Food Sensitivities & Food Allergies

in Functional GI Disorders:
The Clinical Perspective
Sheila E. Crowe, MD, FRCPC, FACP, FACG, AGAF
Department of Medicine
University of California, San Diego
 An Everyday Case in My Clinic
A 24 yr old woman comes to see me for food intolerances and
gluten sensitivity. She reports that she has abdominal
bloating and discomfort after eating various foods,
abdominal cramping and loose stools ranging from 2 to 3
a day without blood for the past year. Symptoms are
relieved by passage of stool. She also complains of fatigue.
She went on a gluten free diet two months ago. She feels
better but now finds that other foods are also leading to
bloating, pain and loose stools. She is concerned about food
allergies and if she has celiac disease. She also asks if her
increasingly restrictive diet will cause nutritional problems.
How do you address the patient’s concerns?
 Food and the Digestive Tract:
Friend or Foe?
• The average human ingests a large amount of food
in their lifetime
• ~ 60,000 pounds - 27,273 kilograms - 3 tons
• The vast majority benefit from this ingestion but a
small percentage develop complications:
• Food poisoning
• Food allergies
• Food sensitivities
• There is a reported increase in food allergies, celiac
disease and seemingly of food sensitivities too
 Influence of the Environment on Gut–Host
Communication and Immunological Development

Brandtzaeg, Nat Rev Gastroenterol Hepatol, 7: 380-400, 2010

 Biological Variables that Influence
the Developing Immunophenotype of an Infant

Brandtzaeg, Nat Rev Gastroenterol Hepatol, 7: 380-400, 2010

External Influences on Gut Disorders
• Dietary factors
• Low intake of necessary elements for health
• Excesses, detrimental intake (fat, calories)
• Specific foods that cause disease or symptoms
• Other ingested components
• Toxins, food additives or preservatives
• Microbes
• The microbiome, commensals as well as pathogens
• Other external influences
• Stress, exercise, tobacco, undetermined factors
Classification of Adverse Reactions to Food

Adapted from Boyce JA et al. JACI.2010;126(6):1105

Adverse Reactions to Food (ARF)

Food allergy or Food sensitivities or

hypersensitivity: intolerances (non-
• Immediate immune):
hypersensitivity • Food toxicity
• Allergic eosinophilic • Pharmacological
gastroenteritis
• Metabolic
• Food protein induced
• Physiological
enterocolitis syndromes
(FPIES) • Psychological
• Celiac disease • Idiosyncratic

