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Key Differences Between Food Allergy and Intolerance

John Leung, M.D.

CEO and Founder of Boston Specialists

Adjunct Professor, Tufts University

Board certified gastroenterology and allergist

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Clinical interests

2

GI

AI

Food intolerance/allergy
EoE, EG/EoD, EC
Celiac/NCGS
Mast cell related GI disorders
Biological desensitization
Misc enteropathy (Lichen planus, lymphocytic, autoimmune enteropathy, CVID)

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WHEAT

Protein

(gliadin component of gluten)

Celiac

IgE Allergy

Serology

Endoscopy

f416 & f98 IgE

Skin testing

Protein

(Tri a19 & Gliadin)

Eosinophilic

Esophagitis

Endoscopy

Protein

(Unknown)

Fructan

Intolerance

FODMAP

Breath test

Unknown

? amylase trypsin inhibitors (ATIs)

NCGS

Elimination

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Agenda

Overview of adverse food reactions

key differences between allergy/intolerance

Food allergy

symptoms, evaluation and management

Food intolerance

Case study – practice highlights

4

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You have a 25 yo woman who developed bloating, alternating constipation and diarrhea, and cramps that relieved with BM.

What is the diagnosis?

IgE mediated food allergy
IBS/food intolerance

What to do next?

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You have a 5 yo girl who developed hives, wheezing and vomiting 20 minutes after ingesting a peanut snack.

What is the diagnosis?

IgE mediated peanut allergy
IBS/food intolerance

What to do next?

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Terminology

Examples:

	Food Allergy (8%) Immune mediated		Intolerance (25%) Non-immune
	IgE	Non-IgE
Life-threatening	Yes	Yes	No
Anaphylaxis	Yes	No	No
Examples	Milk, egg, soy, nuts, seafood, wheat allergy	Eosinophilic esophagitis Celiac Allergic colitis	Lactose intolerance GERD MSG Scombroid

Adverse Food Reaction

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Terminology

Examples:

	Food Allergy (8%) Immune mediated		Intolerance (25%) Non-immune
	IgE	Non-IgE
Life-threatening	Yes	Yes	No
Anaphylaxis	Yes	No	No
Examples	Milk, egg, soy, nuts, seafood, wheat allergy	Eosinophilic esophagitis Celiac Allergic colitis	Lactose intolerance GERD MSG Scombroid

Adverse Food Reaction

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Terminology

Examples:

	Food Allergy (8%) Immune mediated		Intolerance (25%) Non-immune
	IgE	Non-IgE
Life-threatening	Yes	Yes	No
Anaphylaxis	Yes	No	No
Examples	Milk, egg, soy, nuts, seafood, wheat allergy	Eosinophilic esophagitis Celiac Allergic colitis	Lactose intolerance GERD MSG Scombroid

Adverse Food Reaction

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Terminology

Examples:

	Food Allergy (8%) Immune mediated		Intolerance (25%) Non-immune
	IgE	Non-IgE
Life-threatening	Yes	Yes	No
Anaphylaxis	Yes	No	No
Examples	Milk, egg, soy, nuts, seafood, wheat allergy	Eosinophilic esophagitis Celiac Allergic colitis	Lactose intolerance GERD MSG Scombroid

Adverse Food Reaction

Food protein induced enterocolitis

(FPIES)

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Terminology

Examples:

	Food Allergy (8%) Immune mediated		Intolerance (50%) Non-immune
	IgE	Non-IgE
Life-threatening	Yes	Yes	No
Anaphylaxis	Yes	No	No
Examples	Milk, egg, soy, nuts, seafood, wheat allergy	Eosinophilic esophagitis Celiac Allergic colitis	Lactose intolerance GERD MSG Scombroid

Adverse Food Reaction

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Terminology

Examples:

	Food Allergy (8%) Immune mediated		Intolerance (25%) Non-immune
	IgE	Non-IgE
Life-threatening	Yes	Yes	No
Anaphylaxis	Yes	No	No
Examples	Peanut allergy	Celiac	IBS

