Non-IgE Food Allergy

A Food allergy is defined, as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a the food (antigen) that are either IgE or Non-IgE mediated.  Food Allergy is now being increasingly recognized as classified, IgE and/or Non-IgE mediated. 

 

IgE stands for Immunoglobin E, a measurable antibody producing immune response to a food protein.  Symptoms are immediate onset (0-2hrs within ingestion) and can include, but not limited to: hives, sneezing, wheezing, itching, red eyes, throat swelling, allergic asthma, and severe reactions can include rapid heart rate, low blood pressure, anaphylaxis (see table below).   The most common ("top 8") food allergens include: eggs, milk, peanut, tree nut, wheat, shellfish, and soy but are not limited to these foods,  any food with a protein can elicit an allergic reaction.  Also included in the immediate immune response is Oral Allergy Syndrome (OAS) and some components of Eosinophilic disorders (EGID).

A Non-IgE Allergy is cell-mediated (vs.antibody) and defined by a delayed response of the immune system, typically involving the gut.  No measurable antibodies are produced, symptoms are delayed (2+hours from ingestion) and include, but not limited to: sneezing, itching, runny nose, asthma, reflux, colic, abdominal pain, nausea, vomiting and diarrhea, and severe reactions can include lethargy, hypotension, and shock (see table below).  Like IgE allergies, the "Top 8" are included but are not limited in Non-IgE food allergies as any food protein can elicit this response.  Diagnosis included in this immune response are: Milk/Soy Protein intolerance, Multiple Food Protein Intolerance, Food Protein-Induced Allergic Colitis, Food Protein-Induced Allergic Procolitis, Food-Protein Induced Enterocolits, Food Protein Enteropathy, Celiac Disease, and Eosinophilic Disorders.  

IgE FOOD ALLERGY: (Typical food allergy) Immediate onset reactions	Non- IgE Food Allergy: (PROTEIN INTOLERANCE) Delayed onset reactions
Mediated by production of Immunoblogin E antibodies in response to a food, usually a protein.	Mediated by non-IgE antibodies and/or cellular immune responses to a food-protein.
Common Conditions*: 1.     IgE food allergy (ie egg, milk, peanut, tree nut, soy, wheat, shell fish…) 2.     Eosinophilic Disorders 3.     Oral Allergy Syndrome *list is not inclusive, please see your doctor for any symptoms/diagnosis	Common conditions*: 1.     Food Protein-Induced Allergic Colitis 3.     Food protein-Induced Allergic Protocolitis 4.     Food Protein -Induced Enterocolitis Syndrome 5.     Food Protein-Induced Enteropathy 6.     Celiac Disease (also auto-immune) 7.     Eosinophilic Disorders (also IgE) M     Milk/Soy Protein Intolerance 2.     Multiple Food Protein Intolerances *list is not inclusive, please see your doctor for any symptoms/diagnosis
Common Respiratory Symptoms: ·          Sneezing, runny nose, congestion, hay fever ·          Shortness of breath ·          Throat swelling ·          Cough ·          Allergic asthma ·          Pink eye/eye swelling	Common Respiratory Symptoms: ·          Non-allergic sneezing, congestion, runny nose ·          Non-allergic cough, asthma ·          Recurrent or chronic sinus   inflammation/infections ·          Reflux disease ·          Recurrent ear infections ·          Eye swelling ·          Enlarged adenoids
COMMON GI SYMPTOMS: Nausea/Vomiting/Diarrhea Cramping abdominal pain Reflux/Difficulty swallowing Swelling (tongue,lips,face) Itching/swelling of the tongue, lips, mouth Dizziness Fainting Severe reactions (anaphylaxis) can be life threatening and require immediate medical attention and can include: Itching or tightness in the throat Difficulty breathing Wheezing/coughing Rapid heart rate Low blood pressure Loss of consciousness Symptoms usually occur within minutes to 1-2 hours after ingesting the food.	COMMON GI SYMPTOMS: Mucus/Blood in Stools Inconsolable and extended crying/”colic” Loss of appetite Food aversions Disrupted Sleep Malabsorption/Vitamin Deficiency "Spit-up" an hour+ after feeding Sulfur/sour smelling stools Diarrhea and/or constipation Red  "ring" on bottom/peri-anal severe/persistent diaper rash Gas Mouth itching Intestinal dysbiosis Weight loss/difficulty gaining Symptoms can occur hours to days after ingesting the food. Severe reaction (FPIES) can be life threatening and require immediate medical attention and can include: Violent/forceful/projectile vomiting Lethargy Diarrhea Dehydration Low body temp or fever Low blood pressure Shock Click here for more information on: Celiac,  Eosinophilic disorders
Common skin symptoms: ·          Eczema ·          Hives ·          Rashes (dermatitis)	Common skin symptoms: ·          Eczema ·          Rashes/flushing ·          Itchy skin ·          Diaper rash             Dermatitis
Diagnostic Tests: ·          RAST (serum IgE) ·          Skin Prick Testing ·          EE requires endoscopy	Diagnostic Tests: ·          Atopy Patch Testing ·          Food elimination and challenge ·          Endoscopy/colonoscopy ·          Medical history