Bischoff & Crowe, Gastroenterology, 128: 1089, 2005

Leung & Crowe, Food intolerance and food allergy.
In: The Gastrointestinal Nutrition Desk Reference, 2011
 Physiological Food Reactions
• Large volume meals (overeating) cause distension,
promote regurgitation
• Fatty foods delay gastric emptying, alter motility
• Legumes, cruciferous vegetables, garlic, onions, etc,
may lead to flatus (farts)
• Non-absorbable or poorly absorbed sugars and
carbohydrates can cause diarrhea, bloating,
flatulence, etc
• However, intestinal gas is NORMAL (14 X/day)
 Association of Diet, GI Symptoms & IBS
• Romanian study of 193 subjects assessed for eating
habits and diet
• 19.1% met criteria for IBS by Rome III
• IBS subjects ate more canned food, processed meat,
legumes, whole cereals, sweets, fruit compotes
• Swedish study of 197 IBS patients completed
questionnaires for food, depression, anxiety, QoL, etc
• 84% reported symptoms associated with ≥ 1 food
• 70% carbs – dairy, legumes, apple, flour, plums
• Histamine-releasing foods – milk, wine/beer, pork
• Fried or fatty foods
Chirila, I. et al, J Gastrointestin Liver Dis, 21; 357, 2012
Bohn, L, et al, Am J Gastroenterol, 108: 634; 2013
 Food Allergy and IBS
• Controversial area with studies for and against a role for food
allergy in IBS
• 150 outpatients with IBS & various food-specific serum IgG
• Randomized to 3 month of specific elimination versus sham
elimination diet
• Primary outcomes of IBS symptom severity (10% reduction)
and global rating scores were significantly improved with
specific diet
• Trend to benefit with secondary outcomes including QOL
• Most patients have food intolerance with nonspecific reactions to
food - presumed neurohormonal mechanisms
W. Atkinson et al, Gut, 53:1459, 2004
How to Evaluate for Causes of Adverse
Reactions to Food
• History - ? co-factors (exercise, drugs)
• Assess for lactose intolerance
• Skin testing for food allergens / RAST (IgE)
• Eosinophil count
• Celiac serology and/or HLA DQ assay
• Diet diary
• Hypoallergenic diet trial
• Endoscopy and biopsyCrowe, Current Gastroenterology Reports, 3: 351, 2001
DeGaetani & Crowe, CGH, 8: 755, 2010
Laboratory Tests for Immune-Mediated
Adverse Reactions to Foods
• CBC, eosinophil count
• Quantitative immunoglobulins
• Specific IgE levels (RAST, ELISA)
• Serum IgG to foods – No longer accepted
• Basophil histamine release assay
• Basophil leukotriene release assay
• Others for non-IgE mediated reactions
Bischoff & Crowe, Gastroenterology, 128: 1089, 2005
DeGaetani & Crowe, CGH, 8: 755, 2010
Stapel SO, et al, EAACI Task Force Report. Allergy, 63:793, 2008
 Food Antigen Challenges
• Skin prick testing
• Excellent negative predictive value
• Poor positive predictive value
• Skin patch testing for food allergens
• Double blinded food challenge (NG tube, capsule)
• GI tract by endoscopic mucosal testing
• Limited studies but appears useful
• Other sites unproven or not accepted
• Sublingual
• Neuromuscular Bischoff & Crowe, Gastroenterology, 128: 1089, 2005
DeGaetani & Crowe, CGH, 8: 755, 2010
• Iridology Leung & Crowe, Food intolerance and food allergy.
In: The Gastrointestinal Nutrition Desk Reference, 2011
 Wheat Allergy and Anaphylaxis
• 4-8% of children, 2-4% adults have food allergies
• Major allergenic foods (8) in North America are cows’ milk, eggs,
peanuts, wheat, corn, tree nuts, seafood, fish
• 65% of children lose reactivity to wheat by age 12
• GI symptoms in food allergy (in 30-70%):
• Edema of oropharyngeal mucosa
• Nausea/vomiting, diarrhea, abdominal pain, bloating
• Dermatological: Urticaria, eczema
• Respiratory Tract: Asthma, rhinitis, otitis
• Systemic: Anaphylaxis
• Wheat-dependent exercise-induced anaphylaxis (WDEIA)
• IgE to omega-5-gliadin
Keet, CA et al,Ann Allergy Asthma Immunol, 102:410; 2009
Inomata N, Curr Opin Allergy Clin Immunol, 9:238; 2009
Treatment for Food Allergy – the 4E’s

Leung & Crowe, Food intolerance and food allergy.

In: The Gastrointestinal Nutrition Desk Reference, 2011
 Eosinophilic Gastroenteritis
• Affects adults and children
• Not increasing in prevalence unlike EoE,
food allergy, celiac disease
• Can involve all layers of gut wall
• Various GI manifestations
• May have food allergies, specific IgE
• Increased peripheral eosinophils
• Varying response to elimination diets, anti-
allergic therapies
 Celiac Disease
• Immune-mediated disorder in which gluten causes
intestinal damage
• Gluten is a protein found in wheat, rye, barley and some
other grains
• Not rare - occurs as frequently as 1 in 100 to 300
Americans and other parts of the world where there
are genetically susceptible populations
• Often presents as non-GI problems (osteoporosis,
fatigue, depression, miscarriages) and is associated
with other autoimmune conditions
Schuppan et al, Gastroenterology, 137; 1912, 2009
Changing Prevalence of Celiac Disease
• Prevalence of up to ~1:100 in most genetically
susceptible populations, 0.71% in NHANES study
• Less than 10-15% of current cases of CD have been
diagnosed in the US
• CD is 4 to 4.5 times more prevalent than 50 yrs ago
• Cause of “CD epidemic” unknown
• Dietary – grains with increased gluten, increased wheat in
diets worldwide
• Other environmental Fasano et al, Arch Int Med, 163:286, 2003
• Microbiota Rubio-Tapa et al, Gastroenterology, 137: 88, 2009
AGA Technical Review, Gastroenterology, 131:1981, 2006
Virta et al, Scand J Gatroenterol, 44:933, 2009
Rubio-Tapia, Am J Gastroenterol, 2012
Changing Picture of Celiac Disease
• Classical form less prevalent now
• Average age of diagnosis in 5th decade
• Many are overweight
• Seroprevalence M=F, diagnosis M<F
• Other presentations are being increasingly
recognized:
• Obstetrical problems
• Neuropsychiatric manifestations
• Related autoimmune conditions
• Many others – true associations or chance?
 What is Gluten Sensitivity?
Oslo Definitions
Gluten Sensitivity Due to A chronic small intestinal
Celiac Disease (CD) immune-mediated enteropathy
precipitated by exposure to
dietary gluten in genetically
predisposed individuals

