1. The Gut- the incredible organ : the story of Gut immunology Yoshinobu Namihira MD, FACG 300 Halls Ferry road Vicksburg, MS 39180 Ph 601-638-9800, fax 601-638-9808 E mail: namihira @ vicksburg.com

5. Acute pancreatitis

6. The existing problem: The patient can not keep the foods in the stomach because of severe ongoing abdominal pains

7. The important clinical question Should I feed or not feed the patient with acute pancreatitis with jejunal tube placement (small bowel ) ?

8. Do I keep on giving Total parenteral nutrition ( TPN) ? All the nutritions by IV route (carbohydrates, proteins, fats,vitamins, trace minerals) No foods go through GI tract. “GI tract is put to rest “= is it right thing to do? Am I doing favor to GI system ? or am I doing disservice or harm to the whole body?

9. What is the correct answer to the question at hand?

10. Use it or Lose it

11. The normal sequence of degestion(1) 1.Foods on the table 2.Mouth 3.Teeth 4.Oro-pharynx 5.Mechanism of swallowing –complex, miracle of God’s wisdom 6.Esophagus 7.Stomach (cardia-fundus-body- antrum) 8.pylorus

13. Teeth 16 at the top 8 on the right, 8 the left 16 at the bottom 8 on the right, 8 on the left 32 total

15. Pyloric opening 5mm=1/4 inch

17. The normal sequence of degestion(2) 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.Anal sphincters –internal, external 17.Final defecation 18.Bathroom commode !

18. Acute pancreatitis Can not keep foods in the stomach How do I keep the patient alive ? Do I give foods by IV route? Do I give foods by small bowel tube Placement ?

20. 8.Stanga Z et al: Effect of jejunal long term feeding in chronic pancreatitis.JPEN J Parenter Enteral Nutr 29:12,2005 9.Taylor SJ et al: Prospective randomized,controlled trial to determine the effect of early enhanced enteral nutrition on clinical outcome in mechanically ventilated patients suffering head injury. Crit Care Med 27:2527,1999

21. The old concept of “gut rest “ The time of acute pancreatitis =do not feed The gut is passive tube, that is it ! Stress gastropathy = stomach need rest ? GI bleeding = need rest ? ileus ( abdominal distention ) = no feeding at all ? The Old thinking= the GI tract is previously considered as “ organ of inconvenience “ You have to go to bathroom for bowel movements !

22. 6.McClave SA et al: Enteral tube feeding in the intensive care unit :factors impeding adequate delivery. Crit Care Med 27:1252.1999 7.McClave SA et al: Nutrition management in actue and chronic pancreatitis. Gastroenterology Clin North Am 27:421,1998

23. 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{interleukin } ( 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

24. 1.Gut epithelium programmed death ( apotosis ) —death of the epithelium cells 2.Increased gut permeability !!! 3.Bacteria translocation from gut into blood stream

28. epithelium

30. Innate gut immune response(4) 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

31. 4.Lewis SJ et al: Early enteral feeding versus “nil by mouth “ after gastrointestinal surgery: systematic review and meta-analysis of controlled trials. BMJ 323:773,2001 5.Mark PE et al: Early enteral nutrition in acutely ill patients: systematic review. Crit Care Med 29:2264,2001

32. When channels open !, (1) 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 !!

33. When channels open !, (2) 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 )

34. When channels open !, (3) 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 )

35. Oxidative Burst Bombs, missals and grenades =very dangerous explosives Are produced and are transported from GI tract to the distant sites ( lungs, liver, heart, kidney, circulation ),& still restrained Restrictions are released at the sites Explosion takes place at the distant sites Damage = “leaky membrane syndrome”

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

37. The gut The lungs Liver Heart Kidney Circulation sepsis

38. 10.Zeigler TR et al: Increased intestinal permeability associated with infection in burn patients. Arch Surg 123:1313,1988

39. 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 )

40. 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

41. 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 ) !!!: ICU, mechanical ventilation,

47. Take home point No foods in the GI tract !!! Increased sepsis Increased septic shock ARDS (adult respiratory distress syndrome) Increased death rate !!!

48. An important question What happens to the gut when you do not eat foods? When the gut is not in use, what will happen to the gut and what is the final outcome of the whole being ?

49. Innate gut immune response(1) 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, !!!

50. Innate gut immune response(2) 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

51. Innate gut immune response(3) 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

52. starvation Starvation ( no foods in the GI tract ) activates T H-1 Pahway.

53. 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 (TNF) !!! {bad news }

54. 20.Spill over systemic circulation

55. The Bottom line TH-1 pathway activation = a bad news for you ! Is not good for your health.

57. What happens after you eat food? TH-2 pathway starts

58. TH-2 pathway 1.Foods in the GI tract (eating, feeding GI ) 2.Shut down the TH-1 pathway ! 3.Less inflammatory response 4.Less tumor necrosis factor (TNF-factor ) 5.T cell regulatory type 1 (TR-1 ) 6.Th-3 pathway activates oral-tolerance 7.Release of beneficial cytokines (reduce inflammation ) = { anti inflammation } 8.{ cooling effect in immune system }!!!

