Nutrients and immunity

Advances in Autism Research
compiled by Teresa Binstock for ARI
April 2008

The relationship between immunity and nutrients within the human body merits attention in autistic children. The work of Dr. Jyonouchi and colleagues is very important and, in this document, is interspersed amid citations delineating nutrients and their effect upon immunity.

1: Early nutrition and immunity - progress and perspectives

Calder PC et al.
Br J Nutr. 2006 Oct;96(4):774-90. free online
http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=928956

The immune system exists to protect the host against pathogenic organisms and highly complex pathways of recognition, response, elimination and memory have evolved in order to fulfil this role. The immune system also acts to ensure tolerance to 'self', to food and other environmental components, and to commensal bacteria. A breakdown in the tolerogenic pathways can also lead to inflammatory diseases. The prevalence of inflammatory diseases, including atopic disorders, has increased over the last 60 years. The development of tolerance is the result of active immune mechanisms and both development and maintenance of tolerance are lifelong processes which start very early in life, even prenatally. Profound immunologic changes occur during pregnancy, involving a polarization of T helper (Th) cells towards a dominance of Th2 and regulatory T cell effector responses in both mother and fetus. This situation is important to maintain pregnancy through avoidance of the rejection of the immunologically incompatible fetus. During the third trimester of human pregnancy, fetal T cells are able to mount antigen-specific responses to environmental and food-derived antigens and antigen-specific T cells are detectable in cord blood in virtually all newborns indicating in utero sensitization. If the neonatal immune system is not able to down-regulate the pre-existing Th2 dominance effectively then an allergic phenotype may develop. Changes occur at, and soon after, birth in order that the immune system of the neonate becomes competent and functional and that the gut becomes colonized with bacteria. Exposure to bacteria during birth and from the mother's skin and the provision of immunologic factors in breast milk are amongst the key events that promote maturation of the infant's gut and gut-associated and systemic immune systems. The introduction of formula and of solid foods exposes the infant to novel food antigens and also affects the gut flora. Nutrition may be the source of antigens to which the immune system must become tolerant, provide factors, including nutrients, that themselves might modulate immune maturation and responses, and provide factors that influence intestinal flora, which in turn will affect antigen exposure, immune maturation and immune responses. Through these mechanisms it is possible that nutrition early in life might affect later immune competence, the ability to mount an appropriate immune response upon infection, the ability to develop a tolerogenic response to 'self' and to benign environmental antigens, and the development of immunologic disorders. A Workshop held in February 2006 considered recent findings in the areas of oral tolerance, routes of sensitization to allergens and factors affecting the development of atopic disease; factors influencing the maturation of dendritic cells and the development of regulatory T cells; the influence of gut microflora on immunity, allergic sensitization and infectious disease; the role of nutrition in preventing necrotizing enterocolitis in an animal model of preterm birth; and the role of PUFA of different classes in influencing immune responses and in shaping the development of atopic disease. This report summarizes the content of the lectures and the subsequent discussions.
PMID: 17010239

2. Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders

Jyonouchi H et al.
J Pediatr. 2005 May;146(5):605-10.

OBJECTIVE: To evaluate an association between cytokine production with common dietary proteins as a marker of non-allergic food hypersensitivity (NFH) and gastrointestinal (GI) symptoms in young children with autism spectrum disorders (ASD). STUDY DESIGN: Peripheral blood mononuclear cells (PBMCs) were obtained from 109 ASD children with or without GI symptoms (GI [+] ASD, N = 75 and GI (-) ASD, N = 34], from children with NFH (N = 15), and control subjects (N = 19). Diarrhea and constipation were the major GI symptoms. We measured production of type 1 T-helper cells (Th1), type 2 T-helper cells (Th2), and regulatory cytokines by PBMCs stimulated with whole cow's milk protein (CMP), its major components (casein, beta-lactoglobulin, and alpha-lactoalbumin), gliadin, and soy. RESULTS: PBMCs obtained from GI (+) ASD children produced more tumor necrosis factor-alpha (TNF-alpha)/interleukin-12 (IL-12) than those obtained from control subjects with CMP, beta-lactoglobulin, and alpha-lactoalbumin, irrespective of objective GI symptoms. They also produced more TNF-alpha with gliadin, which was more frequently observed in the group with loose stools. PBMCs obtained from GI (-) ASD children produced more TNF-alpha/IL-12 with CMP than those from control subjects, but not with beta-lactoglobulin, alpha-lactoalbumin, or gliadin. Cytokine production with casein and soy were unremarkable. CONCLUSION: A high prevalence of elevated TNF-alpha/IL-12 production by GI (+) ASD PBMCs with CMP and its major components indicates a role of NFH in GI symptoms observed in children with ASD.
PMID: 15870662