References:

1. Guidelines for Diagnosis and Management of Food Allergy in the United States (2010)
2. Medical Journal Article on Protein Intolerance (April 2010)
3. Nonimmunoglobin E-Mediated Immune Reactions to Foods by Dr.Spergel (2006)
4. Non-Ige Food Allergy by Dr.Jyonouchi (2008)
5. Food Allergy: Review, Classification and Diagnosis by Dr.Spergel & Dr.Cianferoni (2009)
6. Food protein-induced proctitis/colitis, enteropathy, and enterocolitis of infancy by Up To Date (2011)

Non-IgE Food Allergy is on the rise, and increasing in awareness as a seperate and valid clinical entity of food allergy, over the past 5-10years.   Although still little medical research and reports exist on this allergy subset.  Information can be found in the above resources, as outlined below:

As stated in the 2010 Guidelines for Diagnosis and Management of Food Allergy in the United States , "There is no current treatment for Food Allergy, the disease can only be managed by allergen avoidance or treatment of symptoms.   Moreover, the diagnosis of Food Allergy may be problematic, given that nonallergic food reactions, such as food intolerance [sugar,chemical,pharmacological], are frequently confused with Food Allergy's".  

This is a comprehensive report from an expert panel and includes:

• Definitions of Non-IgE food allergys, with symptoms and a table of Immediate and Delayed symptoms with their target organs affected (table IV on page 21).
• Diagnosis of Non-IgE mediated immunologic adverse reactions to food (section 4.3, page 27)
• Eosinophilic GI diseases
• Food protein induced enterocolitis
• Food protein induced allergic proctocolitis
• Food protein induced enteropathy syndrome
• Allergic contact dermatitis
• Systemic contact dermatitis
• Heiner syndrome. 

The Medical Journal Article on Protein Intolerance article (last updated April 2010) provides a full overview of the many manifestation of protein intolerance's. Discussions of IgE and Non-IgE Protein intolerance with a focus on GI symptoms being the most common in children with reactivity to food proteins.

The article outlines a basic discussion on oral tolerance and the immunologic and inflammatory mechanisms related to this process.   "Under normal circumstances, food antigen exposure via the GI tract results in a local immunoglobin A (IgA) response and in activation of suppressor CD8+ lymphocytes that reside in the gut-associated lymphoid tissue (Oral tolerance).  In some children who are genetically susceptible, or for other as-of-yet unknown reasons, oral tolerance does not develop and different immunologic and inflammatory mechanisms can be elicited".