59. The end result of foods in the GI tract 1.Mitigate immune system 2.Cool off or calm down immune system! 3.Less inflammation 4.Less oxygen free radical damage on the tissues ( lungs, kidneys, heart, circulation) 5.Less pneumonia, less ARDS (respiratory failure)

60. 6.Less infection (down by 50 % ) 7.Low incidence of surgical anastomosis breakdown 8.Shorter length of stay (LOS) in hospital

61. References 1.Feeding the critically ill patient- Steven A. McClave,MD, professor of medicine,University of Louisville school of Medicine, Louisville, KY 2.Audio digest gastroenterology 21:08,the 42 nd annual Gastroenterology Update,held November 16-17,2006 in Cleveland,OH 3.Hendon DN et al: increased mortality with intravenous supplemental feeding in severely burned patients. J Burn Rehabil 10:309,1989

62. No food in the GI tract TH-1 pathway Activation Pro-inflammatory responses Leaky membrane syndrome Infection, organ failure(lung,kidney,heart) Foods in the GI tract TH-1 pathway- shut down Cooling off, calming effect on activated immune system Less inflammatory responses Less infection, less organ failures

63. Take home point The foods in the GI tract are essential for good health !

64. Foods In the GI tract Spiritual application

65. John 6:35 “ I am the bread of life. “ “ He who comes to me shall never hunger,and he who believes in me shall never thirst “.

66. Hunger= eat foods= GI tract ! Thirst= dehydration = drink water

67. John 6:51, “ I am the living bread which came down from heaven.

68. John 6:47-48 “ he who believes in Me (Jesus Christ ) has everlasting life. “ “ I am the bread of life “ “this is the bread which comes down from heaven, that one may eat of it and not die.”

69. John 6: 51 I am the living bread which came down from heaven. If anyone eats of this bread, he will live for ever, and the bread that I shall give is My flesh, which I shall give for the life of the world. “

70. John 6:57 “As the living Father sent Me ( Jesus Christ ), and I live because of the Father,so he who feeds on Me ( Jesus Christ ) will live because of Me ( Jesus Christ )”

71. Connecting dots Feeding on Jesus Christ= digesting the words of God=bile study Living for ever= eternal life

72. The GI tract Eating foods Digestion Bible study Everlasting life

73. John 6:58 “ this is the bread which came down from heaven – not as your fathers ate the manna, and are dead. He who eats this bread will live forever “

74. Matthew 6:9-13 Our father in heaven. Hallowed be your name. Your kingdom come. Your will be done on earth as it is in heaven. Give us this day our daily bread. And forgive us our debts As we forgive our debtors. And do not lead us into temptations But deliver us from the evil one. For yours is the kingdom and the power and the glory for ever. Amen

75. John 6:10 Give us this day our daily bread.

76. Time of need= today ! Frequency of need=each day,1x, 2x, 3x Party involved= individual Subject matter= GI tract matter= eating !!!

77. Psalm 139:14 “I will praise you, for I am fearfully and wonderfully made ; Marvelous is Your works, and that my soul knows very well ”

78. The design and function of the GI tract are, indeed, fearfully, and wonderfully made, and executed smoothly. The every detail of the mechanism of action for each component of the GI tract is just beyond comprehension.

79. But I am eternally grateful that God is in control of every detailed mechanism of action of the complex human machinery. for the time being, I continue to trust in God’s wisdom and His mercy and keep on going, maintaining good health with good habits.

80. Conclusions 1 1.Normal sequence of the GI tract 2.The old concept of gut rest = wrong 3.Epithelium cell death = apotosis 4.Increased gut epithelial permeability 5.Pro-inflammatory response=lnterleukin 12 6.Cytokine shower into systemic circulation

81. Conclusions 2 6.Leaky membrane syndrome 7.Multi-organ failure (lungs,liver, kidney, heart, circulation ) 8.No foods in the GI tract= increased infection, multi-organ failure, death rate 9.“when the gut goes down, it will pull other organ with it “ 10.TH-1 pathway= very dangerous, bad news

82. Conclusions 3 11.TH-2 pathway= cooling effect on the immune system, good news ! 12.Foods in the GI tract= less infection, less organ failure, less surgical anastomosis breakdown 13.Foods in the GI tract= essential for good health! 14.Jesus Christ= the bread of life

83. Conclusions 4 15.Feeding on Jesus=digestion of God’s words=== eternal life 16.Human machinery is fearfully and wonderfully made and works very well according to God’s design and his blue print.

84. References 1.Feeding the critically ill patient- Steven A. McClave,MD, professor of medicine,University of Louisville school of Medicine, Louisville, KY 2.Audio digest gastroenterology 21:08,the 42 nd annual Gastroenterology Update,held November 16-17,2006 in Cleveland,OH 3.Hendon DN et al: increased mortality with intravenous supplemental feeding in severely burned patients. J Burn Rehabil 10:309,1989

85. 4.Lewis SJ et al: Early enteral feeding versus “nil by mouth “ after gastrointestinal surgery: systematic review and meta-analysis of controlled trials. BMJ 323:773,2001 5.Mark PE et al: Early enteral nutrition in acutely ill patients: systematic review. Crit Care Med 29:2264,2001

86. 6.McClave SA et al: Enteral tube feeding in the intensive care unit :factors impeding adequate delivery. Crit Care Med 27:1252.1999 7.McClave SA et al: Nutrition management in actue and chronic pancreatitis. Gastroenterology Clin North Am 27:421,1998

87. 8.Stanga Z et al: Effect of jejunal long term feeding in chronic pancreatitis.JPEN J Parenter Enteral Nutr 29:12,2005 9.Taylor SJ et al: Prospective randomized,controlled trial to determine the effect of early enhanced enteral nutrition on clinical outcome in mechanically ventilated patients suffering head injury. Crit Care Med 27:2527,1999

88. 10.Zeigler TR et al: Increased intestinal permeability associated with infection in burn patients. Arch Surg 123:1313,1988

89. The END Thank you for coming !

91. Sermon details Opening hymn :499,what a friend we have in Jesus Scripture reading: John 6:35 Special music: the namihira’s Sermon “the gut- incredible organ, the story of gut immunology “ Closing hymn: 632, until then

92. The place of visit 12-1-2007,vicksburg MS