Food  intolerance  and  Food  allergy  as  a  consequence  of  impaired  gastro-­intestinal  function.    Food  intolerance  and  food  allergy  are  an  increasing  issue  for  human  health  and  well-­‐being.  Classic  IgE  food  allergy  is  present  in  3-­‐6%  of  the  population  (1)  with  increasing  tendency.  Environmental  pollution  (2),  use  of  certain  drugs  such  as  antibiotics  and  H2  pump  inhibitor  (3)  are  some  of  the  modern  triggers  of  food  allergy.  Beside  IgE-­‐mediated  food  allergy,  IgG  mediated  food  allergy  becomes  more  and  more  important,  particularly  in  chronic  inflammatory  diseases.  (4,5,6,7,8,9,10,11,12).  It  has  also  been  shown  that  IgG  alone  with  neutrophyls  can  induce  an  anaphylactic  shock  in  experimental  conditions.  (13)    Thus,  IgE  food  allergy  is  mainly  responsible  for  acute  life-­‐threatening  conditions,  such  as  anaphylactic  shock  and  skin  itching  or  mucosa  swelling,  caused  by  the  excessive  release  of    histamine,  while  IgG  mediated  allergy  is  a  non  acute  condition.  Symptoms  often  appear  delayed,  only  after  hours  or  days  after  the  consumption  of  the  concerned  food.  Positive  blood  tests  are  sometimes  without  symptoms.  It  may  also  take  weeks  or  months  after  sensitization  until  the  first  symptoms  appear.  This  is  due  to  the  necessity  of  a  sensitized  organ  or  tissue  where  immune  complexes  adhere  and  are  destroyed.  During  the  destruction  of  these  immune  complexes  the  surrounding  tissue  is  also  damaged  and  after  a  certain  time,  specific  symptoms  may  occur.  IgG  food  allergy  is  a  low  grade  inflammatory  condition  which  becomes  symptomatic,  if  it  turns  into  a  chronic  inflammatory  condition.  This  occurs  when  the  concerned  foods  are  consumed  on  a  regular  basis,  e.g.  more  than  2-­‐3  times  a  week.    While  IgE  mediated  allergic  reactions  are  limited  to  a  few  symptoms,  IgG  mediated  allergy  may  lead  to  or  maintains  any  chronic  inflammatory  process  (14)    

• every  chronic  inflammatory  disease  • articulations,    glandular    • diabetes,  hypothyroidism  • intestinal  lesions,  Crohn  disease,  celiac  disease,  irritable  colon  • cutaneous  manifestations  :  atopic  eczema,  pruritus,  acne  • migraine,  chronic  headache  • psychic  disorders  -­‐  depression  • chronic  fatigue  (CFS)  • overweight,  obesity,  hypertension  • malabsorption  syndrome  • autoimmune  diseases  • fibromyalgia  • respiratory  disease,  asthma  • chronic  non-­‐infectious  rhinitis  • chronic  iron  deficiency  

     But  why  is  the  immune  system  aggressing  harmless  proteins  which  cannot  multiply  in  our  body,  like  viruses  or  bacteria?  It  is  not  normal  that  the  immune  system  recognizes  food  protein  as  invaders!  80%  of  our  immune  system  is  located  in  the  gut!  It  is  organized  in  the  gut  membrane  in  the  so-­‐called  Peyer  patches.  They  host  some  109  lymphoctes.  It  is  here  where  the  decision  for  tolerance  or  intolerance  is  made.    The  organism  has  developed  a  very  high  degree  of  tolerance  against  food,  which  of  course  is  essential  for  

surviving.  

     But  why  is  food  allergy  an  increasing  problem?  More  and  more  evidence  show  that  the  integrity  of  the  gut  barrier  plays  a  key  factor  in  the  development  of  food  allergy.(13)    Gut  barrier  It  is  essential  for  food  allergy,  that  undigested  or  poorly  digested  food  can  pass  the  intestinal  barrier  and  are  recognized  by  the  immune  system  as  being  foreign.  A  healthy  intestine  protects  the  organism  from  adverse  reactions  to  food.    

   The  gut  barrier  is  build  up  by  4  distinct  compartments:    

1. The  enterocytes,  which  constitute  a  monolayer  of  cells  glued  one  to  another,  by  the  so-­‐called  tight  junctions,  that  in  the  ideal  condition  won’t  let  any  undigested  proteins  or  peptides  pass  the  barrier,  unless  they  are  degraded  to  amino  acids.    If  

these  tight  junctions  are  disrupted,  macro-­‐molecules  may  pass  the  gut  barrier  uncontrolled  and  lead  to  immune  reactions  as  seen  below.  This  condition  is  called  leaky  gut.    