Other points of interest:

• Food protein intolerance's can be IgE or Non-IgE mediated, studies have shown the role of gut T cell lymphocytes in the development of GI food allergy. 
• Mention here of IgG antibodies, but that their role is still not clear.  
• Protein Intolerance's generally resolve by age 5, with the maturing of the mucosal immune system. 
• A table is included to classify adverse reactions to foods. 
• With food protein intolerance's, GI symptoms are most commonly presented and can include:
• Oral Allergy Syndrome (IgE)
• Immediate GI hypersensitivy (IgE)
• Eosinophilic esophagitis, Eosinophilic gastrities, Eosinophilic gastroenteritis (IgE and Non-IgE)
• Food Protein Induced Enterocolitis
• Food-induced enteropathy
• Gluten-sensitive enteropathy
• Protein-losing enteropathy
• Food-Induced Proctocolitis
• Food-Allergy induced gastroesophageal reflux (GERD)
• Chronic constipation
• Colic
• Allergic dysmotility
• Multiple Food protein intolerance of infancy
• Dermatologic symptoms
• Respiratory symptoms
• General and non-specific symptoms are also recognized.  

A Review article on Nonimmunoglobin E-Mediated Immune Reactions to Foods by Dr.Jonathan Spergel (from 2006) discusses an overview of Non-IgE Food allergy that includes a table for differential diagnosis, with detailed discussions on:

• Skin reactions (Dermatitis herpetiformis and atopic dermatitis)
• Gastroinestinal Disorders (FPIES, Celiac)
• Combined IgE and T-cell mediated GI disorders (Eosinophilic)
• Non-IgE-Mediated Respiratory Reactions (Food-Induced Pulmonary Hemosiderosis)
• Clincal Tests for Non-IgE-Mediated Reactions
• Oral Food Challenges

In 2009, Dr. Jonathan Spergel with Dr. Antonella Cianferoni wrote Food Allergy: Review, Classification and Diagnosis outlines the increased recognition of cell-mediated disorders such as eosinophilic esophagitis and food protein induced enterocolitis.  The document also includes an easy to read chart for the classification of adverse reactions to foods. 

Manifestations of Food Allergy: Evaluation and Management was written by Dr.Scott Sicherer and reviewed by Dr.Hugh Sampson (in 1999) and includes tables that provide the differentiation of Food Intolerance's (Non-immunologic adverse reactions to food) and Food Allergy (IgE and Non-IgE and their target organs and disorders.   Dr.Sicherer also provides a sample Emergency Health Care Plan for children with allergies. 

In the article Non-IgE Mediated Food Allergy by Dr.Harumi Jyonouchi, the gut mucosal barrier and it's involvement in Non-IgE food allergy is thoroughly reviewed.   "The gut mucosal barrier is thought to have developed to execute an immensely difficult task; digestion and absorption of nutrients without provoking immune responses and cohabiting with commensal flora in a mutual beneficial relationship while maintaining an immune defense against pathogenic microbes".  Her review discusses, with immunological details:

• Intestinal Mucousal Immune System-discusses components of the mucosal immune system associated with the development of food allergy.
• Intestinal Homeostasis - Tolerance Induction and Maintenance- discusses mechanisms of tolerance induction and immune homeostasis.
• Factors Affecting Intestinal Immune Homeostasis- discusses genetic and environmental factors
• Non-IgE Food Allergy- discussed the pathogenesis of Non-IgE food allergy and clinical and laboratory findings.
• Diagnosis and Treatment- discussed importance of elimination diet and the importance of developing reliable laboratory testings for diagnosis of Non-IgE food allergy.  

Dr.Jyonouchi concludes to say that Non-IgE food allergy is "an easily treatable clinical entity. However when under-diagnosed/under-treated, serious and possibly irreversible complications can occur."

These delayed non-IgE cell-mediated food allergic responses are increasing in numbers.  More, and continued, research into the pathophysiology of the mechanisms of Non-IgE food allergy spectrum is needed, as well as awareness of clinical symptoms for timely diagnosis and treatment.

Nutrigenomics: The Scientific Link Between Genetics and Nutrition

"Nutrigenomics: The Scientific Link Between Genetics and Nutrition".   A home study course I completed, put out by the Institute for Natural Resources and I am unable to locate an online version.   But I did find this link that outlines much of the same information:  Nutrigenomics

The article begings with a great introduction essentially introducing you to the world of nutrigenomics...did you ever wonder what it would be like if we knew what we could and couldn't eat from the day we are born?....or if we knew what we were predisposed to and could alter our eating habits specifically for those diseases. (Diabetes, heart disease, Cronhs, Cancer).   We may be able to with combining the worlds of Nutrition and Genomics.  "Nutrigenomics tries to determine the influence of common dietary ingredients on the genome and relate the resulting phenotypes to differences in the cellular and/or genetic response of biologic systems.  It analyzes the response of whole systems to nutrients and studies how food or food ingredients affect the metabolic pathways and alter gene expression".  

