Introduction

It is well known that diet and gut health affect mental health symptoms such as stress-related disorders, depression and anxiety [1]. Bi-directional signalling between the gut and the brain includes communication via the immune system, central nervous system and the endocrine (hormonal) system which in turn impacts mood and behaviour. This "communication" is under the influence of the gut microbiota; the gut is home to hundreds of trillions of microorganisms which form part of the gut-microbiome-brain axis. The complex interactions involved are influential in a number of disorders in which inflammation has been implicated including depression, schizophrenia, autism-spectrum disorders (ASDs) and attention-deficit hypersensitivity disorder (ADHD) [2]. Mood states have even been linked with the composition of the microbiome in mentally and physically healthy adults [3].

Increased gut permeability appears to be the cornerstone of gutmicrobiome- brain interaction. This can lead to translocation of gut microbiota and their products, and incompletely digested nutrients such as food proteins, into the blood stream [4,5] Structural similarities exist between the intestinal and blood brain barriers [6], and studies have shown that the blood brain barrier may also be vulnerable to changes in the gut microbiota [7]. Blood brain barrier breakdown is complex and due to disruption of the tight junctions, altered transport of molecules and inflammatory responses which appear to initiate and/or contribute to disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, ASD and others [8,9]. The immune system and immune inflammatory process provide key communication pathways between the gut and brain. Diet, the composition of the gut microbiota, and health are intrinsically linked [10].

Measurement of food-specific IgG antibodies is used as a strategy for identifying foods to which a subject may be sensitive. This type of testing is now considered "mainstream" as many choose to use this approach as a starting point for an elimination diet. The test is not diagnostic of any condition, but is used as an aid to management of dietary intake, a "starting point" for an elimination diet. Increased intestinal permeability can allow larger food proteins to pass through into the blood stream where they may, or may not, trigger an IgG immune response (see Figure 1). There is evidence across a growing number of trials that diet adjusted to food-specific IgG levels to foods can lead to symptom improvement [11].These include those in IBS [12-18], inflammatory bowel disease (IBD) [19,20], migraine[17,21], weight gain [22], rheumatoid arthritis [23] and looking at overall quality of life measures [22].

Key Words: Food Intolerance; Food IgG; Mental Health; Gut Microbiota; Microbiome; Brain; Depression; Autism; ADHD; Schizophrenia, Intestinal Permeability; Blood Brain Barrier; Dietary Change Elimination Diet

Gut Microbiome

The biggest changes in the composition of the gut microbiome and neuronal development occur in childhood and adolescence [24] Psychiatric, and other, illnesses such as schizophrenia, substance abuse, irritable bowel and mood disorders frequently first manifest themselves during the teenage years and there is a call to better understand the way that gut microbiota can be manipulated to contribute to treatment of mental illnesses in the developing teen [25]. Early life stress can also have a significant impact on the microbiological content of the intestine and immune functioning; that early life stress can also impact adult psychopathology has also long been appreciated in psychiatry [26].There is also increasing evidence that brain inflammation involved in the pathogenesis of neuropsychiatric diseases. For example, mast cells are present in the brain where they regulate blood brain permeability and brain function, and it is proposed that they may be involved in the pathogenesis of "brain fog", headaches and ASDs, which worsen with stress [27]. Mast cells, and other immune cells, can be activated through IgG-dependent mechanisms [28-30], and IgG antibodies to foods are associated with inflammation [31].This is significant in relation to the inflammatory component of many disorders. It is known that diet strongly influences the composition of the microbiome. Gut microbiota are known to be influential in the susceptibility to food sensitivities [32], and there is a strong statistical correlation between risk for ASD and atopic diseases, such as asthma, eczema, food allergies and food intolerance [33]. Food provocation in food intolerant patients is characterised by a general and systemic immune activation [34].

Depression

Depression is not only linked to changes in neurotransmission in the central nervous system but also changes via hormonal, inflammatory and immune mechanisms, and many studies have shown elevated levels of pro-inflammatory cytokines in those with depression. Serotonin is a critical signalling molecule in the braingut- microbiota axis, approximately 95% of serotonin in the body is compartmentalised in the gut, and there is emerging evidence that the serotonergic system may be under the influence of the gut microbiota; references in Kelly et al (2015) [7]. A role for IgG hyper-sensitivity in the pathogenesis and therapy of depressive disorders has been reported [5]. Indeed, in the largest study of its kind, Allergy UK commissioned a retrospective postal survey of those who had elevated food specific IgG levels and had purchased a YorkTest food-specific IgG-guided diet programme. Of the 708 subjects reporting psychological conditions, including depression, anxiety, behavioural problems, hyperactivity, mental fog, ASD and panic attacks, 81% reported an improvement in their condition following food-specific IgG-guided elimination diet [11].

