2. The Gut- the incredible organ : the story of Gut immunology

3. The normal sequence 1.Foods on the table 2.Mouth 3.Teeth 4.Oro-pharynx 5.Mechanism of swallowing 6.Esophagus 7.Stomach (cardia-fundus-body- antrum) 8.pylorus

4. 9.Duodenum (bulb, 2 nd part, 3 rd part, 4 th part) 10.Jejunum 11.Ileum 12.Colon 13.Cecum-ascending- transverse,descending,sigmoid, 14.Rectum 15.Anus 16.Final defecation 17.Bathroom commode !

5. 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,lymphocytes 6.Release of IL -12 ( pro inflammation ) 7.Migration along lamina propria 8.Gut epithelium programmed death ( apotosis )—death of the epithelium cells 9.Increased gut permeability !!! 10.Bacteria translocation from gut into blood stream

6. 7.Bacteria in the blood stream- very bad news ! 8.Sepsis- septic shock 9.Bacteria –gut epithelium encounter, interaction 10.Macrophages, lymphocytes under the gut epithelium 11.Pro-inflammatory reaction !!! 12.Cytokine (IL-9 )

7. 13.Travel through lymphatic system up toward the thoracic duct 14.Into the blood circulation 15.Lymphocytes reach the lungs 16.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

8. 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 ) !!!

9. The simple message No foods in the GI tract !!! Increased sepsis Increased septic shock ARDS (adult respiratory distress syndrome) Increased death rate !!!

10. 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- activated 6.Gut neutrophils- be primed!!! 7.Gut lymphocytes- activated, !!!

11. 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

12. 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

13. 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

14. 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 !!

15. 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 )

16. 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 )

17. Take home point When the gut goes down, It will pull other organs with it !!!

18. The gut The lungs Liver Heart Kidney Circulation sepsis

19. T H 1 pathway 13.Helper 1 T lymphocytes pathway 14.IL-12 release 15.Macrophages back to lamina propria 16.CD-4 helper lymphocytes 17.Cytokine shower !!! 18.Pro-inflammatory reaction !!! 19.Cells release 1) interferon, 2) tumor necrosis factor !!! {bad news }

20. 20.Spill over systemic circulation

21. What happens after you eat food? 1.TH-2 pathway start

22. TH-2 pathway 1.Foods in the GI tract 2.Shut down the TH-1 pathway ! 3.Less inflammatory response 4.less