Food intolerance.pdf

Food intolerance and
Scombroidosis
Natasorn Lekuthai,MD.
Allergy and Immunology fellowship

Food intolerance
u Food intolerance is non-immunological and may occur in response to
u pharmacological effects of food
u food components eg. non celiac gluten sensitivity
u enzyme/ transport defects.
u Non-allergic food reactions do not involve the immune system.
u Food intolerance is common in the modern world, and depending on data collection
methods and definitions, it affects up to 15–20% of the population. Even 20 years ago,
20% of the population reported food intolerance.
- Gargano, Domenico et al. “Food Allergy and Intolerance: A Narrative Review on
Nutritional Concerns.” Nutrients vol. 13,5 1638. 13 May. 2021
- Lomer, M.C.E. (2015), Review article: the aetiology, diagnosis, mechanisms and
clinical evidence for food intolerance. Aliment Pharmacol Ther, 41: 262-275

Turnbull, J. L., H. N. Adams, and D. A. Gorard. "The diagnosis and management of food allergy
and food intolerances." Alimentary pharmacology & therapeutics 41.1 (2015): 3-25.

Food intolerance
u It is categorized into 3 types ;
u Enzymatic and transport defect
u Pharmacological
u undefined or idiopathic food intolerance.
u The most common intolerant foods include dairy products, products containing sulfites,
salicylates, FODMAPs, biogenic amines, gluten, lactose, and food additives.
u Indications of food intolerance or sensitivity are varied.
Muthukumar, Janani, et al. "Food and food products associated with food allergy and food intolerance–An
overview." Food Research International 138 (2020): 109780

overview." Food Research International 138 (2020): 109780.

Signs and symptoms
u Symptoms may not occur until several hours after food consumption and can last for hours to days.
u Gastrointestinal symptoms such as increased flatulence, abdominal pain, bloating or diarrhea.
u Respiratory symptoms ; asthma, rhinitis
u Extra-intestinal symptoms such as eczema, urticaria and angioedema arising from food intolerances are
similar to those arising from food allergy.
u Other varied symptoms may include headaches and migraine, fatigue, musculoskeletal problems and
behavioral changes.
u Often overlapping with symptoms found in IBS and fibromyalgia.
u However, unlike in true food allergy, in intolerance there is a delay in symptom onset, prolonged
symptomatic phase and negative IgE serology
-Tuck, Caroline J., et al. "Food intolerances." Nutrients 11.7 (2019): 1684.
-Turnbull, J. L., H. N. Adams, and D. A. Gorard. "The diagnosis and management of
food allergy and food intolerances." Alimentary pharmacology & therapeutics 41.1
(2015): 3-25.

Pharmacological
: FOOD CHEMICALS

Etiology : Food chemicals
Ø The mechanism of food additives and chemicals associated with the gastrointestinal and extra-
intestinal symptoms are undefined and poorly studied. Therefore, controlled studies to elucidate
the symptom provoking mechanism of individual food additives are highly recommended.

Salicyclate intolerance
u The prevalence of salicylate intolerance in Europe is 2.5%.
u Pathogenesis of salicylate intolerance is based on an inhibition of cyclooxygenase-1 by
salicylates and other non-steroidal pain medications, but also by salicylate-containing
foods and other acids (such as benzoic acid or colorants) resulting in reduced
prostaglandin synthesis . In intolerant individuals this leads to activation of the
leukotriene metabolism with increased formation of LTB4 and/or LTC4-E4.
u The classical symptoms of salicylate intolerance
u respiratory systems :blocked or runny nose, sinusitis, nasal polyposis, bronchial asthma
u gastrointestinal systems : meteorism, flatulence, diarrhea and, rarely, to colitis with strictures
and ulcers
Zopf, Yurdagül, et al. "The differential diagnosis of food
intolerance." Deutsches Ärzteblatt International 106.21 (2009): 359.

u This condition is detected by a blood cell test (heparinized blood) with incubation of 5-
acetylsalicylic acid and arachidonic acid or by provocation tests (nasal, bronchial,oral ).
u If dietary therapy alone is insufficient, treatment with leukotriene receptor blockers or
deactivation with acetylsalicylic acid should be attempted.
u The recommended treatment is abstinence from the inducing substances.
Zopf, Yurdagül, et al. "The differential diagnosis of food intolerance." Deutsches
Ärzteblatt International 106.21 (2009): 359

Symptoms of Salicylate Intolerance

Biogenic amines
u Biogenic amines (BA) are described as biologically active amines, which are low molecular
weight organic bases that can be found in a wide range of food and constitute a potential
health risk to the consumer.
u They are produced by microbial enzymatic decarboxylation of the specific amino acids with
the formation of correspondent CO2 and amines.
u The significant relative precursors and BAs present in the food are histamine, tyramine,
cadaverine, tryptamine, 2-phenylethylamine, putrescine, agmatine, spermidine, and spermine.
- Santos, MH Silla. "Biogenic amines: their importance in foods." International journal of food microbiology 29.2-3 (1996): 213-231.
- Montanari, Chiara, et al. "Effects of the diameter on physico-chemical, microbiological and volatile profile in dry fermented sausages
produced with two different starter cultures." Food bioscience 22 (2018): 9-18.
- Bover-Cid, Sara, et al. "Reduction of biogenic amine formation using a negative amino acid–decarboxylase starter culture for fermentation
of Fuet sausages." Journal of Food Protection63.2 (2000): 237-243.