3: Comparative nutrition and metabolism: explication of open questions with emphasis on protein and amino acids

Baker DH.
Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):17897-902.
http://www.pnas.org/cgi/content/full/102/50/17897

The 20th century saw numerous important discoveries in the nutritional sciences. Nonetheless, many unresolved questions still remain. Fifteen questions dealing with amino acid nutrition and metabolism are posed in this review. The first six deal with the functionality of sulfur amino acids (methionine and cysteine) and related compounds. Other unresolved problems that are discussed include priorities of use for amino acids having multiple functions; interactions among lysine, niacin and tryptophan; amino acid contributions to requirements from gut biosynthesis; the potential for gluconeogenesis to divert amino acids away from protein synthesis; the unique nutritional and metabolic idiosyncrasies of feline species, with emphasis on arginine; controversies surrounding human amino acid requirements; and the potential for maternal diet to influence sex ratio of offspring.
PMID: 16326801

4. Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention

Jyonouchi H et al.
Neuropsychobiology. 2005;51(2):77-85.

OBJECTIVE: Our previous study indicated an association between cellular immune reactivity to common dietary proteins (DPs) and excessive proinflammatory cytokine production with endotoxin (lipopolysaccharide, LPS), a major stimulant of innate immunity in the gut mucosa, in a subset of autism spectrum disorder (ASD) children. However, it is unclear whether such abnormal LPS responses are intrinsic in these ASD children or the results of chronic gastrointestinal (GI) inflammation secondary to immune reactivity to DPs. This study further explored possible dysregulated production of proinflammatory and counter-regulatory cytokines with LPS in ASD children and its relationship to GI symptoms and the effects of dietary intervention measures. METHODS: This study includes ASD children (median age 4.8 years) on the unrestricted (n = 100) or elimination (n = 77) diet appropriate with their immune reactivity. Controls include children with non-allergic food hypersensitivity (NFH; median age 2.9 years) on the unrestricted (n = 14) or elimination (n = 16) diet, and typically developing children (median age 4.5 years, n = 13). The innate immune responses were assessed by measuring production of proinflammatory (TNF-alpha, IL-1beta, IL-6, and IL-12) and counter-regulatory (IL-1ra, IL-10, and sTNFRII) cytokines by peripheral blood mononuclear cells (PBMCs) with LPS. The results were also compared to T-cell responses with common DPs and control T-cell mitogens assessed by measuring T-cell cytokine production. RESULTS: ASD and NFH PBMCs produced higher levels of TNF-alpha with LPS than controls regardless of dietary interventions. However, only in PBMCs from ASD children with positive gastrointestinal (GI(+)) symptoms, did we find a positive association between TNF-alpha levels produced with LPS and those with cow's milk protein (CMP) and its major components regardless of dietary interventions. In the unrestricted diet group, GI(+) ASD PBMCs produced higher IL-12 than controls and less IL-10 than GI(-) ASD PBMCs with LPS. GI(+) ASD but not GI(-) ASD or NFH PBMCs produced less counter-regulatory cytokines with LPS in the unrestricted diet group than in the elimination diet group. There was no significant difference among the study groups with regard to cytokine production in responses to T-cell mitogens and other recall antigens. Conclusion: Our results revealed that there are findings limited to GI(+) ASD PBMCs in both the unrestricted and elimination diet groups. Thus our findings indicate intrinsic defects of innate immune responses in GI(+) ASD children but not in NFH or GI(-) ASD children, suggesting a possible link between GI and behavioral symptoms mediated by innate immune abnormalities. Copyright 2005 S. Karger AG, Basel.
PMID: 15741748

5: Physiological functions should be considered as true end points of nutritional intervention studies

Genton L et al.
Proc Nutr Soc. 2005 Aug;64(3):285-96.
http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=814028