Adverse food reaction

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IgE mediated food allergy

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http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/LabelingNutrition/ucm059098.htm

$25,000,000,000

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IgE food allergy - Key concepts

IgE-mediated, immediate, reproducible allergic reaction to a specific food

Definition

Egg: >50% by age 5
Milk: >60% by age 5
Wheat >80% by age 5
Peanut: ~20%

Outgrowing phenomena

Milk, soy, eggs, wheat, peanuts, tree nuts, fish and shellfish, sesame

Big 9

>70% egg/milk-allergic tolerates baked goods

Cross-allergy among nuts and shellfish is common

GMO foods are not allergic-prone

Pearls

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Various hypotheses have been put forward to explain the rise in food allergy. Integration of the

vitamin D deficiency, hygiene, and dual-allergen exposure hypotheses (which is the focus of this

chapter) are shown in Figure 1.

This paper focuses on the ‘dual allergen exposure hypothesis’ which suggests that allergic

sensitization to food occurs through low-dose cutaneous sensitization, whilst early consumption

of food protein induces oral tolerance.7 This hypothesis was developed following publication of

studies demonstrating a strong association between dietary exposure, eczema and the

development of food allergy.

i) Studies demonstrating the role of cutaneous sensitization in FA

Animal and human observational and in-vitro studies demonstrate transcutaneous sensitization to

food allergens through inflamed eczematous skin. In humans, the topical application of Arachis

(peanut) oil onto eczematous skin during infancy was significantly associated with peanut allergy

in eczematous children.8 Environmental exposure to peanut during infancy (assessed by

household peanut consumption) increased the risk of peanut allergy; however, if the infant had

consumed peanut in the first year of life, they were protected against developing peanut allergy.9

More recent studies found that eczema severity amplifies the risk of peanut sensitization and

likely allergy resulting from exposure to peanut antigen in household dust.10 A similar increase

of peanut sensitization and allergy risk was seen in children with filaggrin loss-of-function

mutations exposed to high levels of peanut allergens in the household dust.11 This provides a

good example of gene-environment interactions leading to the development of peanut allergy in

young infants.

A cross-sectional study assessed the route of peanut exposure in the development of allergy and

captured maternal peanut consumption during pregnancy, breast-feeding, and in the first year of

life via a questionnaire. Household peanut consumption was also quantified. The median weekly

household peanut consumption in the patients with PA was significantly increased (18.8 g)

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IgE food allergy - diagnosis & treatment

Skin test ⇿ Blood test

PPV 50%; NPV >90%

History is key

Oral challenge

Hives most common

Multi-organs

No hives <> No rxn

Epinephrine stops Rx

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Xolair - “an option” (2/2024)

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IgE food allergy - prevention

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Early introduction

w/ cautions

Omalizumab Immunotherapy

Nuts consumption

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IgE food allergy - summary

Adverse food rx = Food allergy + intolerance
Food allergy vs intolerance
Food allergy (IgE vs non-IgE)
IgE mediated food allergy

Quick and reproducible
Dual antigen hypothesis
9 common allergens, outgrow
Hives is the most common
Diagnosis hinges on history, tests are supportive
Epinephrine is the only rx for anaphylaxis
Avoidance, Xolair, Immunotherapy are options
Early and peri-pregnancy exposure
Baked eggs and milk are often tolerated

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You have a 25 yo woman who developed non-specific abdominal pain, bloating, nausea, 6 loose BM/day. Symptoms are worsened with meals. She suspects gluten and sweet foods seem to be trigger(s), but she is not sure

What will you do next?

Labs
Reassurance
FODMAP

What to do next?

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You have a 25 yo woman who developed non-specific abdominal pain, bloating, nausea, 6 loose BM/day. Symptoms are worsened with meals. She suspects gluten and sweet foods seem to be trigger(s), but she is not sure

What will you do next?

Labs
Reassurance
FODMAP

What to do next?