Biogenic amides

Biogenic amides
u Accumulation of BA is also reported in dry fish, fermented fish, vacuum packaged fish, and fermented
cold-smoked fish.
u European legislation (EC 2073/2005) limits the concentration of histamine to <200 mg/kg for fresh fish
and <400 mg/kg for cured fish products.
u Fermented meat products contain a higher concentration of tyramine. The presence of tyramine at
levels exceeding 400 mg/kg in the dry fermented sausage.
u In relevance to dairy products, milk contains a low level of BA, about 1 mg/dm3 whereas the
concentration of BA in yogurt ranges between milligram to tens of milligram/kg. The concentration of
BA higher than 1000 mg/kg was detected in cheese.
u Red wine exhibit high content of histamine whereas the white wine contains a lower level of histamine
due to the different fermentation process.
- Visciano, Pierina, et al. "Biogenic amines in raw and processed
seafood." Frontiers in microbiology 3 (2012): 188.

Biogenic amides
u In beer , microbial contamination during the process of brewing is reported to be
associated with a higher amount of histamine and tyramine .In contrast, the natural
occurrence of agmatine, spermidine, and spermine in beer as a constituent originated
from malt is documented.
u Cider, a fermented alcoholic beverage obtained from apple juice is an excellent source
of histamine, tyramine, putrescine as the fermentation process is driven by yeast and
LAB microbiota.
- Sarkadi, L. Simon. "Biogenic amines in fermented foods and health implications." Fermented foods in
health and disease prevention. Academic Press, 2017. 625-651.
- Ruiz-Capillas, Claudia, and Ana M. Herrero. "Impact of biogenic amines on food quality and
safety." Foods 8.2 (2019): 62.

Histamine Intolerance
u Histamine is a biogenic amine that is present in the body but also in many foods.
u It is found in significant amounts in fermented and similar biogenic amines and can also
be found in canned food, ready meals, semi-finished products or products that have
been stored for a long time.
u Histamine intolerance results from an imbalance of accumulated or ingested histamine
and the reduced ability to degrade histamine. In healthy individuals, amine oxidases can
quickly detoxify histamine ingested with food, while people with low amine oxidase
activity run the risk of histamine toxicity.
Tuck, C. J., Biesiekierski, J. R., Schmid-Grendelmeier, P., & Pohl, D. (2019). Food
intolerances. Nutrients, 11(7), 1684.

Histamine Intolerance
u Histamine intolerance can lead to unspecific GI symptoms and extra-intestinal
symptoms, which occur mainly during and immediately following meals. Symptoms
associated with histamine can occur in isolation or in combination.
Tuck, C. J., Biesiekierski, J. R., Schmid-Grendelmeier, P., & Pohl, D. (2019). Food
intolerances. Nutrients, 11(7), 1684.

Food additives: Monosodium glutamate
u Monosodium glutamate (MSG) is a sodium salt of glutamic acid that enhances the
flavor and sensory acceptance of savory foods.
u MSG is commonly found in pickles, spices and condiments, candies, soups, meats, and
bakery products.
u MSG also occurs naturally in tomatoes, cheeses, malted barley, rice syrup, and gelatin.
- Walker, Ronald, and John R. Lupien. "The safety evaluation of monosodium glutamate." The
Journal of nutrition 130.4 (2000): 1049S-1052S.
- Ramesh, Muthusamy, and Arunachalam Muthuraman. "Flavoring and coloring agents: Health risks
and potential problems." Natural and artificial flavoring agents and food dyes. Academic Press,
2018. 1-28.