A major project took place from 1990-2003: The Human Genome Project yielded this field of nutrigenomics.  "Information from the human genome is making it possible to identify the genetic factors that influence a person's susceptibility to disease associated with diet.....In dietary related disorders, these interventions will involve dietary changes or the inclusions of functional food components, or both."

"Genes evolve in response to many types of environmental stimuli including nutrition." (genetics loads the gun, environment pulls the trigger).   There are genetic markers for many chronic diseases, one has not been found yet for FPIES but it is clear from the research thus far that there is a genetic component.   But what component turns it on?   It is the maternal diet?   Is it the infants diet?   Is it the gut flora?  It is antibiotic use? 

The tools used in Nutrigenomics are multidisplinary: Transcriptomics, Proteomics, Metabolomics, and Bioinformatics.  
"Transcriptomics measures the level of expression of all or a selected subset of genes based on the amount of RNA in a sample, using mircoarray analysis to see how genes react to change.  Nutrients can have a direct effect and interact with transription factors to regulate gene expression."  
"Proteomics is the study of proteins that can be expressed within an organism.  Proteomics focuses on the analysis of proteins and their interactions with other biologic molecules>'
"Metabolomics is the study of the complete set of metabolites that an organism produces.  Genes are turned on and off according to metabolic signals that the nucleus receives from internal factors such as horomones and external factors such as nutrients."
"Bioinformatics handle the vast amount of data produced.  It is now possible to predict gene function and identify the regulatory regions in the genome that influence gene expression". 

Understanding nutrigenomics requires an understanding of the cell.   DNA is the genetic material of the cell, it is arranged in untis called chromosomes, of which we have 23 and genes are spread throughout these chromosomes. 

The study of nutrigenomics also requires knowledge of polymorphisms.   "A polymorphism is the quality of existing in several different forms.  These differences can result from genetic predisposition, environmental influences, or a combination of both.....Several genetic polymorphisms important to nutrition have been identified."  These can be catagorized into 2 catagories:
1). Monogenic Diseases, in which a disease arises from on abnormal gene, these can range from lactose intolerance to PKU or galactosemia.  
2). Chronic Diseases such as cardiovascular disease, diabetes, cancer, obesity, and inflammatory bowel disease. 

The course goes on to discuss effects of micro and macro nutrients at the molecular level as well as the current dietary inteventions and guidelines for disease.   This is my job description in a nutshell so I skimmed over this! But essentially, nutrients have many roles in the body from influencing metabolism and physiology at the molecular level to fuel and co-factor roles.  The role of foods from macronutrients (carbohydrates, fats, proteins) to micronutrients (vitamins, minerals) play is complex and closely intertwined.   "Eat a balanced diet" is always good advice!  It does go on to discuss Dietary Interventions and Guidelines and how with the possibilities of nutrigenomics, one could "tailor" their diet to offer precise dietary advice for specific genetic testing results.   Currently, genetic predisposition with generalized healthy recommendations are what we work with but this can be restricting if there are multiple genes interacting with each other coupled with environmental variables that contribute to the diseases.   

It continues to describe how bioactive food components "alter gene expression in a host of cellular events".

The paragraph within the functional food chapter was of interest to me, and I think will be to other FPIES families: "One of the targets of functional foods will be the gut, which acts as an interface between ingested food and the body.  In addition, the gut serves as the barrier to harmful substances entering the circulation.   Ingestion of functional foods will be beneficial to the microflora of the gut.   These bacteria, in addition to their protective function, generate energy by digesting fermentable carbohydrates.  The microflora of the large intestine is aquired shortly after birth, and its composition is dependent on diet.   We all have our own specific microflora.  Certain species of gut microflora can help reduce the risk of gastrointestinal infections, constipation, irritable bowel syndrome, inflammatory bowel diseases, and possibly colorectal cancer.   Therefore, intestinal microflora could be a part of a personalized nutritional program." 