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Diagnostic algorithm

IBS-like

Blood: CBC, CMP, celiac

Stool: c diff, calprotectin & giardia

Alarm features

•Onset after age 50

•Rectal bleeding

•Nocturnal diarrhea

•Progressive abdominal pain

•Weight loss

•Lab abnormalities

•Fx of IBD or colorectal cancer

Neg

AGA Clinical Practice Guideline. Am J Gastroenterol. 2021;116(1):17.

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Food intolerance algorithm

IBS-like

Blood: CBC, CMP, celiac

Stool: c diff, calprotectin & giardia

Alarm features

Elimination diet

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What food to eliminate?

Commercial IgG food panel
Food allergy skin prick testing
Empirical eliminations such as low FODMAP

CGH 2021 Nov;19(11):2030

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What food to eliminate?

Commercial IgG food panel
Food allergy skin prick testing
Empirical eliminations such as low FODMAP

CGH 2021 Nov;19(11):2030

ACG Clinical Guideline 2021

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Therapeutic diets for bowel diseases

Diet	Efficacy	Expert
Low FODMAP diet	~ 40-60% ,13 RCT	Recommended
NICE	Less superior than LFD
Fiber supplement Psyllium	NNT 7 in meta-analysis	Alone or with LFD
Chinese Yin/Yang Ig-G guided Low-residual Mediterranean	N/A	Not recommended

Gastroenterology. 1991;101(4):927.

Am J Gastroenterol 2013;108:634–41.

Affects 15% of the population, 84% identified food as key trigger

NICE = NI health Care and Excellence = regular meal time, fluid, limit fruit intake, more fiber, lactose-free, avoid spicy food and triggers

A multicenter, parallel group, single-blind RCT from Sweden compared a dietitian-led LFD with standard dietary advice (based on the NICE guidelines) over 4 weeks in 75 patients with IBS (⁹). Both groups experienced significant improvement in symptom severity (measured using IBS-SSS) at the end of the 4 weeks compared with that in baseline (P < 0.001), without a difference between the groups (P = 0.62) (⁹). In a US study, 84 patients with IBS-D were randomized to an LFD or modified NICE (mNICE) diet for 4 weeks (⁸). Fifty-two percentage of the patients in the LFD group reported an adequate relief of overall IBS symptoms compared with 41% in the mNICE group; the difference between the groups was not statistically significant (P = 0.31). However, an LFD resulted in a significantly higher proportion of abdominal pain and bloating responders compared with those in the mNICE group (P < 0.01(⁸) for both comparisons). This study also reported improvements in IBS-related quality of life and reductions in activity impairment with LFD compared with those with the mNICE diet (²⁶).

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Standard FODMAP 3 steps approach

Options to do FODMAP

Restrict

Reintroduction

Refine

Issues = take a long time, difficult, frustrating

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Standard FODMAP 3 steps approach

Options to do FODMAP

Undigested sugar reaches colon

Bacteria ferment it and produces gases

Gases H2, CH4 absorb into blood & exhale

Restrict

Reintroduction

Refine

Issues = take a long time, difficult, frustrating

Alternative = breath test guided

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SIBO

Lactose

Fructose

Fructan

Sorbitol

Food intolerance testing

Am J Gastroenterol . 2017 May;112(5):775-784.

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Labs and breath tests were all normal.

No response to low FODMAP.

She still thinks food is the issue and refused to try medications as she believes the root of the problem is food.

What is the next step?

Sucrose deficiency test
Reassurance that medicine is effective

What to do next?

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Labs and breath tests were all normal.

No response to low FODMAP.

She still thinks food is the issue and refused to try medications as she believes the root of the problem is food.

What is the next step?

Sucrose deficiency test
Reassurance that medicine is effective

What to do next?