Food additives: Monosodium glutamate

Food additives : Benzoic acids
u Benzoic acid and its derivatives are used to enhance the sweet astringent taste of the
food products
u occur naturally in a wide range of foods such as vegetables and fruits, fungi, nuts, and spices
u highly found in cocoa, apricots, almonds, cherries, cranberries, snap beans, honey, apple,
banana, lemon, watermelon, orange, peach, strawberry, pineapple, and kiwi.
u Vegetables such as onion, carrot, cauliflower, celery, garlic, and cabbage contain <1 mg/kg of
benzoic acid.
u In spices, cinnamon contains <335 mg/kg, about <50 mg/kg is present in nutmeg, salvia, clove,
and thyme.
u Cereals contain 0.5–1 mg/ kg and nuts contain <1 mg/kg. Among the nuts walnut and peanut
holds the top with 4 mg/kg of benzoic acid
u Benzoates have been linked to chronic urticaria, asthma, atopic dermatitis,
rhinitis and anaphylaxis.
Del Olmo, Ana, Javier Calzada, and Manuel Nuñez. "Benzoic acid and its derivatives as
naturally occurring compounds in foods and as additives: Uses, exposure, and
controversy." Critical Reviews in Food Science and Nutrition 57.14 (2017): 3084-3103.

Food additives : Benzoic acids

Food additives : Sulfites
u Sulphites, readily metabolised to sulphate (SO4) by sulphite oxidase mainly occur in
the human diet due to the addition of sodium/ potassium sulphite/metabisulphite to
foods to prevent enzymatic and non-enzymatic browning, control oxidation and
prevent bacterial growth.
u Sensitivity to sulphites mainly affects patients with asthma, especially those with
severe steroid-dependant asthma.
u Analysis of sulphite-sensitive cases in Korea found that two phenotypes of sulphite
sensitivity existed, those with sulphite sensitive asthma was the most common,
affecting two-thirds of their cohort, with the remainder having sulphite-sensitive
urticaria.
Skypala, Isabel J., et al. "Sensitivity to food additives, vaso-active amines and
salicylates: a review of the evidence." Clinical and translational allergy 5.1
(2015): 1-11.

Nonceliac gluten sensitivity
u Noncoeliac gluten sensitivity is a relatively new definition to describe gastrointestinal symptoms that
occur in response to including gluten in the diet but in the absence of diagnostic features of coeliac
disease or wheat allergy.
u In the absence of coeliac disease or wheat allergy is a somewhat controversial clinical diagnosis in which
dietary exclusion of gluten may improve a multitude of various symptoms including headaches,
abdominal and musculoskeletal complaints, and even behavioral disturbances.
u However, gluten sensitivity may possibly be associated with innate rather than adaptive mucosal immune
responses.
- Elli, Luca, et al. "Diagnosis of gluten related disorders: Celiac disease, wheat allergy and
non-celiac gluten sensitivity." World journal of gastroenterology: WJG 21.23 (2015): 7110.
- Turnbull, J. L., H. N. Adams, and D. A. Gorard. "The diagnosis and management of food
allergy and food intolerances." Alimentary pharmacology & therapeutics 41.1 (2015): 3-25.

u Gluten proteins are the most abundant proteins in the wheat kernel and are essential
for the germination and the development of the seed.
u The average gluten intake in Western diets is estimated in the range of 5–20 g/day.
u Gluten proteins are prolamins, rich in glutamine and proline, and they have different
names, including gliadins (monomers) and glutenins (polymers), wheat, hordeins in
barley, and secalins in rye.
Barbaro MR, Cremon C, Wrona D, Fuschi D, Marasco G,
Stanghellini V, Barbara G. Non-Celiac Gluten Sensitivity in the
Context of Functional Gastrointestinal Disorders. Nutrients. 2020;
12(12):3735. https://doi.org/10.3390/nu12123735

Barbaro MR, Cremon C, Wrona D, Fuschi D, Marasco G,
Stanghellini V, Barbara G. Non-Celiac Gluten Sensitivity in the
Context of Functional Gastrointestinal Disorders. Nutrients. 2020;
12(12):3735. https://doi.org/10.3390/nu12123735

Cárdenas-Torres, F. I., Cabrera-Chávez, F., Figueroa-Salcido, O. G., & Ontiveros,
N. (2021). Non-Celiac Gluten Sensitivity: An Update. Medicina (Kaunas,
Lithuania), 57(6), 526. https://doi.org/10.3390/medicina57060526

u The overall prevalence of NCGS in the general population is still unknown, mainly
because many patients are currently self-diagnosed and start a gluten-free diet (GFD)
without medical advice or consultation.
u The disorder seems to be more common in females and in young/middle age adults.
u Genetic ;Half of the NCGS patients have the genes encoding DQ2 or DQ8 molecules in
their HLA system. It has also been reported that HLA-DQ2 genes are frequently observed
in patients with NCGS and with the diarrhea-predominant irritable bowel syndrome
(IBS)
u The commonly consumed food products such as bread, biscuits, soups, cookies, bagels,
cakes, pasta, etc. are made of wheat and contains gluten.
Czaja-Bulsa, Grażyna. "Non coeliac gluten sensitivity–A new disease with gluten
intolerance." Clinical nutrition 34.2 (2015): 189-194.

u The typical presentation of NCGS is
u combination of IBS-like symptoms, including abdominal pain, nausea, bloating, flatulence,
diarrhea or constipation.
u systemic manifestations such as headache, joint and muscle pain, muscle contractions, leg or
arm numbness, chronic fatigue, “foggy mind”, body mass loss
u they can include behavior disturbances such as the disturbance in attention and depression
u the extra-intestinal manifestations seem to be less frequent
u the most common extra-intestinal symptom being tiredness
Losurdo, Giuseppe, et al. "Extra-intestinal manifestations of non-celiac gluten
sensitivity: An expanding paradigm." World journal of gastroenterology 24.14
(2018): 1521.