It goes on to describe probiotics and prebiotics.  "Probiotics and prebiotics could be developed to alter the microflora of the gut....a prebiotic is a non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or modifying the metabolic activity of one or a limited number of bacterial species in the colon that have the potential to improve host health....to be classified as a prebiotic, a food must not be absorbed in the upper part of the gastrointestinal tract and must stimulate growth of the beneficial microflora that is resident in the colon.   Prebiotics also have additional benefits on the immnue system and may inhibit the formation of adenomas and carcinomas".

The conclusion is "Genes are turned on and off by what we eat".   "The interaction between nutrition and the human genome determines gene expression and the metabolic response".  

So, we really are what we eat....

Research Studies on Non-IgE Allergy

We recently took my son to be involved in a research study at the PCRCD.  

Dr.Jyonouchi runs this clinic and her current research is: Th cell polarization and candida reactivity in autistic children with food allergy. It is described: "Our previous study has shown that a high percentage of ASD children with GI symptoms reveal evidence of non IgE mediated, delayed type food allergy (NFA) against common dietary proteins (DPs) and their clinical features are similar to those in non-ASD children with NFA.  In infants, the gut immune system is immature and oral tolerance develops slowly during the first 2-3 years of life.  Thus, most non-ASD/NFA children outgrow this condition by 3-4 years of age.  However, ASD/NFA children appear to require a longer time to outgrow NFA, indicating a possibility that ASD/NFA children have immune abnormalities rendering them more reactive to ‘harmless’ luminal antigens (food and commensal flora.)  In this study, we thus hypothesize that dysregulated gut mucosal immune homeostasis is associated with altered innate immune responses that affects development of T-helper (Th) subsets.  There are two specific aims for the current study:  (1) Assessment of Th cell polarization in ASD children with NFA by intracellular staining of lineage-specific cytokines in Th cells.  (2) Assessment of anti-inflammatory Th cell responses in ASD children with NFA by measuring production of counter-regulatory cytokines in response to specific luminal Ag

in comparison with responses to stimuli of innate immunity.  Our long-term objective is to assess immune abnormalities associated with oral tolerance in ASD/NFA children. Obtained data are expected to be helpful for identifying risk factors for development of NFA and dysbiosis in autistic children."

(PI: Harumi Jyonouchi, M.D.  University of Medicine and Dentistry of New Jersey-New Jersey Medical School.)

Our son, and the other FPIES children that are going there are among her "control" group.   The Non-IgE Food Allergy children without ASD (autism spectrum disorder).  

Dr.Jyonouchi has done a few studies of this nature.  In the study, she tests for the production of proinflammatory (TNF-a, IFN-g, IL-5, IL-12) and counter-regulatory (Il-10, IL-17, TGF-b, ) cytokines production to milk (whey and casein), soy, wheat (gliadin), as well as Candida.   The results can help determine classic, chronic, aytpical FPIES responses to these proteins; but mostly it can help determine where in these mechanisms the "break down" is.   Does your child have too strong proinflammatory cytokine responses?  Treating every protein as foreign and launching attacks of inflammatory mediators?  Does the body respond with proinflammatory mediators only to lack sufficient counter regulatory cytokines?  Does the body produce minimal proinflammatory mediators but then over-react with counter-regulatory cytokines?   It can define more of what is happening at this cellular level.   Past research has led to the T-cell mechanism of a Non-IgE food allergy; these tests help define that- with dairy, soy, wheat proteins. 

Dr.Jyonouchi has studied the effects of Non-IgE food allergy (by immune mechanisms to food proteins as described above) with populations of Autistic Spectrum disorders, as well as Inflammatory Bowel Diseases.  She describes Non-IgE food allergy in her paper: Non-IgE Food Allergy.