With the beginning of this millennium it has become fashionable to only follow 'evidence-based' practices. This generally-accepted approach cruelly negates experience or intelligent interpretation of pathophysiology. Another problem is that the great 'meta-analysts' of the present era only accept end points that they consider 'hard'. In the metabolic and nutritional field these end points are infection-related morbidity and mortality, and all other end points are considered 'surrogate'. The aim of this presentation is to prove that this claim greatly negates the contribution of more-fundamentally-oriented research, the fact that mortality has multifactorial causes, and that infection is a crude measure of immune function. The following problems should be considered: many populations undergoing intervention have low mortality, requiring studies with thousands of patients to demonstrate effects of intervention on mortality; nutrition is only in rare cases primary treatment, and in many populations is a prerequisite for survival rather than a therapeutic modality; once the effect of nutritional support is achieved, the extra benefit of modulation of the nutritional support regimen can only be modest; cost-benefit is not a valid end point, because the better it is done the more it will cost; morbidity and mortality are crude end points for the effect of nutritional intervention, and are influenced by many factors. In fact, it is a yes or no factor. In the literature the most important contributions include new insights into the pathogenesis of disease, the diminution of disease-related adverse events and/or functional improvement after therapy. In nutrition research the negligence of these end points has precluded the development and validation of functional end points, such as muscle, immune and cognitive functions. Disability, quality of life, morbidity and mortality are directly related to these functional variables. It is, therefore, of paramount importance to validate functional end points and to consider them as primary rather than surrogate end points.
PMID: 16048659

6: Changes in the immune system are conditioned by nutrition

Marcos A et al.
Eur J Clin Nutr. 2003 Sep;57 Suppl 1:S66-9.
http://www.nature.com/ejcn/journal/v57/n1s/pdf/1601819a.pdf

Undernutrition due to insufficient intake of energy and macronutrients and/or due to deficiencies in specific micronutrients impairs the immune system, suppressing immune functions that are fundamental to host protection. The most consistent abnormalities are seen in cell-mediated immunity, complement system, phagocyte function, cytokine production, mucosal secretory antibody response, and antibody affinity. There is a number of physiological situations such as ageing and performance of intense physical exercise associated with an impairment of some immune parameters' response. Nutrition can influence the extent of immune alteration in both of them. There are also numerous pathological situations in which nutrition plays a role as a primary or secondary determinant of some underlying immunological impairments. This includes obesity, eating disorders (anorexia nervosa and bulimia nervosa), food hypersensitivity and gastrointestinal disorders as some examples. The implications of nutrition on immune function in these disorders are briefly reviewed.
PMID: 12947457

7: Interactions between the enteric nervous system and the immune system: role of neuropeptides and nutrition

Genton L, Kudsk KA.
Am J Surg. 2003 Sep;186(3):253-8.

Neuropeptidergic synthesis occurs in enteric nerves and immune cells of the gut-associated lymphoid tissue. Lymphocytes, macrophages, mast cells, and intestinal epithelial cells are capable of responding to these neuropeptides. Neuropeptides generate proliferative or antiproliferative responses of mucosal lymphocytes and intestinal epithelial cells, affect cytokine production and immunoglobulin synthesis by immune cells, and control secretion of water and electrolytes. Some neuropeptides, particularly cholecystokinin, gastrin-releasing peptide, and neurotensin, appear promising to maintain mucosal immunity in patients who cannot receive enteral feeding during critical illness or after GI tract loss. Exogenous administration of neuropeptides to preserve normal immune defenses represents a potential new field of pharmacotherapeutics against bacterial invasion.
PMID: 12946828

8. Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder.

Jyonouchi H, Sun S, Itokazu N.
Neuropsychobiology. 2002;46(2):76-84.