Barbaro MR, Cremon C, Wrona D, Fuschi D, Marasco G, Stanghellini V, Barbara G.
Non-Celiac Gluten Sensitivity in the Context of Functional Gastrointestinal
Disorders. Nutrients. 2020; 12(12):3735. https://doi.org/10.3390/nu12123735
Pathogenesis: nonceliac gluten sensitivity

Diagnosis of nonceliac gluten sensitivity
u The diagnosis cannot be made until CD and WA have been eliminated.
u The food challenge procedure is performed by means of an open test (if the symptoms
are objective; vomiting, diarrhea) or a blind test (when the symptoms are subjective ;
abdominal pain, nausea, headache, tiredness). In NCGS the adverse symptoms appear
several hours or days after gluten consumption, while in IgE-dependent WA symptoms
appear within 2 h from the food intake.
u However, the standards of food challenge tests in NCGS patients have not been yet
developed.
u The only known antibodies observed in the NCGS patients are IgG antigliadin anti-
bodies (IgG-AGA) which, unfortunately, occur in only a half of the patients .
Czaja-Bulsa, Grażyna. "Non coeliac gluten sensitivity–A new disease with
gluten intolerance." Clinical nutrition 34.2 (2015): 189-194.

Treatment of nonceliac gluten sensitivity
u A Gluten free diet is the treatment of choice in NCGS cases.
u Low-FODMAP diet is still controversial.
Cárdenas-Torres, F. I., Cabrera-Chávez, F., Figueroa-Salcido, O. G., &
Ontiveros, N. (2021). Non-Celiac Gluten Sensitivity: An
Update. Medicina (Kaunas, Lithuania), 57(6), 526.
https://doi.org/10.3390/medicina57060526

Lactose Intolerance
u Lactose is a disaccharide, which is present in many dairy products, composed by
galactose linked to glucose via a β-1→4 glucosidic bond. Lactose is hydrolyzed by β-
galactosidase (lactase) bound to the small intestine brush border membrane, then
the monosaccharides glucose and galactose are both actively absorbed in the small
intestine.
u The lactase activity begins to decrease after a few month of life , sometimes until it
disappears. In humans, a considerable part of the population maintains lactase
activity for all of adulthood, whereas in other mammals, maintaining lactase activity
is unusual.
Fassio, F., Facioni, M. S., & Guagnini, F. (2018). Lactose Maldigestion, Malabsorption, and
Intolerance: A Comprehensive Review with a Focus on Current Management and Future
Perspectives. Nutrients, 10(11), 1599

Definition
Fassio, F., Facioni, M. S., & Guagnini, F. (2018). Lactose Maldigestion,
Malabsorption, and Intolerance: A Comprehensive Review with a Focus on
Current Management and Future Perspectives. Nutrients, 10(11), 1599.

u In people with lactase deficiency, lactose is not hydrolyzed and absorbed in the small
bowel, but passes through the gastrointestinal tract into the colon into where bacterial
fermentation produces gas and short-chain fatty acids and other products that can
cause luminal distension and induce GI symptoms
Lactose Intolerance
Deng, Y., Misselwitz, B., Dai, N., & Fox, M. (2015). Lactose
Intolerance in Adults: Biological Mechanism and Dietary
Management. Nutrients, 7(9), 8020–8035.

Lactose Intolerance
u Lactase-nonpersistence ; Indeed, most people with lactase-nonpersistence can tolerate
small amounts of lactose in the diet when it is spread throughout the day and, in total,
up to 12– 15 g/day.
u Lactase persistence is mediated by several polymorphisms in different populations (G-
13915 in Saudi Arabia and G-14010, G-13915, and G-13907 in African tribes); thus,
lactase persistence seems to have developed independently in different areas of the
world during human evolution.
Deng, Yanyong, et al. "Lactose intolerance in adults: biological mechanism
and dietary management." Nutrients 7.9 (2015): 8020-8035