The association between the gluten-mediated immune response and neurological and psychiatric manifestations is also well established [35]. Non-coeliac gluten sensitivity (NCGS), identified by measuring gliadin-specific IgG antibodies [36], represents a unique condition with different manifestations than coeliac disease [37]. Gluten ataxia has customarily been considered to be the main neurological manifestation of coeliac disease, however, recent findings have shown that gluten ataxia patients are better classified within the NCGS group, than within the coeliac disease group [38]. Interestingly NCGS can also predict vulnerability to dementia [39].

Schizophrenia

Studies have shown that the gut microbiota play a key role in the immunopathogenesis of schizophrenia. There has been a call for strategies that focus on microbiota targeted therapies to improve symptoms and to decrease the immune dysregulation seen in patients with schizophrenia [40,41]. People with schizophrenia have raised anti-gliadin IgG antibodies compared to normal controls [42] similarly reported raised anti-milk casein and antiyeast IgG antibodies, and potentially other food-specific IgG antibodies [43,44].

Severance et al (2015) [45], showed data supporting the concept that cerebral spinal fluid (CSF)-related barrier and flow abnormalities may be present in those with schizophrenia and this may affect the way that food-specific IgG antibodies are distributed between the CSF and serum. The study postulated that food-specific IgG antibodies might pass through a transiently permeable blood CSF, or blood brain, barrier and be directly pathological to the brain, perhaps binding to important brain proteins. Immune sensitivities to foods have been found in a variety of other brain diseases and conditions including bipolar disorder, ataxia, epilepsy and autism [46]. Therapies which aim to remove the antigenic (food) source and normalise gut and brain barrier functions in schizophrenia have been proposed [45].

ASD

Many children with ASDs present with gut symptoms, altered gut microbiota and intestinal permeability. Increasing evidence indicates that ASD pathogenesis also involves brain inflammation (2) and a permissive blood brain barrier [47]. There is an increase in intestinal permeability in those with ASD compared to healthy children; this correlates with the production of higher levels of anti-gliadin and anti-casein specific IgG antibodies concluding that IgG-guided elimination diet could be considered as a medical nutrition therapy in ASD [48]. In addition, there are increased plasma concentrations of IgG-specific antibodies to milk proteins and gliadin in those with autism compared with their siblings [49]. Children with ASDs have higher levels of immunoglobulins against cow's milk-derived allergens, and milk intake by these patients has been shown to significantly worsen some of their behavioural symptoms [50]. These data were backed up by a small pilot study in ASD showing an overall improvement in behavioural symptoms after IgG-guided elimination diet [51]. The behavioural improvement in ADHD that accompanied an improved IgG score has also been documented [52].

Conclusion

The food choices that are made by every individual, both because of survival needs and taste preference, cause a substantial and significant variability in gut microbiota. Alterations in the gut, including gut permeability and the composition of the gut microbiome are now considered to be important for treatment across an array of medical conditions. This emphasises the importance of targeting regulators of the immune system in a wide range of medical conditions, particularly psychiatric disorders [10]. Manipulating the microbiota, either by dietary changes, prebiotics, probiotics or even fecal microbial transplantation, seem rational strategies for the prevention and treatment of diseases [53].

There is an increasing body of literature that links diet and the composition of the gut microbiome to mental health disorders, but, so far, very little about what specific targeted dietary changes are needed to help [54]. Whether food-specific IgG-guided elimination dietary changes could fulfil such a role, directly or indirectly, has yet to be evidenced fully, however, the new paradigm linking leaky gut, food-specific IgG, inflammation and mental health is both interesting and encouraging in helping our understanding [5]. Much of the focus on a role for food-specific IgG antibodies in mental health disorders has been on gliadin, wheat, yeast and milk, particularly in ASD and schizophrenia. This approach has now been broadened out to include testing for IgG reactions to a wide range of food proteins that are reflective of a typical diet. The important point here is that dietary intervention, on this basis, is personalised; dependent on specific tailored food- IgG test results, providing a unique targeted approach, and this makes sense immunologically. What is clear is that restoration and maintenance of healthy intestinal, and blood brain, barriers, and the composition of the gut microbiota, are key to improved health, and dietary changes based on IgG-guided elimination diet show promise as a viable intervention strategy.