OBJECTIVES: Children with autism spectrum disorder (ASD) frequently reveal various gastrointestinal (GI) symptoms that may resolve with an elimination diet along with apparent improvement of some of the behavioral symptoms. Evidence suggests that ASD may be accompanied by aberrant (inflammatory) innate immune responses. This may predispose ASD children to sensitization to common dietary proteins (DP), leading to GI inflammation and aggravation of some behavioral symptoms. METHODS: We measured IFN-gamma, IL-5, and TNF-alpha production against representative DPs [gliadin, cow's milk protein (CMP), and soy] by peripheral blood mononuclear cells (PBMCs) from ASD and control children [those with DP intolerance (DPI), ASD siblings, and healthy unrelated children]. We evaluated the results in association with proinflammatory and counter-regulatory cytokine production with endotoxin (LPS), a microbial product of intestinal flora and a surrogate stimulant for innate immune responses. RESULTS: ASD PBMCs produced elevated IFN-gamma and TNF-alpha, but not IL-5 with common DPs at high frequency as observed in DPI PBMCs. ASD PBMCs revealed increased proinflammatory cytokine responses with LPS at high frequency with positive correlation between proinflammatory cytokine production with LPS and IFN-gamma and TNF-alpha production against DPs. Such correlation was less evident in DPI PBMCs. CONCLUSION: Immune reactivity to DPs may be associated with apparent DPI and GI inflammation in ASD children that may be partly associated with aberrant innate immune response against endotoxin, a product of the gut bacteria. Copyright 2002 S. Karger AG, Basel
PMID: 12378124

9: The history of nutrition: malnutrition, infection and immunity

Keusch GT.
J Nutr. 2003 Jan;133(1):336S-340S
http://jn.nutrition.org/cgi/content/full/133/1/336S

The relationship between nutritional status and the immune system has been a topic of study for much of the 20th century. Dramatic increases in our understanding of the organization of the immune system and the factors that regulate immune function have demonstrated a remarkable and close concordance between host nutritional status and immunity. This report traces the increasing sophistication of our understanding of these relationships and their impact on susceptibility to infection through six stages to the present time. The cyclical relationship between poor nutrition, increased susceptibility to infectious diseases, leading to immunological dysfunction and metabolic responses that further alter nutritional status is described and, wherever possible, related to physiological mechanisms. In addition, the particular role of Nevin Scrimshaw in guiding the progress over the past 50 y is discussed.
PMID: 12514322

10: Nutrition and the immune system from birth to old age

Chandra RK.
Eur J Clin Nutr. 2002 Aug;56 Suppl 3:S73-6.
http://www.nature.com/ejcn/journal/v56/n3s/abs/1601492a.html

For millennia, food has been at the center of social events, in times of joy and in times of sorrow. Protein-energy malnutrition is associated with a significant impairment of cell-mediated immunity, phagocyte function, complement system, secretory immunoglobulin A antibody concentrations, and cytokine production. Deficiency of single nutrients also results in altered immune response: this is observed even when the deficiency state is relatively mild. Of the micronutrients, zinc, selenium, iron, copper, vitamins A, C, E and B(6), and folic acid have important influences on immune responses. Overnutrition and obesity also reduce immunity. Low-birth-weight infants have a prolonged impairment of cell-mediated immunity that can be partly restored by providing extra amounts of dietary zinc. In the elderly, impaired immunity can be enhanced by modest amounts of a combination of micronutrients. These findings have considerable practical and public health significance.
PMID: 12142969

11: Nutritional factors and immune functions of gut epithelium

Sanderson IR.
Proc Nutr Soc. 2001 Nov;60(4):443-7.
http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=804204

The intestinal epithelium acts as a barrier to the external environment contained within the lumen of the gut. It also transports solutes for nutrition and for immunological surveillance. The present review develops the hypothesis that changes in diet, through the composition of the lumen environment, alter the expression of genes in the epithelium. These genes include those that encode for proteins that signal to the mucosal immune system. Directly changing the expression of signalling molecules in the intestinal epithelium using transgenic techniques alters immune function. For example, up regulation of the chemokine macrophage inflammatory protein-2 increases neutrophil recruitment. Furthermore, lumen molecules such as short-chain fatty acids regulate chemokine expression by epithelial cells. By this means, the epithelium acts as a transducing monolayer signalling between the contents of the intestine and the mucosal immune system.
PMID: 12069396

12. Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression

Jyonouchi H, Sun S, Le H.
J Neuroimmunol. 2001 Nov 1;120(1-2):170-9.