Dr.Jyonouchi concludes much of her findings for treatment around gut homeostasis, and notes in this Pediatric Allergy and Immunology article that "it is crucial for gut mucousal immmune system to establish immune homeostasis that permits us to 1). cohabit with commensal flora under a mutual benefiical relationship, 2). digest huge amounts of macronutrients without provoking immune reactions (oral tolerance), and 3). maintain effective immune defense against pathogens.  This somewhat conflicting task may make the gut mucousal immune system error prone, requiring active counter-regulatory measures such as developement of regulatory T (Treg) cells.   These measures appear to develop gradually during the first few years of life and this is why infants are prone to be reactive to common dietary proteins in IgE or Non-IgE dependent manner." 

I follow her here as much of my own research leads me here as well.   While there is much of her research that we can transfer to learn more of FPIES immune responses, mechanisms, gut flora and homeostasis in our own children....but more FPIES-specific research is needed.  

Pros of Probiotics

There is SO much information on probiotics, from research studies to yogurt advertisements to health claims of yeast overgrowth control.   I wanted to find a quick/easy read that would sum up the good information well, I did find this article on the: Pros of Probiotics, but to sum it up....

Probitoics can help restore your good gut flora.  

Good gut bacteria aids in: digesting food, producing vitamins, preventing infections, and regulating the immune system. 

This alone tells us why probiotics are so important to the health of an FPIES child.   Finding one free of triggers (even trace amounts) and strains that are tolerated (due to extreme dysbiosis) can be a challenge.

We begin our journey with gut flora in the birth canal, and it is further established in breastmilk.  These are critical times for establishment of gut flora since babies immune systems are still developing.

Studies have proven the beneficial effects of specific strains of probiotics on viral and antibiotic induced diarrhea.   More studies continue to show the health benefits.  Probiotics balance the immune system, they grow and flourish in the GI tract but their benefits travel through the body.  

Without good gut flora, digestion and absorption of nutrients can't proceed naturally.   The increased acidity of the GI tract (from good gut flora) protects against yeast.   Candida albicans yeast grows and spreads when good gut bacteria fall.

Factors that can make gut flora decline: refined foods, antacids and other acid-lowering drugs, intestinal flu, colonoscopy (cleansing for), antibiotic and steroid drugs, and stress.

Intestinal inflammation is reduced by good gut flora.   Inflammation that can cause tiny holes in intestinal walls and allow larger proteins to pass through into the bloodstream, resulting in a toxic effect.  

Good gut flora protects against bacteria, infections, enhances WBC activity and supports cytokine production (so cells can communicate effectively), as well as cancer prevention.

The beneficial bacteria manufacture nutrients in the body such as amino acids, antioxidants, B complex and Vit.K, short chain fatty acids.    Fermented foods make nutrients more available for absorption in the body (functional foods). 

And finally, this particular article outlines this final recommendation that is echoed in the literature:  
"Nutritionist Betty Kamen, PhD, calls live culture probiotics (available in a yogurt-like mix or nondairy medium) the "gold standard." But she also recommends dry capsule products for a mix of different species. "Ideally, the probiotic supplement you choose should contain L. acidophilus and/or other Lactobacillus strains and strains of Bifidobacteria," says Dr. Earl Mindell. "Probiotics are safe even in doses far greater than anyone would intentionally take," he adds. However, anyone with severe immune dysfunction or any life-threatening disease should use probiotics only under professional supervision."

Gut Homeostasis

The functioning of the gut is important to our overall health.
Indeed, we now know that intestinal flora plays an important role in health: stimulating the immune system, protecting the host from invading bacteria and viruses, aiding digestion and assimilation of food. Yet, the importance of these bacteria in the gastro-intestinal “GI” tract has been neglected for a long time, while the focus was merely placed on enteric pathogens and other factors leading to gastrointestinal "disorders".Custom Probiotics

Gut microflora is specific to each individual, established at birth- resident flora does not change substantially from birth.   However, many things in life can change the density,numbers/concentration, and ratio of good to bad microflora.  These things include: diet, antibiotics, illness, stress, infection, the list goes on but these are the main effectors.  To achieve homeostasis, there needs to be a balance of good gut flora to bad. "Lactobacilli and Bifidobacteria, should predominate, presenting a barrier to invading organisms. Around 85% of the intestinal microflora in a healthy person should be good bacteria and 15% bad bacteria. The greater the imbalance, the greater the symptoms" Custom probiotics

You'll notice my above links, a fellow FPIES mom shared the link in her search for probiotics for her child.   I typically don't quote websites that are also selling something and proceed with caution with their information (as I just need to re-research it to be sure it is medically sound information) but the above information is good information from their site, which I found easy to read through (although they are selling something and although it looks like a promising probiotic, as always check with the manufacturer for safe ingredients first!).   The reason I have bookmarked their site is because they have a GREAT illustration of the intestines and it's tie to the immune system.  So, if you'd like a look at that- visit this site and scroll down the page a few paragraphs. 