Non-Celiac Gluten Sensitivity One or more immunological,

(NCGS) morphological and/or
symptomatic alterations
triggered by gluten ingestion in
individuals in whom celiac
disease has been excluded

Ludvigsson, J et al, Gut, 62(1):43-52; 2013

 IBS or Celiac Disease?
• Some studies suggested a subset of patients diagnosed as
IBS may have celiac disease
Wahnschaffe et al, Gastroenterology, 121: 1329, 2001
Sanders et al, Lancet, 358: 1504, 2001

• Decision analysis studies suggest that there is an acceptable

cost of testing for celiac disease in IBS-D patients
Spiegel et al, Gastroenterology, 126:1721, 2004
Ladabaum et al, Aliment Pharmacol Ther 19:1199, 2004

• Over 4-fold increase prevalence of celiac disease in IBS cases

compared to controls in a meta-analysis
Ford, et al, Arch Int Med 13:651, 2009

• One study reports prevalence of CD in non-C IBS is similar to

controls Cash, et al, Gastroenterolology 141:1187, 2011

• ACG recommendations for evaluation of IBS-D include

screening for celiac disease but not infection, IBD, CRC
Dietary Treatments for IBS, FGIDs

Diet Evidence for use

Low fat Limited
Gluten-free Limited
Specific carbohydrate intolerance Little to none
FODMAP Limited
Paleolithic Minimal
Candida None
Others…. ?
 Gluten Free Market
low fat diet low carb diet gluten free diet

The market for gluten-free food and beverage products grew at a

compound annual growth rate of 28 percent from 2004 to 2008, to
finish with almost $1.6 billion in retail sales. By 2012 sales were
expected to reach $2.6 billion.

Sales are now predicted to be $1.68 billion in the USA and $3.38
billion worldwide by 2015 (Reuters on line, Sept 2012)
 Dietary Response to a Gluten Free Diet
(GFD) – Is this Diagnostic of CD?
• Placebo response in IBS up to 70%
• Gluten (increased prolamines) is hard to digest,
increases stool volume
• GFD often eliminates other dietary factors
• Potentially other mechanisms explain benefit – false
neurotransmitter, activation of TG6
• PPV of symptom improvement after gluten withdrawal
for celiac disease only 36% in one study1

1Campanella et al, Scand J Gastroenterol, 43:1311, 2008

 Possible Mechanisms of Wheat Intolerance in
IBS and other FGID

Innate immune
reaction to gluten

Nocebo effect IgE mediated

wheat allergy
Non-Celiac
Wheat
Low grade
Intolerance Starch/CHO
inflammation Malabsorption
Opioid-like activity
of gluten

Sabatino & Corazza, Ann Int Med 2012;156:309-11

Gluten Causes Symptoms in IBS Patients
Without Celiac Disease
 Controlled Trial of GF Diet in IBS-D
• RCT in 45 subjects with IBS-D comparing 4 wks of
GFD versus GCD
• Stratified by HLA DQ 2/8 status
• Assessed BMs, gut transit, permeability, histology
• More BMs in GCD, especially if HLADQ2/8+
• GCD increased SB permeability, > in HLA DQ2/8+
• GFD benefitted IBS-D patients (stool frequency,
permeability) especially if HLA DQ2/8 positive1
• No effect on transit or histology
Vasquez-Roque, et al, Gastroenterol, in press
 Between Celiac Disease & IBS:
The “No Man’s Land” of Gluten Sensitivity
 Non-Celiac Gluten Sensitivity
• Not a new entity, reported in 19801
• Prevalence unknown, probably greater than celiac
disease but no data
• Varies from 0.548% (NHANES) to 30% of US!!
• Studies reporting prevalence reflect referral bias
• Currently no specific criteria or validated tests for
diagnosing NCGS!!
• Reported in association with allergic diseases2
1. Cooper, BT, et al, Gastroenterol, 79; 801, 1980
2. Massari, S, et al, Ine Arch Allergy Immunol, 155;389, 2011
3. Sabatino, AD & Corazzo, GR, Ann Intern Med, 156, 309: 2012
 Putative Mechanisms of NCGS
• Elevated AGA IgA, IgG (up to 50% +AGA IgG)1
• No specific HLA association
• Some studies suggest gluten may activate the innate
immune system (IL-8, IFN-γ, etc) in NCGS
• Increased permeability, mucosal inflammation,
basophil activation but found not in a recent study2
• Other proposed mechanisms include immune (immune
complex, autoimmune, toxicity, false neurotransmitters,
leaky gut, TG6, etc…
1. al, J Clin Gastroenterol, 46, 680, 2012
2. Ciacci, C et al, Clin Gastro Hepatol, in press
Sabatino, AD & Corazzo, GR, Ann Intern Med, 156, 309: 2012
Summary: Non-Celiac Gluten Sensitivity
• A condition for which clear diagnostic criteria are
not yet established
• Prevalence therefore cannot be determined
• Estimated prevalence figures are inflated by
referral bias
• Cannot readily differentiate between intolerance
of gluten, wheat starch or other causes of wheat
intolerance or sensitivity
• Much more research is needed
Role of HLA DQ Screening Tests in NCGS
Risk of celiac disease and
HLA status