We determined innate and adaptive immune responses in children with developmental regression and autism spectrum disorders (ASD, N=71), developmentally normal siblings (N=23), and controls (N=17). With lipopolysaccharide (LPS), a stimulant for innate immunity, peripheral blood mononuclear cells (PBMCs) from 59/71 (83.1%) ASD patients produced >2 SD above the control mean (CM) values of TNF-alpha, IL-1beta, and/or IL-6 produced by control PBMCs. ASD PBMCs produced higher levels of proinflammatory/counter-regulatory cytokines without stimuli than controls. With stimulants of phytohemagglutinin (PHA), tetanus, IL-12p70, and IL-18, PBMCs from 47.9% to 60% of ASD patients produced >2 SD above the CM values of TNF-alpha depending on stimulants. Our results indicate excessive innate immune responses in a number of ASD children that may be most evident in TNF-alpha production.
PMID: 11694332

13: Nutrients and their role in host resistance to infection

Field CJ, Johnson IR, Schley PD.
J Leukoc Biol. 2002 Jan;71(1):16-32.
http://www.jleukbio.org/cgi/reprint/71/1/16

Almost all nutrients in the diet play a crucial role in maintaining an "optimal" immune response, such that deficient and excessive intakes can have negative consequences on immune status and susceptibility to a variety of pathogens. Iron and vitamin A deficiencies and protein-energy malnutrition are highly prevalent worldwide and are important to the public health in terms of immunocompetence. There are also nutrients (i.e., glutamine, arginine, fatty acids, vitamin E) that provide additional benefits to immunocompromised persons or patients who suffer from various infections. The remarkable advances in immunology of recent decades have provided insights into the mechanisms responsible for the effects of various nutrients in the diet on specific functions in immune cells. In this review, we will present evidence and proposed mechanisms for the importance of a small group of nutrients that have been demonstrated to affect host resistance to infection will be presented. An inadequate status of some of these nutrients occurs in many populations in the world (i.e., vitamin A, iron, and zinc) where infectious disease is a major health concern. We will also review nutrients that may specifically modulate host defense to infectious pathogens (long-chain polyunsaturated n-3 fatty acids, vitamin E, vitamin C, selenium, and nucleotides). A detailed review of the effect of long-chain polyunsaturated n-3 fatty acids on host defense is provided as an example of how the disciplines of nutrition and immunology have been combined to identify key mechanisms and propose nutrient-directed management of immune-related syndromes.
PMID: 11781377

14: Nutritional modulation of immune function

Grimble RF.
Proc Nutr Soc. 2001 Aug;60(3):389-97.

The inflammatory response to injury and infection, although an essential part of immune function, carries the risk of severe tissue depletion and immunosuppression. These outcomes increase morbidity and delay recovery. Evidence is accumulating that single-nucleotide polymorphisms in the genes controlling pro-inflammatory cytokine production adversely influence the response. Immunonutrition provides a means of modulating the inflammatory response to injury and infection, and thereby improves clinical outcome. n-3 Polyunsaturated fatty acids (n-3 PUFA), glutamine, arginine, S amino acids and nucleotides are important components of immunonutrient mixes. While animal model studies suggest that all these components may exert a beneficial effect in patients, the number of large randomized placebo-controlled trials utilizing immunonutrition is fairly limited and the observed effects are relatively small. Meta-analyses suggest that while immunonutrition may not reduce mortality rates, a reduction in hospital length of stay, decreased requirements for ventilation and lower infection rates are achieved by this mode of nutrition. The present paper discusses some underlying reasons for the difficulty in demonstrating the clinical efficacy of immunonutrition. Paramount among these reasons is the antioxidant status and genetic background of the patient. A number of studies suggest that there is an inverse relationship between inflammation and T-cell function. Immuno-enhancive effects have been shown in a number of studies in which n-3 PUFA, glutamine and N-acetyl cysteine have been employed. All these nutrients may exert their effects by suppressing inflammation; n-3 PUFA by direct suppression of the process and glutamine and N-acetyl cysteine by acting indirectly on antioxidant status. Glutamine and nucleotides exert a direct effect on lymphocyte proliferation. Preliminary data suggests that not all genotypes are equally sensitive to the effects of immunonutrition. When further studies have been conducted to discern the precise interaction between each individual's genotype of relevance to the response to injury and infection, and immunonutrients, the level of precision in the application of immunonutrition will undoubtedly improve.
PMID: 11681814

15: Early nutrition and the development of immune function in the neonate

Kelly D, Coutts AG.
Proc Nutr Soc. 2000 May;59(2):177-85.
http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=796320