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Congenital Sucrase-Isomaltase deficiency (CSID)

Some experts believe that it should be checked
Overall rare, higher in refractory IBS

3-step concept

Empirical
Reintroduction
Personalize

http://dx.doi.org/10.1136/gutjnl-2021-326153

Gastroneterology & Hepatology 2022, vol 16, Issue 10

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CSID

0.2 % in gen pop, 4.2%-35% in IBS
7 phenotypes, various severity, young adults
IBS refractory to low FODMAP
Diarrhea, loose BM, gas, bloating, cramping, nausea
8 tests, but C13-sucrose breath test is preferred
Supplemental enzymes are available via prescription

J Pediatr Gastroenterol Nutr. 1999;28(2):137-142

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Food intolerance - summary

Food intolerance: common & not immune
Alarming symptoms (appetite/weight loss)
Routine labs
Dietary treatment for IBS

FODMAP +/- Psyllium

Empirical or breath-test guided
Suspect CSID in refractory cases

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CSID was ruled out. She also failed to respond to low dose TCA , psyllium, peppermint oils, and reassurance/rapport. She now develops food aversion and slowly losing weight.

What is the next step?

Try pro-and pre- biotics
Check for candida overgrowth
Fix the leaky gut
Low histamine diet

What to do next?

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Probiotics/Microbiomes

Fecal transplant not working (4 studies/n=254)

Probiotics do not work

ACG Clinical Guideline: Management of Irritable Bowel Syndrome 2021;116:17–44

Fecal transplant not working (4 studies/n=254)

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Candida overgrowth

Curr Opin Microbiol. 2011 Aug; 14(4): 386–391.

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Candida overgrowth

CO is more common in ulcers and IBD
Same dx use more antibiotics + immunosupp
CO may not be the cause, but consequence
CO causes inflammation and delays healing
Candida colonization has protective effects
No treatment for CO is effective

Curr Opin Microbiol. 2011 Aug; 14(4): 386–391.

PLoS Pathog . 2021 Jul 22;17(7):e1009710

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Leaky gut concept

No consensus on the diagnostic criteria
No available test in clinical practice
No validated treatment for leaky gut
No evidence to show that restoration of intestinal barrier can reverse diseases

Camilleri. Current Opinion in Clinical Nutrition and Metabolic Care. 2021

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Low histamine diet

Appear in literature in 1980’s
Exploded in the # world
Histamine is degraded by diamine oxidase and histamine N-methyl-transferase
No validated biomarkers to diagnose
No agreement on what food is low in histamine
Too restrictive, confusing, and no proven result

Germann guideline. Allergo J Int. 2017; 26(2): 72–79.

Nutrients. 2021 May; 13(5): 1395.

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Try pro-and pre- biotics
Check for candida overgrowth
Fix the leaky gut
Low histamine diet

What is the next step?

What to do next?

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Let’s refer to GI, Allergy and RD

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What is next?

Allergist: Food allergy testing was neg. She did not think the symptoms are consistent with food allergy.

GI: Normal US + EGD + colonoscopy + capsule endoscopy.

She tried low histamine diet, but no luck, and lost more weight due to extremely restrictive diet.

What differential diagnoses should be considered at this time for GI symptoms triggered by food(s) but negative workup?

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Differential diagnosis for food related GI disorders

Eosinophilic gastrointestinal disorders
Mast cell gastrointestinal disorders

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EG/EoD and MGID Have Similar Symptoms

Bledsoe et al. Abstract for DDW 2020

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EGID/MGID

IBS- like symptoms
More common than we used to think
Diagnosis is easily missed

GI does not do biopsy, or bx enough
Pathologist may not report eos/mast cell count

If you don’t look for it, you miss it
Food elimination is effective (but difficult)
Clinical trials are underway

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What to do?

Patient was diagnosed with EGID
She has been enrolled into the clinical trial

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Take home points

Adverse food reactions: allergy vs intolerance
Food allergy (IgE and non-IgE)
IgE food allergy
Food intolerance
FODMAP ± psyllium
CSID in refractory IBS
EGID and MGID is more common than you think
EGID/MGID will be missed if you don’t look for it
Role of IgG test, leaky gut, Candida overgrowth, Low histamine diet, Probiotics

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The end

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Clinical trials

Study	Disease	Drug
PRV-015-002b	Celiac	PRV-05
TAK-101-2001	Celiac	TAK-101
RVLO 121-04	EoE	IRL-201104
AK002-014	EoE	Anti-Siglec 8
MESSINA	EoE	Anti-IL5
SP-1011-004	EoE	Fluticasone tab
CC-93538-EE-01	EoE	Anti-IL13
Ak002-016X	EoG/EoD	Anti-Siglec 8
PT-01	Peanut allergy	SLIT
AK002-027	Chronic hives	Anti-Siglec 8

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Mechanisms of eos and mast cells

Am J Gastroenterol 2022;117:937–946.