Introduction

  1. Schnorr S, Bachner H (2016) Integrative therapies in anxiety treatment with special emphasis on the gut microbiome. Yale J Biol Med 89(3): 397-422.
  2. Petra A, Panagiotidou S, Hatziagelaki E, Stewart JM, Conti P, et al. (2015) Gut-microbiota-brain axis and effect on neuropsychiatric disorders with suspected immune dysregulation. Clin Ther 37(5): 984- 995.
  3. Li L, Qiang Su, Xie B, Liu H (2016) Gut microbes in correlation with mood: case study in a closed experimental human life support system. Neurogastroenterol Motil 28(1): 1233-1240.
  4. Yarandi S, Peterson DA, Treisman G J, Moran TH, Pasricha PJ (2016) Modulatory effects of gut microbiota on the central nervous system: How gut could play a role in neuropsychiatric health and diseases. J Neurogastroenterol Motil 22(2): 201-212.
  5. Karakuła-Juchnowicz H, Patrycja Szachta, Aneta Opolska, Lasik Zofia (2017) The role of IgG hypersensitivity in the pathogenesis and therapy of depressive disorders. Nutr Neurosci 20: 110-118.
  6. Doran K, Banerjee A, Disson O, Lecuit M (2013) Concepts and mechanisms: crossing host barriers. Cold Spring Harb Perspect 3(7): a010090.
  7. Kelly J, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, et al. (2015) Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Frontiers in Cellular Neuroscience Front Cell Neurosci 9: 392.
  8. Zlokovic B (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57(2):178-201.
  9. Ueno M, Chiba Y, Murakami R, Matsumoto K, Kawauchi M, Fujihara R, et al. (2016) Blood–brain barrier and blood–cerebrospinal fluid barrier in normal and pathological condition. Brain Tumor Pathol 33(2): 89-96.
  10. Anderson G, Maes M (2017) How Immune-inflammatory processes link CNS and psychiatric disorders: Classification and Treatment Implications. CNS Neurol Disord Drug Targets: 16.
  11. Hardman G, Hart G (2007) Dietary advice based on food-specific IgG results. Nutrition and Food Science 37(1): 16-23.
  12. Atkinson W, Sheldon T, Shaath N, Whorwell P J (2004) Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut 53(10): 1459-1464.
  13. Zar S, Mincher L, Benson MJ, Kumar D (2005) Food-specific IgG4 antibody guided exclusion diet improves symptoms and rectal compliance in IBS. Scand J Gastroenterol 40(7): 800-887.
  14. Drisko J, Bischoff B, Hall M, McCallum R (2006) Treating IBS with a food elimination diet, followed by food challenge and probiotics. J Am Coll Nutr 25(6): 514-522.
  15. Yang C, Li Y (2007) The therapeutic effects of eliminating allergic foods according to food-specific IgG antibodies in irritable bowel syndrome. Zhonghua Nei Ke Za Zhi 46(8): 641-643.
  16. Guo H, Wang J, Chang Y, Guo H, Zhang W (2012) The value of eliminating foods according to food-specific immunoglobulin G antibodies in irritable bowel syndrome with diarrhoea. The Journal of International Medical Research 40(1): 204-210.
  17. Aydinlar E, Dikmen PY, Tiftikci A, Saruc M, Aksu M, et al. (2013) IgGbased elimination diet in migraine plus IBS. Headache 53(3): 514-525.
  18. Kim-Lee C, Suresh L, Ambrus JL Jr (2015) GI disease in Sjogren's syndrome: related to food hypersensitivities. Springer Plus 4: 766.
  19. Gunasekeera V, Mendall MA, Chan D, Kumar D (2016) Treatment of Crohn's Disease with an IgG4-Guided Exclusion Diet: A Randomized Controlled Trial. Digestive Diseases and Sciences61 (4): 1148-1157.
  20. Bentz S, Hausmann M, Piberger H, Rogler G (2010) Clinical relevance of IgG antibodies against food antigens in Crohn's disease: a doubleblind cross-over diet intervention study. Digestion 81(4): 252-264.