The present review will concentrate on the development of the gut-associated lymphoid tissue and the role of early nutrition in promoting immune function. The intestine is the largest immune organ in the body, and as such is the location for the majority of lymphocytes and other immune effector cells. The intestine is exposed to vast quantities of dietary and microbial antigens, and is the most common portal of entry for pathogens, some of which are potentially lethal. The development of normal immune function of the intestine is therefore vital for survival, and is dependent on appropriate antigen exposure and processing, and also an intact intestinal barrier. In early life innate mechanisms of defence are probably more important than active or adaptive mechanisms in responding to an infectious challenge, since the healthy neonate is immunologically naïve (has not seen antigen) and has not acquired immunological memory. During this period maternal colostrum and milk can significantly augment resistance to enteric infections. The mechanisms of enhancing disease resistance are thought to be passive, involving a direct supply of anti-microbial factors, and active, by promoting the development of specific immune function. A tolerance response to dietary and non-invasive antigens is generally induced in the gut. However, it must also be able to mount an adequate immune response to ensure clearance of foreign antigens. It is now recognized that regulation of tolerance and active immune responses is critical to health, and failure to regulate these responses can lead to recurrent infections, inflammatory diseases and allergies. The education of the immune system in early life is thought to be critical in minimizing the occurrence of these immune-based disorders. During this phase of development maternal milk provides signals to the immune system that generate appropriate response and memory. One factor that has been proposed to contribute to the increase in the incidence of immune-based disorders, e.g. atopic diseases in Western countries, is thought to be the increased prevalence of formula-feeding.
PMID: 10946785

16: Role of nutrients and bacterial colonization in the development of intestinal host defense

Walker WA.j Pediatr
J Nutr. 2000;30 Suppl 2:S2-7

In this introduction to the supplement on the use of pre- and probiotics in the health and disease of pediatric patients, I have summarized factors affecting the initial colonization of the neonatal intestine. The term bacterial-epithelial cross-talk was defined, and examples of the enterocyte response to both pathologic and indigenous flora stimulation illustrated. Immaturities in the human neonatal intestinal response to bacteria and their toxins were reviewed in the context of the pathogenesis of age-specific, bacterial gastrointestinal infectious diseases. Finally, the importance of pre- and probiotics as measures to strengthen the neonate's intestinal host defenses in the prevention and treatment of specific age-related disease were considered.
PMID: 10749395

17: Nutrition and intestinal mucosal immunity

Johnson CD, Kudsk KA.
Clin Nutr. 1999 Dec;18(6):337-44.
PMID: 10634917

18: Nutrition and immunology: from the clinic to cellular biology and back again

Chandra RK.
Proc Nutr Soc. 1999 Aug;58(3):681-3.
http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=800048

Diet and immunity have been known to be linked to each other for centuries. In the last 30 years systematic studies have confirmed that nutrient deficiencies impair immune response and lead to frequent severe infections resulting in increased mortality, especially in children. Protein-energy malnutrition results in reduced number and functions of T-cells, phagocytic cells and secretory immunoglobulin A antibody response. In addition, levels of many complement components are reduced. Similar findings have been reported for moderate deficiencies of individual nutrients such as trace minerals and vitamins, particularly Zn, Fe, Se, vitamins A, B6, C and E. For example, Zn deficiency is associated with profound impairment of cell-mediated immunity such as lymphocyte stimulation response, decreased CD4+:CD8+ cells, and decreased chemotaxis of phagocytes. In addition, the level of thymulin, which is a Zn-dependent hormone, is markedly decreased. The use of nutrient supplements, singly or in combination, stimulates immune response and may result in fewer infections, particularly in the elderly, low-birth-weight infants and malnourished critically-ill patients in hospitals. The interactions between nutrition and the immune system are of clinical, practical and public health importance.
PMID: 10604203

19: Nutrient Tasting and Signaling Mechanisms in the Gut II. The intestine as a sensory organ: neural, endocrine, and immune responses

John B. Furness et al.
Am J Physiol Gastrointest Liver Physiol 277: G922-G928, 1999
http://ajpgi.physiology.org/cgi/content/full/277/5/G922