2. In  this  monolayer  of  enterocytes  are  incorporated  the  so-­called  M-­cells.  They  enable  the  penetration  of  dedicated  macro-­‐molecules  through  the  gut  barrier,  such  as  vitamins,  drugs,  hormones,  proteins  and  so  on.    Below  these  M-­‐cells  are  the  so-­‐called  Antigen  Presenting  Cells.  They  actually  decide  whether  a  substance  is  regarded  as  tolerant  or  intolerant.  If  macro-­‐molecules  pass  the  gut  barrier  uncontrolled,  certain  cytokines  are  produced  and  lead  to  the  rejection  of  this  macro-­‐molecule  by  the  immune  system.  

   

3. sIgA  is  an  antibody  produced  by  plasma  cells  within  the  gut  walling.  sIgA  pass  thru  the  enterocytes  and  are  released  into  the  gut  lumen  to  catch  and  neutralize  antigens  before  they  penetrate  the  gut  barrier.  sIgA  are  mainly  produced  against  potentially  pathological  bacteria.  But  it  seems  that  not  only  bacteria,  but  also  candida  and  food  components  may  be  addressed  by  sIgA.  There  is  growing  evidence  that  sIgA  deficiency  and    low  levels    of  sIgA  in  stool    correlate  with  the  incidence  of  allergic  conditions.      sIgA  may  be  an  important  predictive  marker  for  the  risk  of  developing  allergic  reactions.    

4. The  physiological  flora  plays  an  important  role  to  guarantee  the  integrity  of  the  gut  barrier.  Certain  strains  of  bacteria,  like  enterococcus,    Escherichia  coli,  Lactobacillus  and  Bifidobacterium  to  name  a  few,  are  extremely  important  for  the  micro-­‐environment  in  the  gut.  They  produce  bacteriocines  to  avoid  the  colonization  of  pathogenic  bacteria  and  the  colonization  of  candida  (15).  In  case  of  a  dysbiosis  (dysbalance  of  the  gut  flora)  pathogenic  bacteria  and  candida  can  colonize  the  gut  and  lead  to  increased  gut  permeability.  

 One  or  more  of  these  conditions,  destruction  of  tight  junctions,  dysbiosis,  deficiency  in  sIgA  lead  to  increased  gut  permeability  and  increased  immune  reactions  to  harmless  proteins  leading  to  allergic  reaction.    Allergic  reactions  in  the  gut  also  mean  increased  inflammatory  processes  in  the  gut.  Inflammatory  processes  also  lead  to  increased  permeability.    The  vicious  circle  is  closed.    

     Case  report  Patient:  male,  58  years,  good  physical  condition.  3  month  ago  he  had  an  acute  diarrhea  with  high  temperature  and  watery  stool  for  6  days.  Acute  diarrhea  disappeared  without  further  treatment  and  the  patient  was  well  for  3  weeks.  Then  he  started  to  have  persistent  diarrhea  without  temperature  for  3  months  until  he  decided  to  perform  an  IgG  test  against  food.  All  other  invasive  and  non-­invasive  diagnostic  attempts  remained  without  diagnosis  of  the  cause:  Coloscopy:  no  abnormality  Biopsy:  no  abnormality  Faeces  examination:  virus,  bacteria,  mycosis,  parasites:  negative  Blood:  main  serology,  hormones,  tumor  markers  :  negative  The  ImuPro  300test  showed  18  minor  reactions,  with  a  strong  reaction  against  Pineapple    The  patient  ate  fruit  salad  containing  pineapple  every  day  for  several  years  without  any  problem.  Only  after  the  massive  impairment  of  the  gut  barrier  and  increased  permeability  caused  by  the  acute  intoxication,  his  immune  system  started  to  fight  against  the  pineapple  protein.  He  became  intolerant  to  pineapple  due  to  an  uncontrolled  passage  of  the  gut  barrier.  Interestingly  it  took  3  weeks  before  chronic  diarrhea  started,  exactly  the  time  the  immune  system  needs  to  produce  antibodies,  as  known  by  vaccination.  By  avoiding  pineapple  symptoms  disappeared  within  3  days.    A  challenge  test  with  pineapple  4  weeks  later,  lead  to  diarrhea  within  1  day.  This  case  nicely  describes  the  impact  of  disturbed  gut  permeability  on  the  development  of  food  intolerance.      Conditions  leading  to  increased  gut  permeability  (14)  •bacterial  and  viral  infections  •  parasites  and  Candida  albicans  •  conservation  agents  •  colorants  •  heavy  metals  •  environmental  toxins  •  stress-­‐  Interferon-­‐g,  TNF-­‐a  

