Nutritional Modulation of Immune Functions

1. NUTRITIONAL MODULATION OF
IMMUNE FUNCTION: ANALYSIS OF
EVIDENCE, MECHANISMS, AND CLINICAL
RELEVANCE
Dr. Pramesh Prasad Shrestha
Medical Officer
Department of GI Surgery and Digestive Diseases
Nepal Mediciti

2. Introduction:
THE IMMUNE SYSTEM
■ The immune system, composed of innate and acquired immunity, allows an organism
to fight off foreign pathogens
■ Healthy immunity accomplishes four essential principles:
– ability to detect and fight off infection;
– ability to recognize a host's own cells as "self," thereby protecting them from attack;
– a memory from previous foreign infections; and
– ability to limit the response after the pathogen has been removed.
■ Without adequate execution of immunologic mechanisms, a host is rendered
defenseless against pathogens.Conversely, an unchecked immune response can be
self-destructive.

3. THE IMMUNE SYSTEM (CONTD)
■ There is considerable heterogeneity among individuals in the vigor of their
immunological function, owing to
– genetics,
– environment,
– lifestyle,
– nutrition,
– and the interaction of these factors.
■ Nutrition is a the most easily modifiable factor in impacting immune function

4. ■ In less developed regions, nutritional deficiencies are still prevalent that contributes to
the high incidence of morbidity and mortality from infectious diseases
■ In developed countries, less ideal diet composition and excess calorie consumption are
still a challenging reality

5. Vitamin D
■ Vitamin D is unique compared to other vitamins in that human body can synthesize it
in the skin from the precursor 7-dehydrocholesterol when exposed to sunlight
■ Classical function ofVitamin D has long been recognized to be the regulation of
calcium homeostasis and bone health.
■ However, more extra-skeletal effects of vitamin D have been revealed, [1]
– vitamin D receptor (VDR) and vitamin D-activating enzymes (hydroxylases) are
present in the tissues and cells not involved in mineral and bone metabolism

6. Vitamin D (Contd)
Immunologic Effect and Mechanism
■ Most immune cells expressVDR
■ Stimulator effect on Innate immunity
– Monocytes and macrophages are stimulated to proliferate; promote chemotactic
and phagocytic capacity
– Monocytes, Neutrophils, epithelial cells are induced to produce several endogenous
antimicrobial peptides
■ Inhibitory effect onAdaptive Immunity
– Inhibits proliferation ofT Cells
– Inhibits production of IL-2 and IFN-γ
– Inhibits differentiation of CD4+T cells into subpopulations

7. ■ Adequate intake of vitamin D is anticipated to help maintain/strengthen the body's
defense against infection by promoting the innate immunity
■ Its regulatory effect onT cells and Dendritic Cells suggest that vitamin D may help
mitigateT cell-mediated autoimmune inflammatory diseases.
Vitamin D (Contd)
Clinical Relevance

8. ■ Vitamin E is a generic term for all tocopherols and tocotrienols that exhibit the
biological activity of α-tocopherol.
■ Vitamin E is a chain-breaking, lipid-soluble antioxidant present in the membrane of all
cells
■ immune cells contain particularly high levels of vitamin E, which protects them from
oxidative damage related to high metabolic activity
Vitamin E

9. ■ Deficiency ofVitamin E causes Depressed lymphocyte proliferation, which can be
reversed by repletion ofVit E.
■ Current RDA ofVit E intake may not be optimal to different bodily systems or
individuals
■ AdequateVit E intake results in :
– EnhancedT cell mediated function including DelayedType Hypersensitivity,
– Lymphocyte proliferation
– Increased IL-2 Production
– Decreased Prostaglandin E2 production
Vitamin E (Contd)
Immunologic Effect and Mechanism

10. ■ Protective againstViral Influenza
■ Reduced Bacteria burden in Pulmonary infections, lethal septicemia and lung
inflammations after infection with Streptococcus pneumoniae
■ Healthy elderly individuals receiving higher doses ofVit E (200g/Day) are reported to
have lower incidence of Infections (Upper respiratory infections and common cold)
compared to those receiving placebo [2]
Vitamin E (Contd)
Clinical Relevance