It shows the villi and crypt of the intestines.  The villi and crypt can be damaged in severe/chronic FPIES inflammation, therefore causing further cascading problems of illness from increased intestinal permeability (leaky gut) due to the inflammation opening "holes" in the intestine, thereby causing further damage, deficiencies and mostly allergies/intolerance's as proteins "leak" into the blood stream (via the lymph).   Villi damage can also lead to nutritional deficiencies and weight loss as this is where nutrients are picked up from the broken down food molecules. 

Intestinal flora forms a natural barrier to pathogens and also work together with the GALT (intestinal immune system within the GI tract made of lymphoid cells), comprised of Peyer's Patches (which facilitate the beginning of the immune response in the GI tract), Paneth cells (control microbes) and dendritic cells (micro flora communication).   When the antigenic presenting dendritic cell (where micro flora have their role) activates the lymphocytes,  it leaves the mucousa via the lymph and enters the blood stream via the thoracic duct.  The activated lymphocytes then travel back to the gut and can colonize in the same mucousa or other mucousal sites along the GI tract.    This is where the Tmemory cells are then stored and activated upon re-exposure to trigger (antigen) proteins (and likely why the re-exposure can be a more intense response because of the recognition from previous activated lymphocytes. 

Probiotics can help manage that balance once it has been established (past infancy).   Probiotics have antimicrobial effects (pathogens, toxins), maintain intestinal epithelium (barrier), and regulate the immune system via the GALT (inflammatory responses to allergens and other inflammatory substances). 

It is clear the balance (homeostasis) of micro flora in the gastrointestinal tract is important to immune responses.

Gut Flora and Immune System

One of the roles of gut micro flora is to help regulate the immune system.  Probiotics aren't residential gut flora- they are visitors to help that flora flourish, and even heal a damaged or immature gastrointestinal system. 

We are most familiar with probiotics being responsible for changing the composition (numbers and density) of the resident microflora and thereby restore gut damage but another critical role is in regulation of the immune system. 

"As such, your gastrointestinal tract is lined with its own set of immune cells to help prevent these harmful substances from gaining entry to your body. These immune cells are called the gut-associated lymphoid tissue (GALT). The GALT is the largest mass of immune tissue (lymphoid tissue) in the human body and as such is an important element of the body's immune system. You may be familiar with other lymphoid tissues such as the tonsils and spleen. The tonsils are also located in an area where you are commonly exposed to harmful substances (the throat)."- Allison Tannis, Probiotic Rescue: How You can use Probiotics to Fight Cholesterol, Cancer, Superbugs, Digestive Complaints and More.

Multiple studies have shown Lactobacillus strains promote Th3 (oral tolerance) immune responses.
This article shows that "overall pieces of evidence are beginning to accumulate that support a model whereby disruption of the micobiota also disrupts oral tolerance, potentially by interfering with the dendritic cells (DC) that promote allergen specific regulatory Tcell responses".

The mucosal barrier function of the gut depends on the establishment of of the microflora (at birth). "The immature gut barrier may lead to aberrant antigen transfer and immune responses, thus explaining increased vulnerability to breakdown of oral tolerance....In particular, intestinal colonization acts as an important antigenic stimulus for the maturation of the gut-associated lymphoid tissue. The demonstration that the gut microflora are an important constituent of the intestine's nonimmunologic and immunologic barrier has brought about the concept of probiotic therapy: therapeutic application of consumption of cultures of potentially beneficial bacteria.....Moreover, the intestinal microflora contribute to the processing of food antigens in the gut, and probiotics have been shown to modify the structure of potentially harmful antigens and reduce their immunogenicity in vitro and in vivo, together with a potential to dampen hypersensitivity reactions . These effects are seen as a significant improvement in the clinical course of atopic dermatitis (eczema) in infants given probiotic-supplemented elimination diet, and in parallel, markers of intestinal and systemic allergic inflammation decreased significantly."Functional Foods and Probiotics.