Lactose intolerance
u Symptoms of lactose intolerance generally do not occur until there is less than 50% of
lactase activity.
u Even lactose malabsorbers who consider themselves to be very lactose intolerant can
actually tolerate moderately large amounts (12–24 g) of lactose (1–2 glasses milk) daily
without symptoms.
u However, lactose malabsorption is rarely a clinical problem in adults, since
malabsorbers usually recognise that excess dairy products cause upset and modify
their diet without medical consultation. Furthermore, when lactose malabsorbers
chronically ingest lactose, colonic bacterial flora adaptation occurs with increased
tolerance for lactose.
Fassio, F., Facioni, M. S., & Guagnini, F. (2018). Lactose Maldigestion,
Malabsorption, and Intolerance: A Comprehensive Review with a Focus on
Current Management and Future Perspectives. Nutrients, 10(11), 1599.

Signs and symptoms
Several factors including
the dose of lactose
consumed, residual lactase
expression, food matrix
(ingestion with other
dietary components), gut-
transit time, and enteric
microbiome composition.
Fassio, F., Facioni, M. S., & Guagnini, F. (2018). Lactose Maldigestion, Malabsorption, and
Intolerance: A Comprehensive Review with a Focus on Current Management and Future
Perspectives. Nutrients, 10(11), 1599

u Yogurt contains all the milk constituents with lower content of lactose. In comparison to
other milk products, yogurt is better tolerated by lactose-intolerant individuals as the
lactose is partially hydrolyzed into glucose and galactose by the fermentative bacteria
u A wide range of fermented milk products such as sour cream, labaneh, kefir, mursik,
labaneh, and viili also have similar advantages as that of yogurt due to their low lactose
content and higher lactase content
u In addition to dairy products, lactose is commonly used as a food additive in non-dairy
products due to its lower price, unique flavor, binding properties, etc. Those nondairy
products include processed meats, bread, protein supplements, breakfast cereals,
margarine, gravy stock powder, meal replacements, and various other processed foods.
The processed meat products that are produced with milk such as sausage, egg
substitutes, breaded fish or meat, and scrambled egg contains a low amount of lactose.
u Dressings, margarine, etc., contains low lactose content. Sweets and desserts that contain
lactose such as pudding, cookies, pastries, cheese-filled pastries, coated candies,
chocolate bars, and ice creams should be avoided.
Lactose Intolerance
Silanikove, Nissim, Gabriel Leitner, and Uzi Merin. "The
interrelationships between lactose intolerance and the modern dairy
industry: global perspectives in evolutional and historical
backgrounds." Nutrients 7.9 (2015): 7312-7331.

Lactose tolerance test
u The patient takes 1 g lactose per kg body weight up to a maximum of 50 g in a flavoured
drink over 10 min.
u Blood specimens are taken pre-test and half hourly for 2 h.
u The specimens are analyzed for glucose (spectrophotometry).
u Plasma glucose should increase by at least 1.0 mmol/L in normal individuals. Subnormal
rise in plasma glucose indicates lactose intolerance.
•https://www.rcpa.edu.au/Manuals/RCPA-Manual/Pathology-Tests/L/Lactose-
tolerance-test

H2 breath test ( HBT)
u Gold standard for lactose intolerance diagnosis due to its high
sensitivity(76-100%)and specificity(90-100%)
u Simply and non-invasiveness, and its low cost.
u It is based on the measurement of the quantity of hydrogen exhaled and
recollected in samples every 30 min after the oral administration of
lactose (usually 25 g, corresponding to approximately 500 mL of milk).
u The HBT is positive when the hydrogen level in the exhaled air is at least
20 parts per million greater than the baseline value.
u False negative >> the lack of hydrogen production by colic bacterial
flora or the recent administration of antibiotics
u False positive >> the presence of bacterial overgrowth of the small
intestine (SIBO) must be considered.
u To increase the accuracy of the test
u it is recommended to avoid antibiotics in the four preceding weeks
u to consume complex carbohydrates the preceding day
u refrain from smoking and physical activity on the day of the test.

H2 breath test
Di Costanzo, Margherita, and Roberto Berni Canani. "Lactose intolerance:
common misunderstandings." Annals of Nutrition and Metabolism 73.4
(2018): 30-37.

u Reducing/eliminating the dietetic amount of lactose until the symptoms disappear.
u “lactose-free”—has resulted in the proliferation of many dairy products claiming the absence or reduction
of lactose, despite the presence of a small amount (usually <0.01%) in such products, which, although
reduced, is still enough to induce symptoms in at least a portion of lactose-intolerant patients.
u Lactase can be administered as an enzymatic food supplement, but its efficacy, of which convincing
evidence is still lacking, is short-lived, and therefore, the supplement has to be consumed approximately
5–30 min before the lactose-containing meal
u The non-absorbable antibiotic rifaximin has been evaluated in a single trial. After a course of 10 days, the
lactose-related symptoms were reduced with respect to the baseline evaluation, reaching a level
comparable to that after a 40-day lactose-free diet ; this result, however, has not been replicated in
placebo-controlled trials or other independent studies.
Lactose Intolerance : Treatment
Fassio, F., Facioni, M. S., & Guagnini, F. (2018). Lactose Maldigestion, Malabsorption,
and Intolerance: A Comprehensive Review with a Focus on Current Management and
Future Perspectives. Nutrients, 10(11), 1599.