11. Zinc
■ Transitional metal
■ Essential micronutrients
■ Required for
– NormalGrowth and Development
– Repair of cells
– Metabolism and
– Maintenance of cell integrity and functionality
■ Deficiency of Zinc is the Fifth leading risk factor for bacterial diarrhea and pneumonia
in developing countries [3]
■ In developed countries, its deficiency contribute to development of
immunosenescence

12. ■ Crucial for maintaining homeostasis of immune system.
■ Deficiency manifests with
– Thymus involution
– Reduced number of CD4+T cells
– Impairment of immune functions including
■ lymphocyte proliferations,
■ Increased IL-2 production,
■ Increased DTH response
■ Decreased Antibody Response
■ Decreased NK cellActivity
■ Decreased Macrophage PhagocyticActivity, and
■ Decreased functions of Neutrophils
Zinc (Contd)
Immunologic Effect and Mechanism

13. ■ Correction of Zinc deficiency by supplementation can reverse impairment of immune
system and reduce mortality from infectious diseases
■ Supplementation Boosts defense related immune responses
– Reduction in diarrhea and pneumonia in children and elderly
■ Reduces systemic inflammatory response in sepsis.
– Thus it has been suggested that supplementation of Zinc might be a treatment
option to improve thee outcomes of sepsis [3]
Zinc (Contd)
Clinical Relevance

14. Fish Oil and n-3 Polyunsaturated Fatty
Acid (PUFA)
■ Energy providing macroneutrient
■ Capable of regulating cell functions
■ PUFA, mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) greatly
impact immune cell functions.
■ n-6 PUFA are less significant

15. ■ Anti-inflammatory properties of n-3 PUFA (inhibition of proinflammatory mediators)
– Inhibit production of PGE2 and Leukotrienes
– Inhibit proinflammatory cytokines (IL-1β,TNF-α, IL-6)
– Inhibit chemokines (IL-8, MCP-1)
– Inhibit adhesion molecules (ICAM-1,VCAM-1, selectins)
– Inhibit platelet activating factor, and
– Inhibit reactive oxygen and nitrogen species
– Inhibits NF-κB signaling
■ Increase production of anti-inflammatory cytokines (IL-10)
■ Serve as precursors of Pre-resolving mediators including EPA-derived E-series
resolvins, DHA-derived D-series resolvins, DHA derived protectins and maresins.
Fish Oil and n-3 PUFA (Contd)
Immunologic Effect and Mechanism

16. ■ Protective effects have been reported in
– Chronic inflammations such as asthma, IBD includingCrohn’s disease and ulcerative
colitis,
– Autoimmune disorders such as Rheumatoid arthritis
Fish Oil and n-3 PUFA (Contd)
Clinical Relevance

17. Probiotics
■ Live microorganisms, when administered in adequate amounts, confer health benefits
on the host.
■ Primary genera of probiotic microorganisms include:
– Lactobacillus
– Bifidobacterium
– Streptococcus
■ Lactobacillus and Bifidobacterium are being safely used in dairy prodcuts and are also
found to be a part of the gut microbiota

18. ■ Dietary intake allows their intimate interactions with the gut mucosa and mucosal immune
system, which hosts the largest part of the body’s immune cells.
■ However, effect on immunity is not limited to gut, and effect has been observed in Mucosa of
Upper respiratory tract
– Increasing evidence suggests that probiotics positively impact systemic immunity [4]
■ Lactobacilli are shown to increase intestinal IgA secretion
■ They reinforce the intestinal barrier and helps maintain normal permeability
■ Compete with pathogenic microorganisms for Gut for nutrients and attachment to gut epithelium,
thereby reducing pathogenic microorganism load.
Probiotics
Immunologic Effect and Mechanism

19. ■ Increases host’s resistance against infections, shown by consumption of probiotic milk
during respiratory and gastrointestinal infections shortened the duration of illness and
reduced risk of common cold.
■ They compete with pathogens for colonizing epithelium and also release antimicrobial
substances together leading to an unfavorable microenvironment for pathogens
■ They have been tested improving allergies
■ Effect onAntigen presenting cells and Cell mediated functions suggests increasing
efficacy of vaccination.
Probiotics
Clinical Relevance

