The Gut-the incredible organ :

the story of Gut immunology

The normal sequence

1. Foods on the table 2. Mouth 3. Teeth 4. Oro-pharynx5. Mechanism of swallowing 6. Esophagus7. Stomach (cardia-fundus-body- antrum)8. pylorus

9. Duodenum (bulb, 2nd part, 3rd part, 4th part)10. Jejunum11. Ileum12. Colon13. Cecum-ascending-

transverse,descending,sigmoid,14. Rectum15. Anus16. Final defecation 17. Bathroom commode !

What happens when there are no foods in the stomach ?

1. No foods in the stomach, ( GI tract )2. No stimuli to the GI tract at all !3. Bacterial overgrowth 4. Gut bacteria engaging with gut epithelia (bacteria-

epithelium interaction )5. Proliferation of dendritic macrophages ,lymphocytes6. Release of IL -12 ( pro inflammation )7. Migration along lamina propria8. Gut epithelium programmed death ( apotosis )—death

of the epithelium cells9. Increased gut permeability !!!10. Bacteria translocation from gut into blood stream

7. Bacteria in the blood stream- very bad news !

8. Sepsis- septic shock9. Bacteria –gut epithelium encounter,

interaction 10.Macrophages, lymphocytes under the

gut epithelium11.Pro-inflammatory reaction !!!12.Cytokine (IL-9 )

13. Travel through lymphatic system up toward the thoracic duct

14. Into the blood circulation 15. Lymphocytes reach the lungs16. Immune lymphocytes, CD-4 encounter, & activation 17. Primed lymphocytes encounter another insults

(hypotension, hypoxemia )18. Cytokine shower !!! { bad news ! }19. Pulmonary capillary (blood )20. Alveoli (pulmonary )21. Alveoli membrane=very leaky 22. Leaky membrane syndrome

20.Edema, hemorrhage in the lung alveoli

21.Decreased oxygen saturation ( poor oxygen exchange between air-lung alveoli and hemoglobin in the blood )

22.Respiratory failure

23.ARDS ( adult respiratory distress syndrome ) !!!

The simple message

• No foods in the GI tract !!!

• Increased sepsis

• Increased septic shock

• ARDS (adult respiratory distress syndrome)

• Increased death rate !!!

Innate gut immune response

1. Gut disuse ( no foods in the GI tract )2. Gut bacteria 3. Gut bacteria- gut epithelium interaction 4. Bacteria, decreased blood flow,

ischemia-reperfusion start and activate !!!5. Gut macrophages- activated6. Gut neutrophils- be primed!!!7. Gut lymphocytes- activated, !!!

7. Driving forces:

8. Bacteria –gut epithelium interaction

9. Reduced blood flow ( hypotension, shock)

10. Ischemia –reperfusion

11. Increased gut permeability

12. { gut epithelium channels open !!! }

13. Activate gut macrophages, gut lymphocytes

14. Loss of functional and structural integrity

15.Channel between gut epithelia open !!!

16.Bacteria stick to gut epithelium cells

17.Gut macrophages ,and gut lymphocytes =become immune- active !

18.Gut epithelium programmed death ( apoptosis ) = within 3-5 hours

19.Time dependent phenomenon

20.Window of opportunity to rescue !!!

21.4-6 hr—burns patient

22.24-48 hr—pancreatitis patient

23.48-72 hr– after major elective surgery patient

When channels open !,mechanism

1. When the channels between epithelium open

2. Bacteria move across and walk toward the lungs ( bacteria translocation concept )

3. Bacteria do not have to go through the portal vein ! ( gut –portal vein-liver –systemic circulation)= no !!

4. Opening of the channels allows bacteria to engage macrophages and neutrophils at the surface of the gut

5. Cytokine and activated neutrophils released into lymphatic channels

6. Lymphatic systems carry them to distant sites ( lungs)

7. Immune system activation at the distant sites ( lungs, liver ,kidney )

8. Pro-inflammatory response ensues

9. Oxidative stress on the tissues (lungs, liver, kidney, heart )

10. “Oxidative burst “ at lungs, kidney, liver, heart

11.The leaky membrane syndrome

12.The multi organ failures (lungs, liver ,heart, kidney, sepsis )

Take home point

•When the gut goes down,

•It will pull other organs with it !!!

The gut

The lungsLiverHeart

KidneyCirculation

sepsis

T H 1 pathway

13.Helper 1 T lymphocytes pathway14. IL-12 release 15.Macrophages back to lamina propria16.CD-4 helper lymphocytes17.Cytokine shower !!!18.Pro-inflammatory reaction !!!19.Cells release 1) interferon , 2) tumor

necrosis factor !!! {bad news }

20.Spill over systemic circulation

What happens after you eat food?

1.TH-2 pathway start

TH-2 pathway

1. Foods in the GI tract

2. Shut down the TH-1 pathway !

3. Less inflammatory response

4. less