Increased  gut  permeability  Marker  α1-­‐AT    

Increased  risk  for  allergic  reaction  

Marker  sIgA  

Food  allergies  Marker    food  speciaic  IgG  

Gastro-­‐intestinal  

inalammation  Marker  

Calprotectin  

•  drugs  •  alcohol  •  exocrine  pancreas  insufficiency  •  malnutrition  •  dysbiosis  •  putrefaction  flora    Diagnostic  tools  to  estimate  the  risk  for  increased  gut  permeability  and  the  assessment  of  intestinal  inflammation          Determination  of  sIgA  in  stool  is  a  valid  tool  to  estimate  the  ability  to  produce  sufficient  sIgA  necessary  for  the  defense  against  pathogenic  agents.  Decreased  values  of  sIgA  indicate  a  higher  risk  for  allergic  conditions  and  increased  risk  for  gastro-­‐intestinal  infection  and  colonization  of  candida  albicans.  Increased  values  of  sIgA  indicate  an  ongoing  fight  against  those  agents  and  may  indicate  the  presence  of  those  agents  in  the  intestine.  Specific  treatments  may  enhance  sIgA  production.    Indications:  Recurrent  infectious  diseases  Food  and  air  born  Allergies  Candidosis  Food  intolerance      Alpha-­1-­anti-­trypsine  α-­‐1-­‐AT,  is  a  protease  produced  by  the  liver.  α-­‐1-­‐AT  is  normally  not  present  in  the  gut  or  only  at  low  concentrations.  Presence  of  α-­‐1-­‐AT  indicates  an  increased  gut  permeability,  as  a  loss  from  proteins  from  blood  to  the  gut  lumen.  Vice  versa  the  migration  of  proteins    and  pathogens  from  the  gut  to  the  blood  is  also  increased.    A  second  reason  for  increased  α-­‐1-­‐AT  is  the  regulation  of  inflammatory  processes  in  the  gut.    Therefore  the  interpretation  of  increased  α-­‐1-­‐AT  should  always  be  performed  in  conjunction  with  Calprotectin.    Calprotectin  is  a  stable  marker  for  gastro-­‐intestinal  inflammation.      Interpretation  

 

Indications:  Chronic  inflammatory  diseases  Gastro-­‐intestinal  disorders  Protein  loss  Food  allergies  and  food  intolerance      Calprotectin  is  a  calcium-­‐binding  protein  of  the  cytoplasm  of  granulocytes.  It  represents  about  5%  of  the  protein  content  of  neutrophil  granulocytes  and  60%  of  the  cytosol.  It  is  resistant  against  the  degradation  of  proteases  and  is  one  week  stable  in  the  stool.  Calprotectin  is  a  sensitive  inflammation  marker  which  is  not  influenced  by  drugs,  food  or  enzymatic  metabolism.  Calprotectin  is  known  for  its  ability  to  discriminate  between  IBD  and  IBS.  In  IBD  Calprotectin  values  are  well  above  50  µg/ml,  known  as  the  cut-­‐off  value  for  IBD  But  values  for  Calprotectin  below  50  µg/ml  are  not  necessarily  meaningless  or  to  be  considered  as  healthy.  Values  between  10µg/ml  and  50  µg/ml  may  indicate  low-­‐grade  intestinal  inflammation  as  caused  by  food  allergy.    In  a  retrospective  study  we  examined  Calprotectin  values  from  patients  in  our  lab.  

       Subjects  with  values  between  10  µg/ml  and  50 µg/ml  undergoing  an  IgG  guided  diet  normalized  their  Calprotectin  values  within  a  few  weeks,  meaning  they  became  undetectable.  In  a  study  in  Turkey  (17)  we  could  show  that  IgG  positive  foods  were  able  to  boost  Calprotectin  values  within  2  days  in  patients  with  Crohn’s  disease  under  remission.  