The lining of the gastrointestinal tract is the largest vulnerable surface that faces the external environment. Just as the other large external surface, the skin, is regarded as a sensory organ, so should the intestinal mucosa. In fact, the mucosa has three types of detectors: neurons, endocrine cells, and immune cells. The mucosa is in immediate contact with the intestinal contents so that nutrients can be efficiently absorbed, and, at the same time, it protects against the intrusion of harmful entities, such as toxins and bacteria, that may enter the digestive system with food. Signals are sent locally to control motility, secretion, tissue defense, and vascular perfusion; to other digestive organs, for example, to the stomach, gallbladder, and pancreas; and to the central nervous system, for example to influence feeding behavior. The three detecting systems in the intestine are more extensive than those of any other organ: the enteric nervous system contains on the order of 108 neurons, the gastroenteropancreatic endocrine system uses more than 20 identified hormones, and the gut immune system has 70- 80% of the body's immune cells. The gastrointestinal tract has an integrated response to changes in its luminal contents. When this response is maladjusted or is overwhelmed, the consequences can be severe, as in cholera intoxication, or debilitating, as in irritable bowel syndrome. Thus it is essential to obtain a full understanding of the sensory functions of the intestine, of how the body reacts to the information, and of how neural, hormonal, and immune signals interact.
PMID: 10564096

20. Nutrient Tasting and Signaling Mechanisms in the Gut III. Endocrine cell recognition of luminal nutrients

Buchan AM.
Am J Physiol. 1999 Dec;277(6 Pt 1):G1103-7.
http://ajpgi.physiology.org/cgi/content/full/277/6/G1103

The profile of hormone secretion from the gastrointestinal tract on food ingestion depends to a great extent on the composition of the meal. High levels of protein result in a quantitatively and qualitatively different response compared with a meal rich in fats. The outstanding question is whether this differential response is driven by the ability of gastroenteric endocrine cells to directly sense the contents of the lumen via apical microvilli. Alternative effectors would include activation of the intrinsic and extrinsic innervation or other epithelial cell populations. The data available indicate that the role of the gastrointestinal innervation is relatively limited and is probably a major factor only in the postprandial responses of hormones released from endocrine cells in the distal small intestine. However, whether nutrients directly stimulate gastroenteric endocrine cells or another epithelial cell type has yet to be established.
PMID: 10600808

21. Nutrient tasting and signaling mechanisms in the gut. IV. There is more to taste than meets the tongue

Katz DB, Nicolelis MA, Simon SA.
Am J Physiol Gastrointest Liver Physiol. 2000 Jan;278(1):G6-9.
http://ajpgi.physiology.org/cgi/content/full/278/1/G6

The tongue is the principal organ that provides sensory information about the quality and quantity of chemicals in food. Other information about the temperature and texture of food is also transduced on the tongue, via extragemmal receptors that form branches of the trigeminal, glossopharyngeal, and vagal nerves. These systems, together with information from the gastrointestinal (GI) system, interact to determine whether or not food is palatable. In this themes article, emphasis is placed on the integrative aspects of gustatory processing by showing the convergence of gustatory information with somatosensory, nociceptive, and visceral information (from the GI system) on the tongue and in the brain. Our thesis is that gustation should be thought of as an integral part of a distributed, interacting multimodal system in which information from other systems, including the GI system, can modulate the taste of food.
PMID: 10644555

22. Nutrient tasting and signaling mechanisms in the gut V. Mechanisms of immunologic sensation of intestinal contents

Shanahan F.
Am J Physiol Gastrointest Liver Physiol. 2000 Feb;278(2):G191-6.
http://ajpgi.physiology.org/cgi/content/full/278/2/G191

Immune perception of intestinal contents reflects a functional dualism with systemic hyporesponsiveness to dietary antigens and resident microflora (oral tolerance) and active immune responses to mucosal pathogens. This facilitates optimal absorption of dietary nutrients while conserving immunologic resources for episodic pathogenic challenge. Discrimination between dangerous and harmless antigens within the enteric lumen requires continual sampling of the microenvironment by multiple potential pathways, innate and adaptive recognition mechanisms, bidirectional lymphoepithelial signaling, and rigorous control of effector responses. Errors in these processes disrupt mucosal homeostasis and are associated with food hypersensitivity and mucosal inflammation. Mechanisms of mucosal immune perception and handling of dietary proteins and other antigens have several practical and theoretical implications including vaccine design, therapy of systemic autoimmunity, and alteration of enteric flora with probiotics.
PMID: 10666042

23: Nutrition and the immune system of the gut

Cunningham-Rundles S, Lin DH.
Nutrition. 1998 Jul-Aug;14(7-8):573-9.