20. GreenTea and Epigallocatechin-3-
Gallate (EGCG)
■ Green tea contains high content of catechins
– Epigallocatechin-3-Gallate is the most abundant and most biologically active
■ These have been shown to be effective in modulating multiple aspects immunity

21. ■ EGCG reduces neutrophil migration induced by chemokine IL-8
■ Inhibits monocyte migration by reducing secretion of the chemokine Moocyte
chemotactic protein -1 (MCP-1) and its receptor (CCR2) expression
■ Inhibits pro-inflammatory mediators from monocytes and macrophages
■ Retards bone marrow derived dentritic cells maturation and inhibits their function
■ Inhibits B cell proliferation, splenocyte proliferation,T-cell division.
■ Decreases IL-2,TNF-α, and IFN-γ procudtion,
GreenTea and EGCG
Immunologic Effect and Mechanism

22. ■ Administration of EGCG has been shown to improve several autoimmune disease,
including autoimmune encephalomyelitis and multiple sclerosis,Collagen or Antigen
induced arthritis and IBD
■ Most of the evidence is from animal studies and efficacy and safety for EGCG’s clinical
application in human diseases remain to be established
GreenTea and EGCG
Clinical Relevance

23. Glutamine
■ Glutamine is the most abundant and versatile amino acid in the body
■ In health and disease, the rate of glutamine consumption by immune cells is similar or
greater than glucose
■ Its release into the circulation is controlled by the gut, liver, and skeletal muscles.
■ During catabolic/hypercatabolic situations glutamine can become essential for
metabolic function, but its availability may be compromised due to the impairment of
homeostasis in the inter-tissue metabolism of amino acids

24. ■ Glutamine is an essential nutrient for
– lymphocyte proliferation and cytokine production,
– macrophage phagocytic plus secretory activities, and
– neutrophil bacterial killing
■ Converted to glutamate in immune cells, and the release of NH3 during this
conversion leads to synthesis of purines and pyrimidines of DNA and RNA. Hence,
expression of several genes in immune system cells is largely dependent on glutamine
availability
■ As a precursor for glutathione, prevents oxidative stress by neutralizing reactive
oxygen species.
■ Also reduces oxidative stress as Glutamine reinforces the substrate availability for GSH
synthesis
Glutamine
Immunologic Effect and Mechanism

25. ■ Balanced intake of Glutamine is essential for homeostasis, growth and health
maintenance.
■ Supplementation of Glutamine in healthy individual with balanced intake of glutamine
in regular diet does not affect immunity
■ On the contrary, during major/critical illness, sepsis, trauma, post surgery status,
chronic weakness and nutritional limitations,Glutamine is essential to maintain the
level of immune cell count.
■ During hypercatabolic state, glucose and fat metabolism is impaired, results in
increased muscle breakdown to provide essential substrate for protein synthesis and
energy production.
Glutamine
Clinical Relevance

26. PERIOPERATIVE
NUTRITION

27. Dogma of nutrition in surgery
■ NPO at midnight for all surgical procedures
■ NPO until bowel functions resumes
■ Clear liquids -> Full Liquid -> Soft Diet -> Normal Diet
■ Feeding stresses surgical anastomosis
■ TPN early in malnourished patients
■ No enteral feeding with vasopressors
■ No enteral feeding with open abdomen

28. 5-7 High risk Initiate early intervention nutritional care plan
4 At risk
Initiate nutritional care plan (food, oral supplements, tube feeding,
and/or parenteral nutrition as appropriate)
0-3 Low risk Re-screen weekly

29. Pre-Operative Fasting Recommendations
2011 American Society of Anesthesiologists Guidelines
■ 2 hours for CLEAR LIQUIDS
■ 4 hours for BREAST MILK
■ 6 hours for LIGHT MEAL
■ 8 hours for REGULAR MEALS