Di Costanzo, Margherita, and Roberto Berni Canani. "Lactose intolerance:
common misunderstandings." Annals of Nutrition and Metabolism 73.4
(2018): 30-37.

Probiotics
Ø Recently, a systematic review about
the efficacy of several different
probiotic strains in the management of
lactose intolerance was published
Ø Improvement of intestinal conditions
moving towards the amelioration of
lactose intolerance has been
demonstrated in several cases.
Ø variations in probiotic concentration,
preparation, and β-galactosidase
activity may affect the clinical efficacy
of probiotic treatments .
Modulation of the intestinal microbial environment by
promoting intestinal colonization by strains capable of
β-galactosidase activity could be an effective approach
for the treatment of subjects with lactose intolerance. Fassio, F., Facioni, M. S., & Guagnini, F. (2018). Lactose Maldigestion, Malabsorption,
and Intolerance: A Comprehensive Review with a Focus on Current Management and
Future Perspectives. Nutrients, 10(11), 1599.

Fermentable oligosaccharides,
disaccharides, monosaccharides and
polyols (FODMAPS)

Short-chain fermentable carbohydrates
(FODMAPs):
u FODMAPs is an acronym for “Fermentable oligo- di- and monosaccharides and
polyols” which refers to the category of short-chain containing carbohydrates.
u It is highly challenging to decrease the intake of FODMAPs rich foods as they are an
excellent source of health-related constituents such as dietary fiber and micro-
nutrients.
u The major FODMAPs include galacto- oligosaccharides, fructans, glucose, fructose,
lactose, sorbitol, xylitol, and mannitol. They occur naturally in several plant-based,
dairy-based foods, and sweeteners.
Ooi SL, Correa D, Pak SC. Probiotics, prebiotics, and low FODMAP diet
for irritable bowel syndrome - What is the current
evidence?. Complement Ther Med. 2019;43:73-80

FODMAPS
u FODMAPs are poorly absorbed through the small intestine, they pass in the bowel and
increase intestinal luminal water content through their osmotic activity and induce gas
production due to fermentation by gut bacteria. The increased content of water and
gas causes luminal distension that induces GI symptoms in IBS patients.
Magge, S., & Lembo, A. (2012). Low-FODMAP Diet for
Treatment of Irritable Bowel Syndrome. Gastroenterology &
hepatology, 8(11), 739–745.

Fructose
u There is a limit to the absorptive capacity for fructose
in the human gut which is determined by a number
of different routes of facilitated transport. The GLUT-
2 and GLUT-5 transporters are the ones that have
been most widely researched.
u In a ratio of 1:1, glucose and fructose are co-
transported across the apical surface of the intestinal
mucosa by GLUT-2 whereas GLUT-5 enables
independent fructose absorption through carrier-
mediated facilitative diffusion.
u A glucose-dependent fructose co-transporter GLUT2,
enhances absorption by solvent drag and passive
diffusion. Fructose is absorbed without enzymatic
breakdown. It is transported by facilitated diffusion,
primarily using the GLUT5 transporter.
u GLUT-7, GLUT-8 is also indicated.
Ferraris, R. P., Choe, J. Y., & Patel, C. R. (2018). Intestinal
Absorption of Fructose. Annual review of nutrition, 38, 41–67.

Fructose
u Free fructose, i.e. fructose in excess of glucose appears to have the strongest effect on
whether fructose is malabsorbed.
u A dose of 50 g fructose was shown to be malabsorbed by 9 out of 17 healthy
volunteers using hydrogen production on breath testing, however, when those nine
subjects were given a dose of only 25 g fructose only one still demonstrated fructose
malabsorption.
Lomer, M. C. E. "The aetiology, diagnosis, mechanisms and clinical
evidence for food intolerance." Alimentary pharmacology &
therapeutics 41.3 (2015): 262-275.