 

 

     Calprotectin  and  alpha-­‐1  antitrypsin  are  valuable  follow  up  markers  for  the  beneficial  effect  of  an  IgG-­‐guided  diet  in  gastro-­‐intestinal  diseases,  as  well  in  IBS  as  in  IBD.      Indications  Gastro-­‐intestinal  disorders  Differentiation  between  IBS  and  IBD  Prediction  of  relapse  in  Crohn’s  disease  Evaluation  of  severity  of  diagnosed  Crohn’s  disease  and  ulcerative  colitis  Food  allergy  and  food  intolerance  Follow-­‐up  marker  for  IBS  and  IBD      1.  Scott  H.  Sicherer,  Epidemiology  of  food  allergy  Volume  127,  Issue  3  ,  Pages  594-­‐602,  March  2011    2.    T.H.-­‐T.Tan,  J.A.Ellis,  R.Saffery,  K.J.Allen.  The  role  of  genetics  and  environment  in  the  rise  of  childhood  food  allergy.  Clinical  and  Experimental  Allergy,  Vol  42,  Issue  1  3.    I.  Pali-­‐Schöll  &  E.  Jensen-­‐Jarolim.  Anti-­‐acid  medication  as  a  risk  factor  for  food  allergy    Allergy  66  (2011)  469–477  a  2010  John  Wiley  &  Sons  A/S   (4) Food allergy in irritable bowel syndrome: new facts and old fallacies. Isolauri E, Rautava S, Kalliomaki M, (2004) Gut; 53 (10):1391-3 (5) Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Atkinson W, Sheldon TA, Shaath N and Whorwell PJ. (2004) Gut 53(10):1459-1464.  (6) IgG antibodies against food antigens are correlated with inflammation and intima media thickness in obese juveniles. Wilders-Truschnig M, Mangge H, Lieners C, Gruber HJ, Mayer C and Marz W. (2007). Exp Clin Endocrinol Diabetes (7) Food allergy mediated by IgG antibodies associated with migraine in adults. Arroyave Hernandez CM, Echevarria Pinto M, Hernandez Montiel HL. Rev Alerg Mex (2007); 54: 162–168 (8) Diet restriction in migraine, based on IgG against foods: a clinical double-blind, randomised, cross-over trial. Alpay K, Ertas M, Orhan EK, Ustay DK, Lieners C and Baykan B. (2010) Cephalgia 1-9. (9) Treatment of delayed food allergy based on specific immunoglobulin G RAST testing. Dixon H. (2000). Otolaryngology- Head Neck Surgery Vol 123:48-54 (10) Clinical relevance of IgG antibodies against food antigen in Crohn’s Disease – A double blind cross over diet intervention study S. Bentz, M. Hausmann, S. Paul, W. Falk, F. Obermeier, J. Schölmerich, G. Rogler Digestion (2010);81:252–264

(11) Ovalbumin-specific immunoglobulin G and subclass responses through the first 5 years of life in relation to duration of egg sensitization and the development of asthma. Vance, G.H.S., Thornton, C.A., Bryant, T.N., Warner, J.A. and  (12) Milk protein IgG and igA : the association with milk-induced gastrointestinal symptoms in adults. Anthoni S, Savilahti E, Rautelin H, Kolho KL World J. (2009) Gastroenterol. Oct 21 ; 15 (39) 4915-8    13.  Mason  KL,  Huffnagle  GB,  Noverr  MC,  Kao  JY.  Overview  of  gut  immunology.  Adv  Exp  Med  Biol.  2008;635:1-­‐14.    14.  Lebensmittelunverträglichkeit,  Allergie  Typ  3  erkennen  und  richtig  behandeln.  Hans  J.  Schwyn,  Camille  Lieners  AT-­‐Verlag,  (2009)  ISBN-­‐10:  3038004154    

15.  Noverr  MC  Huffnagle  GB  Regulation  of  Candida  albicans  Morphogenesis  by  Fatty  Acid  Metabolites  Infect.  Immun.  November  2004  vol.  72  no.  11  6206-­‐6210  

16.  Hülya  Uzunismail,  Mahir  Cengiz,  Hafize  Uzun,  Fatma  Özbakır,  Süha  Göksel,  Filiz  Demirdag,  Günay  Can, Huriye Balcı, C.Lieners Changes in fecal Calprotectin, acute phase markers and symptoms after provocation by IgG positive foods in Crohn’s disease Poster presentation Nutrition in Medicine ACNEM Sydney 2011