The forgotten organ Gut-derived sepsis and its pathophysiology

1. The “Forgotten Organ”
GUT-DERIVED SEPSIS AND ITS PATHOPHYSIOLOGY:
WHAT DO WE KNOW SO FAR?
NG ZEE YONG – NUMED, 16/02/2015 – 27/03/2015

2. What has been forgotten?
GUT
1. Up to 50% of patients in ICU who were septic had
no obvious infection but a “hidden” infection in
the abdomen. [1]
2. Gut failure in critically-ill patients is often occult
and difficult to classify by degree.
3. Absence of a consensus definition of GI failure
Gut failure left untreated, increasing risk of gut-
derived sepsis.

3. History
 1949, Schweinburg et al found live enteric bacteria in the peritoneal
washings of dogs after haemorrhagic shock [2]
 1954, Fine et al proved intestinal bacteria crossed mucosal wall after major
trauma and shock [3]
 1977, Polk et al found that intra-abdominal infection can lead to remote
organ failure [4]
 1979, the phenomenon of bacteria crosses intestinal wall was termed as
“Bacterial Translocation” by Berg and Garlington. [5]

4. Bacterial Translocation
The process whereby viable bacteria or other antigenic macromolecules (eg.
lipopolysaccharide and peptidoglycan) which normally reside within the GI
lumen, spread through the intestinal mucosa barrier into to extra-intestinal
sites, (such as the mesenteric lymph node complex (MLN), liver, spleen,
kidney, and bloodstream), where they may either cause infection or activate
the immune system leading to organ damage and failure

5. Sepsis, SIRS, ARDS, MODS
Overview

6. Critical illness
Visceral hypoperfusion
Gut mucosal ischaemia and barrier
disrupted
Increased mucosa permeability
Intestinal bacteria and endotoxins
enter systemic circulation
Secretion of chemokines/cytokines
Sepsis, SIRS, ARDS, MODS
(Bacterial Translocation)
(Pro-inflammatory
response)

7. Three hit model
Critical illness
Loss gut barrier integrity
Ischaemia-reperfusion injury
Visceral hypoperfusion
Intestinal bacteria and endotoxins
enter systemic circulation
Secretion of chemokines/cytokines
Sepsis, SIRS, ARDS, MODS
1st hit
2nd hit
3rd hit
Release of inflammatory mediators from
gut-associated lymphoid tissues
Inflammatory response augmented

8. “Gut-lymph” Theory
Bacteria translocation
Immune cells and mesenteric lymph nodes
trap translocation bacteria
Surviving bacteria, cell wall fragments, pro-
inflammatory mediators travels along
mesenteric lymphatics
Cisterna chyli
Thoracic duct
Left subclavian vein
Pulmonary circulation
Systemic circulation MODS
Acute lung injury or
ARDS

9. Pancreatic enzymes are released into the gut
Stimulates ischaemic gut to release in vivo
activators
Endothelial cells and leukocytes in the
circulation are activated
Production of oxygen
free radicals
Initiation of adhesion
cascade
Accumulation of
leukocytes in distant
organs
Cytotoxicity, cell apoptosis, organ dysfunction
In 2000, Schmid-Schonbein et al proposed…
*Identification of specific pancreatic enzymes constituting activators is still under research

10. In 2000, Jackson et al proposed…
Release of lipopolysaccharide (LPS) / endotoxins
LPS is taken up by liver from blood
Stimulates Kupffer cells production of TNF-a
Secretion of TNF-a into bile and delivery to duodenum
Intestinal damage and disruption of gut mucosal integrity
Systemic inflammatory response syndrome

11. In 2005, Luyer et al proposed…
Dietary fat is administered
Stimulates cholecystokinin (CCK) release by duodenum
CCK binds to CCK-2 receptors of the afferent vagal nerve
Stimulates vagal nerve to secrete acetylcholine
Acetylcholine binds to inflammatory cells
Pro-inflammatory cytokine secretion is suppressed
*The protective effect of dietary fat on intestinal permeability is abolished by vagotomy
Further damage to gut is prevented
Cholinergic anti-inflammatory pathway

12. Summary
 Gut plays an important roles in the development of sepsis and multi-organ
dysfunction syndrome.
 Gut failure is often occult and missed due to
• lack of awareness and more focus is given to other organ systems
• Absence of consensus definition
 Since the first discovery of bacterial translocation in 1949, we are still
researching the cause/causes of gut-derived sepsis.
 Gut-derived sepsis is not independently caused by bacterial translocation,
it is a multi-factorial condition.

13. Reference
1. Fry DE, Pearlstein L, Fulton RL, Polk HC Jr. Multiple system organ failure. The role of uncontrolled infection.
Arch Surg 1980;115:136-140.
2. Schweinburg FB, Frank HA, Frank ED, Heimberg F, Fine J. Transmural migration of intestinal bacteria during
peritoneal irrigation in uremic dogs. Proc Soc Exp Biol Med 1949;71:150-153.
3. Fine J. The bacterial factor in traumatic shock. Springfield, IL: Charles C. Thomas Publisher, 1954
4. Polk HC, Shields CL. Remote organ failure: a valid sign of occult intra-abdominal infection. Surgery
1977;81:310-313.
5. Berg RD, Garlington AW. Translocation of certain indigenous bacteria from the gastrointestinal tract to the
mesenteric lymph nodes and other organs in a gnotobiotic mouse model. Infect Immun 1979;23:403-411.
6. Deitch EA Bacterial translocation or lymphatic drainage of toxic products from the gut: what is important in
human beings? Surgery 2002;131:241-244.
7. Deitch EA. Gut-origin sepsis: evolution of a concept.
Surgeon 2012;10:350-356.
8. Mitsuoka H, Kistler EB, Schmid-Schonbein GW. Generation of in vivo activating factors in the ischemic
intestine by pancreatic enzymes. Proc Natl Acad Sci U S A 2000;97:1772-1777.
9. Jackson GD, Dai Y, Sewell WA. Bile mediates intestinal pathology in endotoxemia in rats. Infect Immun
2000;68:4714-4719.
10. Luyer MD, Greve JW, Hadfoune M, Jacobs JA, Dejong CH, Buurman WA. Nutritional stimulation of
cholecystokinin receptors inhibits inflammation via the vagus nerve. J Exp Med 2005;202:1023-1029