Fructans
u Fructans are short-chain carbohydrates based on linear or
branched fructose polymers.
u These fructose polymers come in 2-9 units length, which
are called oligofructose, as well as > 10 units length,
which are called inulins.
u Absorption is less than 5% in humans due to lacking
enzymes to break down the glycosidic bonds. thus,
fructans are available for colonic fermentation by the
gastrointestinal microbiota.
u Occur naturally as storage carbohydrates in a variety of
cereals (e.g. wheat) and vegetables (e.g. artichoke, garlic,
leeks, onion) and are added to food for their prebiotic
properties (e.g. fructo-oligosaccharides, inulin,
oligofructose).
Robert V. Stick, Spencer J. Williams, in Carbohydrates: The Essential Molecules
of Life (Second Edition), 2009

Galacto-oligosaccharides
u Short-chain carbohydrates of galactose polymers with a
glucose terminal end.
u They are not hydrolysed in the human GI tract due to the
lack of an a-galactosidase enzyme so reach the colon
intact available for colonic fermentation.
u Raffinose and stachyose and common dietary sources are
human milk, legumes and pulses, some grains, some nuts.
u It is well established that legumes and pulses increase
intestinal gas production leading to gastrointestinal
symptoms.

Polyols
u Sorbitol, mannitol, xylitol and are collectively
termed sugar alcohols.
u They are passively absorbed along the small
intestine, the rate at which varies between
individuals depending on the molecular size of
the polyol, the intestinal pore size, the small
intestinal transit time and presence of
gastrointestinal disease.
u Polyols occur naturally in the diet in some fruit
(apricots, peaches, cherries, apples, pears) and
vegetables (mushrooms, cauliflower) but are
also added as artificial sweeteners to food
products (e.g. sugar-free chewing gum) and
pharmaceuticals (sugar-free cough syrup).
Polyols have been associated with having a
laxative effect.
Lenhart, A., & Chey, W. D. (2017). A Systematic Review of the Effects of
Polyols on Gastrointestinal Health and Irritable Bowel
Syndrome. Advances in nutrition (Bethesda, Md.), 8(4), 587–596.
https://doi.org/10.3945/an.117.015560

FODMAPs : Treatment
u The 4-food or 6-food elimination diet seeks to remove milk, wheat, soy, egg, peanuts/tree nuts,
and fish/shellfish from patients’ diets, as these foods are the most common triggers. After 4 to 6
weeks, the foods are reintroduced to an altered immune system and microbiome.
u Other elimination diets include the Paleolithic diet and the low–fermentable oligosaccharide,
disaccharide, monosaccharide, and polyol (FODMAP) diet. Patients who reduce their FODMAP
intake have noted improvement in abdominal pain, bloating, and flatulence.
u There is still a lot that is unknown about the relationship between food, diet, and IBS. Current and
ongoing research has focused on certain foods and their effects on the microbiome.
u Recently, in a randomized double-blind controlled cross- over study, Halmos et al demonstrated
that a diet low in FODMAPs for a 3 wk period effectively reduced overall gastrointestinal symptoms
-abdominal pain, bloating and bowel habit dissatisfaction- in a group of 30 unselected IBS patients,
compared to a standard Australian diet.
Barrett, Jacqueline S., and Peter R. Gibson. "Fermentable oligosaccharides, disaccharides, monosaccharides and polyols
(FODMAPs) and nonallergic food intolerance: FODMAPs or food chemicals?." Therapeutic advances in gastroenterology 5.4
(2012): 261-268

Diagnosis
u Dietary and lifestyle assessment, with a focus on potential food intolerance.
u Investigations may include blood and fecal tests, endoscopy and/or radiological imaging to rule out
any organic disease.
u In the absence of organic disease or food allergy, patients will often be diagnosed with a functional
gastrointestinal disorder, e.g. IBS or functional dyspepsia.
u However, there are a limited number of tests that are clinically useful in the identification of specific
food intolerance.
Lomer, M.C.E. (2015), Review article: the aetiology, diagnosis,
mechanisms and clinical evidence for food intolerance.
Aliment Pharmacol Ther, 41: 262-275.

Food exclusion, symptom improvement and
dietary challenge
u The gold standard food intolerance test is food exclusion to achieve symptom
improvement followed by gradual food reintroduction and subsequent symptom
induction to identify tolerance.
u However, a reduction, rather than complete exclusion, in the intake of the food or
foods in question may be sufficient to induce symptom improvement.
u Generally, once an exclusion diet is implemented, symptoms should resolve within 3–4
weeks.
u Excluded foods should be reintroduced under expert guidance using a food challenge
process to determine which specific foods are responsible for symptom induction.

Breath test
u Hydrogen and/or methane breath testing are useful, non-invasive measurements to assess
carbohydrate malabsorption in the gastrointestinal tract.
u Carbohydrate malabsorption in the gastrointestinal tract. Hydrogen is not produced by humans, so
the theory is that any breath hydrogen in expired air is only from fermentation products produced
by the gastrointestinal microbiota.
u Patient preparation
u No antibiotics, colonoscopy preparation, laxatives or probiotics have been allowed in the previous 14 days
although there is no universal agreement.
u low in fermentable carbohydrates for 24-48 hrs.
u An overnight fast prior to commencement of the test is advised.
u Test positive : A rise in 5 ppm over 3 consecutive measurements or ≥ 20 ppm H2 or ≥ 10 ppm
(CH4) or ≥ 15 ppm H2 and CH4 rise above baseline.