General population < 1.0%

DQ2 homozygous – 31X
DQ2/DQ8 positive – 14X
DQ8 homozygous – 10X
DR3- or DR5/7- – 90-95%
DQ2 heterozygous – 10X
DR4- – 5-10%
DQ8 heterozygous – 2X
DQ2 and DQ8 negative - < 0.1X
Helpful test for its NPV-
absence excludes celiac
Necessary for celiac disease disease but not NCGS
but not sufficient
Pietzak, M, Clin Gastro & Hepatol, 7:996, 2009
 Non-Celiac Wheat Sensitivity

• 10 year review of all subjects with an IBS-like

presentation diagnosed as wheat sensitive (WS) by
double-blind placebo-control challange responses to
gluten or wheat), 276 diagnosed
• Two groups, WS alone or WS with multiple food
sensitivity
• Increased positive AGA IgA and IgG
• Increased eosinophils in duodenal and colonic
mucosa
Carroccio, A et al, Am J Gastroenterol, 2012
 Non-Celiac Wheat Sensitivity

• 10 year review of all subjects with an IBS-like

presentation diagnosed as wheat sensitive (WS) by
double-blind placebo-control challange responses to
gluten or wheat), 276 diagnosed
• Two groups, WS alone or WS with multiple food
sensitivity
• Increased positive AGA IgA and IgG
• Increased eosinophils in duodenal and colonic
mucosa
Carroccio, A et al, Am J Gastroenterol, 2012
Outcomes of IBS Patients After 4 Weeks of an
Elimination Diet and DB Food Challenge

4 week Elimination Diet: cow’s milk, wheat, egg, tomato, and chocolate
DBPC challenge: 2 wks of cow’s milk or wheat proteins
Carroccio A, et al. Clin Gastro Hepatol;9:965, 2012
Summary of Adverse Reactions to
Wheat or Gluten
Type of ARF Immune Tissue Genetic
mediated damage factors

Wheat IgE-mediated Transient Yes

hypersensitivity
Celiac disease T cell mediated Persistent with Yes
gluten ingestion
Non-celiac gluten Innate immune? Microscopic Not known
sensitivity Other
mechanisms
Wheat starch Non-immune Not apparent Seemingly not
intolerance
Proposed Approach to Patients Reporting Adverse
GI Reactions to Eating Wheat or Gluten

Boettcher, E, & Crowe, SE. Am J Gastroenterol. 2013 (in press)

Adverse Reactions to FODMAPS

Fermentable Oligosaccharides,
Disaccharides, Monosaccharides and
Polyols
» Fructose and fructans
» Sorbitol
» Sucrose
» Lactose
 Lactose Intolerance
Symptoms due to lactose malabsorption resulting
from lactose deficiency
• Congenital deficiencies - rare
• Constitutional lactase insufficiency
» Genetically programmed decreased in lactase
synthesis after weaning
» Common in native NA, Asians, Africans, those from
Mediterranean areas
• Secondary lactase insufficiency
» Gastroenteritis, Crohn’s disease, celiac disease
Most common ARF worldwide
Shaukat, A, et al Ann Int Med. 152:797, 2010
 Management of Lactose Intolerance
• Most individuals with lactose intolerance can tolerate 12-15
g lactose (8-10 oz of milk)
• Yoghurt, hard cheeses are naturally lactose-free
• Lactose better tolerated when taken in small, more frequent
amounts and with other foods
• Lactase supplements helpful
• No proven benefit for probiotics, adaptation programs
• Triacylglycerol content of many milk products can cause GI
symptoms unrelated to lactase insufficiency or cows milk
protein (CMP) allergy
Shaukat, A, et al Ann Int Med. 152:797, 2010
 Summary and Future
• Food-induced symptoms are common in IBS and also
common of other FGID
• CD can coexist with or mimic IBS, other FGID
• Increased reporting of NCGS, actual prevalence?
• Elimination of gluten or wheat and other carbohydrates
can benefit IBS
• Few studies to support a proven benefit
• How gluten and other food sensitivities contribute to
FGID remains unclear but multiple mechanisms are
implicated
• Additional research is needed!