As I read through several articles in my research on the role of probiotics and established micro flora, I come across language that suggests that with impaired immunity regulations, the body isn't just attacking food proteins but the established micro flora as well.   This article on Early Nutrition is an insightful read for this concept. 

Within much of the research is reminders that there is so much more to be researched in the field of microbiota and probiotic therapy (effects and limitations of).   Initial research has shown addition of beneficial strains of lactobacillus and bifida bacteria to be a helpful component in the treatment of inflammatory disorders.

The Immunological Basis for Gastroinestinal Food Allergy (Understanding FPIES mechanisms series, part 3)

My review of the article: The Immunological Basis for Gastrointestinal Food Allergy


Summary: Food Allergies are now being recognized as being a treatable component of the atopic march.

Food allergies are common in children. Significant impact on quality of life (more research is needed because of this increasing). Recently there has been a shift in the recommendations after realization that delayed food exposures may be harmful in immune sensitization. “Instead strategies aimed at early introduction of foods to induce oral tolerance are now being re-evaluated…very encouraging results are being obtained in desensitizing allergic children via oral tolerance.” (TH3 vs. Th1 responses). The goal is not to induce complete tolerance in all cases but to raise thresholds, thus minimizing reactions to trace proteins (increasing quality of life by better control of allergy).

Research has shown that all infants have T cell responses to food antigens . In a small subset of children, there is an inappropriate immune response which results to sensitization of food antigens. “The critical question is not necessarily exposure to food antigens but the nature and type of immune response which an individual generates to these antigens.”… not the type, timing or dose of exposure but these variables are imposed on the individual, and complex immune system- in a time when the immune system is still developing (infancy).

Progress in GI food allergy remains slow, given all the complexities. Food allergy in children remains treatable when properly diagnosed and after a period of avoidance, oral tolerance is developed. The studies have increasing emphasis on immunology.

The paper goes on to discuss current research on the timing (early exposures or delayed introductions of food proteins into the infants diet) is affecting the rise in food allergy. It sites this article article for references as an excellent read on the growing/ongoing subject of research into infant food allergy (delayed introductions past 4-6mo. May have negative effects vs. previously thought of protective effects on oral tolerance.

The article goes on to discuss Regulatory T Cells and Food Allergy. “it is clear that there exists a population of CD4+, CD25+ T cells in blood whose primary function is to regulate immune responses”. Studies have shown that infants who develop food allergies have lower Treg cells function than non-allergic infants…”suggesting that a defect in Tregs may predispose to food allergy”. More research is needed in this area.

It covers a little in this article on desensitization in food allergy- by repeated systemic treatment with allergen. It is being recognized as treatment for allergies although specific mechanisms remain unclear it is thought to be “induction of Treg cells or blocking anti-bodies, or both. Desensitization is sublingual immunotherapy (SLIT)- small amount of allergen is placed under the tongue, and oral immunotherapy (OIT) which is feeding small amounts of the allergen". It does go onto to describe a more recent approach of introducing allergens via extensively heated proteins (with IgE antibody allergy) and studies have confirmed this with milk allergic children tolerating extensively heated milk. It goes onto to clarify that the goal of this immunotherapy isn’t only to allow the food to be completely tolerated (non-allergenic) but to simply raise the threshold of tolerance in anaphylaxis response allergy (thereby increasing quality of life).

The article also sites the Finnesh Allergy Programme 2008-2018 as a “highly ambitious project to reduce the burden of allergies” Stating that the background is based on immunological responses- focused on continuous exposure to antigens and strengthening and restoring immune tolerance mechanisms.

The article wraps up with a mention of delayed onset food allergies (and how slow research is in understanding it), but points out that IgE allergy are T-cell dependant as well so that there can be crossovers in strategies.