Carbohydrate breath testing protocol

Confocal laser endomicroscopy (CLE)
u CLE revealed a real-time response to food antigens in 61% of patients.
u Diluted food antigens were directly administered to the duodenal mucosa via the
endoscope and within 5 min of exposure, there were significant increases in
intraepithelial lymphocytes (IEL), epithelial leaks formed and intervillous spaces
widened compared to baseline.

Unvalidated test
in food intolerance

Scombroidosis
u occurs after the ingestion of fresh, canned or smoked fish with high histamine levels due
to improper processing or storage.
u Histamine produced by the decarboxylation of histidine in the muscle of the fish is
primarily responsible for the condition.
u The decarboxylation process is induced by enzymes produced by primarily enteric gram-
negative bacteria (e.g., Morganella morganii, Escherichia coli, Klebsiellaspecies
and Pseudomonas aeruginosa) found in the fish’s cutis and intestines.
u Histamine is heat-stable and remains present after cooking, freezing, canning or
smoking. Outbreaks are most common in summer.
Stratta, P., & Badino, G. (2012). Scombroid poisoning. CMAJ : Canadian Medical Association journal = journal de
l'Association medicale canadienne, 184(6), 674. https://doi.org/10.1503/cmaj.111031

Scombroidosis
u Elevated histamine levels can occur in fish owing to improper refrigeration before
processing or to storage of the fish at room temperature after cooking. Therefore, the
appearance, taste and smell of the fish are poor guides as to the presence of histamine.
u Generally, the formation of BAs in fish products is mainly affected by storage duration
and temperature. Klausen and Lund have reported that histamine, cadaverine,
putrescine, and spermidine amounts in herring and mackerel stored at 10 °C are 2–20
times higher than those in samples stored at 2 °C with the same storage duration.
Histidine Histamine

Scombroidosis
u The term scombroidism derives from the dark-meat species of the Scombridae family
(such as tuna, bonito, skipjack, marlin, and mackerel), although many other non-
scombroid species (such as herring, sardines, anchovies, and mahi-mahi) may be
implicated in the syndrome.
u The tissues of the scombroid fish such as anchovies, tuna, mackerel, sardines, etc
contain high concentration of the histidine which can be microbially converted into
histamine and cause scombroid fish poisoning.

ปลาทูน'าพันธุ,ครีบยาว ปลาสำลีน้ำลึก ปลากะตัก ปลาแซลมอน
ออสเตรเลีย ปลาบลูฟAช ปลาโบนิโต ปลาทูฝรั่ง ปลาเฮอร,ริ่ง
ปลาแม็คเคอเรล ปลาอีโตJมอญ ปลาเข็ม ปลาซอรี่ ปลาซาดีน ปลาโอ
แถบ ปลาวาฮู และปลาโอครีบเหลือง

Signs and symptoms
u Symptoms begin within 10 to 90 minutes after eating the implicated fish. The rash lasts
2–5 hours, and the other symptoms usually disappear within 3–36 hours.
u Symptoms of scombroid poisoning include flushing, rash, urticaria (generally
widespread erythema, usually lacking wheals), and burning of the mouth and throat.
u Gastrointestinal symptoms can include abdominal cramps, nausea, vomiting and
diarrhea.
u Bronchospasm, respiratory distress and vasodilatory shock have also been described.
u Neurological ; palpitations, headache, dizziness, sweating,
Hungerford, James M. "Scombroid poisoning: a review." Toxicon 56.2 (2010): 231-243.

Affected areas are bright red, hot and itchy. The rash is a form of urticaria,
but unlike an allergic reaction, there is no whealing (skin swelling).

Ridolo, Erminia, et al. "Scombroid syndrome: it seems to be fish allergy but... it
isn’t." Current opinion in allergy and clinical immunology 16.5 (2016): 516-521.

Scombroidosis
u The diagnosis is often clinical and can be confirmed by measurement of histamine in
incriminated spoiled food. Determination of the patient’s histamine level in plasma or
the level of histamine metabolites (e.g., n-methylhistamine) in urine can also support
the diagnosis.
u Treatment
Most instances of scombroid poisoning are self-limited. However, if the patient has
symptoms severe enough to require treatment, rapid-acting antihistamines (usually H1-
receptor antagonists) are commonly used, along with supportive care tailored to the
symptoms.
Hungerford, James M. "Scombroid poisoning: a review." Toxicon 56.2 (2010): 231-243.

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