Studies suggest that the development and expression of the regional immune system in the gastrointestinal (GI) tract is relatively independent of systemic immunity. This is reflected in significant differences in functional response of T cells and B cells and affects cytokine patterns and activation pathways when regional immunity is compared to systemic immunity. Nutrients have fundamental and regulatory influences on the immune response of the GI tract and, therefore, on host defense. In addition to the effect of nutrition during development, the local impact of different dietary and antigenic elements on the regional immune system contributes to potential diversion of the two systems throughout life. The route of exposure during antigenic contact is known to affect host immune response, whether it be a normal process, happening in the context of normal environmental encounter with nonpathogenic microbes or planned immunization, or occurring as a result of resolution of a potentially pathologic process i.e., an infectious encounter. Interactions at the local level profoundly influence systemic immune response, in part because of intrinsic differences in these systems, and also because of different requirements for optimal function. Although inflammatory processes are central to host defense in the periphery, the protective blocking action of the secretory immunoglobulin A immune response is crucial to local host defense, and, therefore, to the integrity of GI tract immune function. For these reasons, interaction with normal bacteria of the GI tract may be seen as the model of how the system has evolved and provide clues to the restoration of balance in the immunocompromised host. Reduction of normal commensal bacteria in the context of infection or after antibiotic treatment may interfere with nutrient availability and impair beneficial stimulation of GI immune response. This impairment may be associated with continued colonization with opportunistic microbes and inflammatory immune response that could lead to malabsorption and malnutrition. Study of the impact of nutrient imbalance on the function of the GI tract has profound implications for clinical medicine and may in the future lead to the rational design of preventive approaches to support immune response and host defense.
PMID: 9684259

24: Nutritional modulation of immunity and the inflammatory response

Lin E, Kotani JG, Lowry SF.
Nutrition. 1998 Jun;14(6):545-50.

The metabolic derangements of the injured or stressed patient are governed by multiple factors that partially include the severity of insult, preexisting illnesses, available energy reserves, and appropriateness of intervention. The normal response to injury is further characterized by the release of proinflammatory and antiinflammatory mediators that exert potent effects on cellular and organ function. Although brief periods of starvation and catabolism are tolerable in otherwise healthy individuals, protracted nutritional deprivation can manifest as immunocompromise, irreversible organ injury, and late mortality. Moreover, patients with severe injuries or preexisting illnesses who exhibit exaggerated inflammatory responses may be further predisposed to such deleterious consequences following the insult. The optimal supply of appropriate nutrients and substrates in such circumstances has often been championed as a necessary means of restoring proper cellular metabolism, wound healing, immune competence, and proper organ function. However, much debate surrounds the present efficacy of nutritional therapy in modulating the immune response associated with injury and stress. This article seeks to assess the merits of nutritional therapeutics in the injured patient through available biological and clinical evidence.
PMID: 9646300

25: Interactions among infections, nutrients and xenobiotics

Ilbäck NG, Friman G.
Crit Rev Food Sci Nutr. 2007;47(5):499-519.

During recent years there have been several incidents in which symptoms of disease have been linked to consumption of food contaminated by chemical substances (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD). Furthermore, outbreaks of infections in food-producing animals have attracted major attention regarding the safety of consumers, e.g., Bovine Spongiform Encephalitis (BSE) and influenza in chicken. As shown for several xenobiotics in an increasing number of experimental studies, even low-dose xenobiotic exposure may impair immune function over time, as well as microorganism virulence, resulting in more severe infectious diseases and associated complications. Moreover, during ongoing infection, xenobiotic uptake and distribution are often changed resulting in increased toxic insult to the host. The interactions among infectious agents, nutrients, and xenobiotics have thus become a developing concern and new avenue of research in food toxicology as well as in food-borne diseases. From a health perspective, in the risk assessment of xenobiotics in our food and environment, synergistic effects among microorganisms, nutrients, and xenobiotics will have to be considered. Otherwise, such effects may gradually change the disease panorama in society.
PMID: 17558657

26: Psychoimmunology of nutrition

Lesourd B.
Nestle Nutr Workshop Ser Clin Perform Programme. 2005;10:189-98.
PMID: 15818030

27: Interaction between nutrition, intestinal flora and the gastrointestinal immune system

Lochs H.
Nestle Nutr Workshop Ser Clin Perform Programme. 2005;10:179-85
PMID: 15818029