The gut in critical Illness: A perspective in five acts

1. The Gut Hypothesis of Acute Illness:
A Subjective History in Five Acts
John C. Marshall MD FRCSC
CICM Annual Meeting
Sydney, Australia
May 26, 2017
University of TorontoSt. Michael’s Hospital

2. Dora Mavor Moore
1888 - 1979

3. Prologue:
The emergence of
multicellular organisms

4. Act 1: The Ancient Mediterranean
Ebers Papyrus
1550 BCEUkhedu

5. Asclepion
Of Kos
Hippocrates
460-370 BCE

6. Act 2 19th Century Europe
Louis Pasteur
1822 - 1895
Eli Metchnikoff
1845 - 1916

7. “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.”

8. Sir William
Arbuthnot Lane

10. Act 3 USA; mid-20th Century
Jacob Fine
“The intestinal factor in shock”

12. Mortality(Percent)
0
20
40
60
80
100
Control
Germ-free
Klebsiella M. S. aureus Endotoxin
tuberculosis
- J Exp Med 111:407, 1960

13. The indigenous flora – particularly anerobes
– protect against infection.

14. Endotoxin
(Lipopolysaccharide)

15. “The Gastrointestinal Tract:
The Motor of Multiple Organ Failure”
- Ann Surg 206:427, 1987
John Border
Jonathan Meakins
Act 4 North America 20thc.

16. Edwin Deitch
Bacterial Translocation
• Sepsis
• Trauma
• Endotoxemia
• Burns
• Liver injury
• Parenteral nutrition
• Altered flora
• Cardiac arrest
• Antibiotics
Carole Wells

17. Per cent of Patients Infected
0 10 20 30 40 50 60
MOFScore
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

18. 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

19. 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

20. Gut Flora Can
Modulate Systemic
Immunity
- J Surg Res 55:14, 1993

21. Selective Decontamination of the
Digestive Tract (SDD)
• Topical tobramycin, polymyxin, amphotericin B
• 3 – 4 days systemic cephalosporin

22. • Cluster RCT 100 centres; 25,000 patients
• Ecology study
• Cost-effectiveness study

23. 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

24. Oral Cavity:
700 species
Skin: 1000 species
Gastrointestinal
Tract:
5000 species

25. Impact of Indigenous Flora on
Intestinal Gene Expression
Zebrafish 212 genes
Rawls, PNAS 101:4596, 2004
Mouse 267 genes
Mutch, Physiol Genomics 2004

26. Promotion of Intestinal Angiogenesis by
B. thetaiotaomicron
- Stappenbeck, PNAS 99:15451, 2002

27. The Microbiome
in the
Pathogenesis of
Disease
--Nature 535:65, 2016

28. Dysbiosis of the Microbiome
in Sepsis
mSphere. 2016 Jul-Aug; 1(4): e00199-16

29. HIF-1α from Ischemic Gut
Induces the Virulence Factor
PA-I in Pseudomonas
- Patel, AJP Gastrointest Liver Physiol 292:G134, 2007

30. Probiotics Reduce Rates of VAP

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

32. “… 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

33. Epilogue:
Beyond the Microbiome

34. These our actors,
As I foretold you, were all spirits and
Are 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 dissolve
And, like this insubstantial pageant faded,
Leave not a rack behind. We are such stuff
As dreams are made on, and our little life
Is rounded with a sleep.
Thank you!!
The Tempest Act IV Scene i