allowed to remain in the intestine, certain products are absorbed by the organism, and produce poisoning….

While most microbes are confined within the walls of the alimentary canal, the soluble excretions produced by them pass through into the lymph and blood.”

Sir William Arbuthnot Lane

Act 3 USA; mid-20th Century

Jacob Fine

“The intestinal factor in shock”

Mo

rtality

(P

erc

en

t)

0

20

40

60

80

100Control

Germ-free

Klebsiella M. S. aureus Endotoxin

tuberculosis

- J Exp Med 111:407, 1960

The indigenous flora – particularly anerobes– protect against infection.

Endotoxin(Lipopolysaccharide)

“The Gastrointestinal Tract:

The Motor of Multiple Organ Failure”

- Ann Surg 206:427, 1987

John Border

Jonathan Meakins

Act 4 North America 20thc.

Edwin Deitch

Bacterial Translocation

• Sepsis• Trauma• Endotoxemia• Burns• Liver injury• Parenteral nutrition• Altered flora• Cardiac arrest• Antibiotics

Carole Wells

Per cent of Patients Infected

0 10 20 30 40 50 60

MO

F Sc

ore

1 - 2

3 - 4

5 - 8

9 - 16

Pseudomonas

Candida

S. epidermidis

0

Association of Organ Failure with Nosocomial Infection

- Marshall J Hosp Infect 19:7, 1991

Organism # Patients Mean CFU/ml

Candida 19 4.3 1.6

S. fecalis 12 6.8 0.8

Pseudomonas 10 6.9 1.1

S. epidermidis 10 5.7 1.6

E. coli 7 6.2 1.6

- Ann Surg 218:111, 1993

INFECTION RATE (%)Organism Colonized Not Colonized p.

Pseudomonas 90 19 <0.001

S. epidermidis 80 26 <0.01

Candida 79 36 <0.01

Enterococcus 50 38 N.S.

Proximal Gut Colonization and Systemic Infection

- Ann Surg 218:111, 1993

Gut Flora Can Modulate Systemic

Immunity

- J Surg Res 55:14, 1993

Selective Decontamination of the Digestive Tract (SDD)

• Topical tobramycin, polymyxin, amphotericin B

• 3 – 4 days systemic cephalosporin

• Cluster RCT 100 centres; 25,000 patients

• Ecology study

• Cost-effectiveness study

Act 5 Global 21st C. The Microbiome

The Global Biomass

• 560 Bn tons carbon

• Sub-sea floor 2.9 X 1029 organisms

• ?1 billion species

Oral Cavity:700 species

Skin: 1000 species

Gastrointestinal Tract:

5000 species

Impact of Indigenous Flora on

Intestinal Gene Expression

Zebrafish 212 genesRawls, PNAS 101:4596, 2004

Mouse 267 genesMutch, Physiol Genomics 2004

Promotion of Intestinal Angiogenesis by

B. thetaiotaomicron

- Stappenbeck, PNAS 99:15451, 2002

The Microbiomein the

Pathogenesis of Disease

--Nature 535:65, 2016

Dysbiosis of the Microbiome

in Sepsis

mSphere. 2016 Jul-Aug; 1(4): e00199-16

HIF-1α from Ischemic Gut

Induces the Virulence Factor

PA-I in Pseudomonas

- Patel, AJP Gastrointest Liver Physiol 292:G134, 2007

Probiotics Reduce Rates of VAP

- Crit Care. 2016 Oct 18;20(1):332

“… one of the most important changes

we can make is to supercede the 20th-century

metaphor of war for describing the

relationship between people and infectious

agents. A more ecologically informed

metaphor, which includes the germs’-eye view

of infection, might be more fruitful … they are

equally part of the superorganism genome

with which we engage the rest of the

biosphere.”

- Joshua Lederberg, Science 288:287, 2000

Epilogue:

Beyond the Microbiome

These our actors,As I foretold you, were all spirits andAre melted into air, into thin air:And, like the baseless fabric of this vision,The cloud-capp'd towers, the gorgeous palaces,The solemn temples, the great globe itself,Ye all which it inherit, shall dissolveAnd, like this insubstantial pageant faded,Leave not a rack behind. We are such stuffAs dreams are made on, and our little lifeIs rounded with a sleep.

Thank you!!The Tempest Act IV Scene i