30. ERAS Guidelines 2015
■ Due to glycogen store depletion within 8-12 hours of fasting which
results in subsequent decrease insulin sensitivity
■ Advises providing oral intake of 25-50 grams of clear carbohydrate
drink 2 hours before surgery

32. Post-Operative ileus
■ Anesthesia
■ Hormones and Neuropeptides (CCK, CGRP,VIP, IL-1,TNF-α
■ Surgical Manipulation
■ Exogenous and Endogenous opiates
■ ANS (sympathetic pathway stimulation due to surgical stress)
■ Effect of Substance P and NO on Enteric Nervous System
■ Inflammation
■ Low albumin and/or Potassium
■ IncreasedAge
■ Blood loss

33. Post-Operative Ileus

34. Regular Normal Diet
Nutritional Support
■ START REGULAR NORMAL DIET FROM 24 HOURS OF SURGERY
■ It is not required to start from clear liquids.
■ Indication:
– Unlikely to take in >50% of total energy requirement orally for next 3-5 days
– Inability to meet physiologic demands by oral intake
■ 2 types
– Enteral
– Parenteral

35. Enteral Nutritional Support
■ 24 – 48 Hours post operative period

38. Complications on Enteral Nutritional
Support
■ Distention
■ Aspiration
■ Diarrhea
■ Azotemia
■ Iatrogenic Injury
■ Volume Problems

39. Total Parenteral Nutrition
■ Admixture ofAmino acids, dextrose, lipids, vitamins minerals and electrolytes

41. Access forTPN
■ Central Line
■ Tunneled /Cuffed Catheter
■ PICC Line
■ Peripheral Line

42. Complications ofTPN
■ Catheter related blood stream infections
■ Thrombosis
■ Hepatosteatosis
■ Hyper/hypoglycemia
■ Hyperlipidemia
■ Electrolyte abnormalities
■ Hypervolemic

43. Monitoring Nutritional Support
■ More is not always better
– AccurateCalorie intake
■ Ireton-Jones equation (1997)
– Energy expenditure(Kcal/day)= 1784 – (11 x age) + (5 x weight) + (244 x gender) + (239 x
trauma) + (804 x burns)
■ The New Predictive Equation (2015)
– Total Energy Expenditure (Kcal/kg/day)
= 33 - (3 x Age) - (3 x BMI (18.5-24.9=0, 25-29.9=1, ) - (1 x Gender (M=0, F=1))
■ Age (years) >50 = 1, <50=0
■ BMI (18.5-24.9 = 0, 25 – 29.9=1, 30-34.9=2, 35-39.9 = 3)
■ Gender (Male = 0, female = 1)
– Promote Nitrogen retention/adequate protein intake
■ ~1.5g/kg/day

44. Weaning Nutritional Support
■ Start from Continuous support
■ Then Nocturnal support
■ Then Bolus support
■ Then stop support, when patient consumes >80% of energy requirement orally

45. Can you feed an Open Abdomen?
■ If the Gut works, USE IT
■ Start Slow andAdvance to goal

47. Conclusions
■ Nutrition GREATLY IMPACTS immunity of a person but
■ Many of the studies regarding nutritional modulation of immune status are relatively
new and many studies are contradictory of each other. Hence a final conclusion and
clinical application of many of the nutrients in immunomodulation is yet to b
established
■ Current Recommended Daily allowances of most of these nutrients adequate for
immunomodulation and most patients require and larger doses and doses depends
upon the age, metabolic state and differ from individual to individual
– There is a need to establish the optimal doses for maximum clinical benefits.
■ The effect of Probiotics are largely dependent upon the strain of the bacteria

49. ■ Vitamin D, n-3 PUFA and EGCG are beneficial in chronic inflammatory conditions
■ n-3 PUFA and EGCG are beneficial in Autoimmune disorders
■ Vitamin D, vitamin E, Zinc and Probiotics in Protection against infection
■ However, discrepancy in results from many animal and human studies adds challenge
and complexity of nutritional immunology.
■ And as a result, there is no clear consensus at this time regarding the clinical relevance
of these dietary components

50. ■ Early Enteral feeds is best
■ Parenteral feeds in only select cases
■ Provide sufficient calories more is not always better

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53. Thank you!