Increased mucosal permeability is proposed as an underlying alteration, allowing food proteins in the lumen to activate mast cells and/or eosinophils in DGBI patients. The latter may lead to release of cytokines and other signaling molecules in the circulation, recruitment of inflammatory cells and altered neural (e.g., through eosinophil-derived neurotoxin) and hormonal control of gastrointestinal sensorimotor function, triggering nutrient-induced symptoms. The mechanism through which food proteins activate mast cells or eosinophils in DGBIs remains to be established. Proposed pathways involve locally produced immunoglobulin E (IgE) acting on the FceR receptor, immunoglobulin G (IgG) acting on the FcgR receptor or non-Ig mediated activation of mast cells through pattern recognition receptors (PRRs) or the mas-related G-protein coupled receptor X2 (MRGPRX2). Mast cells can also be activated by corticotrophin releasing hormone (CRH). The submucosal inflammatory cells can be inactivated through sialic acid-binding immunoglobulin-type lectin (SIGLEC) receptors. Further studies will be required to identify the contribution of these putative pathways in (subgroups of) specific DGBIs.

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Mechanisms of eos and mast cells

Am J Gastroenterol 2022;117:937–946.

Food evokes and amplifies visceral hypersensitivity via mast cell dependent (1) and mast cell-independent pathways (2). Ingestion of high FODMAP foods (and other poorly absorbed sugars) leads to bacterial fermentation predominantly in the colon, producing gas and osmotically active metabolites that can distend the colon and amplify pre-existing visceral hypersensitivity. Specific bacteria also produce neuroactive mediators that evoke or amplify visceral hypersensitivity via mast cell dependent and independent pathways. Intermediary cells (e.g., enterocytes, enteroendocrine cells or other immune cells) may also contribute to either pathway. Re-exposure to food antigens following loss of oral tolerance caused by an acute self-limiting infectious colitis or psychological stress could also lead to IgE-dependent mast cell activation and visceral hypersensitivity. 5-HT, 5-hydroxytryptamine; FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides and polyols; LPS, lipopolysaccharide.

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Functional bowel diseases

J Neurogastroenterol Motil 2017;23:151-163

J Neurogastroenterol Motil 2017;23:151-163

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Rome IV Classification of FGID (or Disorders of Gut-Brain Interaction)

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Therapeutic diets for functional esophageal disorders

No proven effective therapeutic diet
Consider EGD in patients > 60 yo or alarm sx
Check HP and PPI

Am J Gastro 2022; 117:965-972

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Therapeutic diets for function dyspepsia

Diet	N		Expert
Low FODMAP	59 105 9 25	50% 67% NS 62%	recommended
Gluten free	77 22	35% NS	Not recommended
6 Food elimination	11	71%
Chinese Yin/Yang Ig-G guided Low-residual Mediterranean

Am J Gastro 2022; 117:965-972 Table 1

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Therapeutic diets for Small Bowel Disorders

Disorders	Diet	Result		Expert
NCGS (0.5%-15%)	10 RTC	18-276	+	recommended
SIBO	No sufficient data			Not recommended

Am J Gastro 2022; 117:958-964 Table 1

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Persistent symptoms relief is not known after treatment of SIBO with abx

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45% of FGID patients have EGID

50%

49%

36%

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Candida

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FODMAP 3 step concept

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EoG and EoD diseases history

First published in NEJM in 2020
No FDA-approved treatment for EoG and EoD
Prednisone is the only treatment
Anti-TNF and other not work
AK002 is anti-Siglec 8 antibody
AK002 is effective in driving EoG+EoD to histological remission