  21. Alpay K, Ertaş M, Orhan EK, Kanca Ustay D, Lieners C, et al. (2010) Diet restriction in migraine, based on IgG against foods: a clinical double- blind, randomized, cross-over trial. Cephalalgia 30(7): 829-837.
  22. Lewis J, Woolger J M, Melillo, Yaima Alonso A, Rafatjah S, et al. (2012) Eliminating Immunologically-Reactive Foods from the Diet and its Effect on Body Composition and Quality of Life in Overweight Persons'. J Obes Weig los Ther 2:1.
  23. Hvatum M, Kanerud L, Hällgren R, Brandtzaeg P, et al. (2006) The gut-joint axis: cross reactive food antibodies in rheumatoid arthritis. Gut 55(9): 1240-1247.
  24. Rea K, Dinan TG, Cryan JF (2016) The microbiome: A key regulator of stress and neuro inflammation. Neurobiol Stress 4: 23-33.
  25. McVey Neufeld K, Luczynski P, Seira Oriach C, Dinan TG, Cryan JF (2016) what's bugging your teen?-The microbiota and adolescent mental health. Neurosci Biobehav Rev 70: 300-312.
  26. Dinan T, Cryan J (2017) Microbes, immunity, and behavior: psychoneuroimmunology meets the microbiome. Neuropsychopharmacology 42(1): 178-192.
  27. Theoharides T, Panagiotidou S, Polyzoidis S, Koletsa T (2016) Mast cells, brain inflammation and autism. Eur J Pharmacol778: 96-102.
  28. Rodrigo L, Hernández-Lahoz C, Lauret E, Kruzliak P (2016) Gluten ataxia is better classified as non-celiac gluten sensitivity than as celiac disease: a comparative clinical study. Immunol Res 64(2): 558-564.
  29. Woolhiser M, Brockow K, Metcalfe DD (2004) Activation of human mast cells by aggregated IgG through FcgammaRI: additive effects of C3a. Clin Immunol 110(2): 172-180.
  30. Nimmerjahn F and Ravetch J (2008) Fcγ receptors as regulators of immune responses. Nature Reviews Immunology 8(1): 34-47.
  31. Wilders-Truschnig M, Mangge H, Lieners C, Gruber H, Mayer C, Marz W, et al. (2008) IgG Antibodies against food antigens are correlated with inflammation and intima media thickness in obese juveniles. Exp Clin Endocrinol Diabetes116: 241-245.
  32. Feehley T, Stefka AT, Cao S, Nagler CR, et al. (2012) Microbial regulation of allergic responses to food. Semin Immunopathol 34(5): 671- 688.
  33. Theoharides T, Tsilioni I, Patel A B, Doyle R (2016) Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders. Transl Psychiatry 6(6): 844.
  34. Jacobsen M, Aukrust P, Kittang E, Müller F, Ueland, et al. (2000) Relation between food provocation and systemic immune activation in patients with food intolerance. Lancet 356(9227): 400-4001.
  35. Casella G, Pozzi R, Cigognetti M, Bachetti F, Torti G, et al. (2017) Mood disorders and non-celiac gluten sensitivity. Minerva Gastroenterol Dietol 63(1): 32-37.
  36. Infantino M, Meacci F, Grossi V, Macchia D, Manfredi M, et al. (2017) Anti-gliadin antibodies in non-celiac gluten sensitivity. Minerva Gastroenterol Dietol 63(1): 1-4.
  37. Jackson J, Eaton W W, Cascella N, Kelly DL (2012) Neurologic and psychiatric manifestations of celiac disease and gluten sensitivity. The Psychiatric Quarterly 83(1): 91-102.
  38. Rodrigo L, Carlos Hernández-Lahoz, Eugenia Lauret, Peter Kruzliak (2016) Gluten ataxia is better classified as non-celiac gluten sensitivity than as celiac disease: a comparative clinical study. Immunol Res 64(2): 558-564.
  39. Daulatzai M (2015) Non-celiac gluten sensitivity triggers gut dysbiosis, neuro inflammation, gut-brain axis dysfunction, and vulnerability for dementia. CNS Neurol Disord Drug Targets 14(1): 110-131.
  40. Caso JR, Balanza-Martínez V, Palomo T, García-Bueno B (2016) The Microbiota and Gut-Brain Axis: Contributions to the Immunopathogenesis of Schizophrenia. Curr Pharm Des 22(40): 6122-6133.
  41. Dinan T, Borre Y E, Cryan J F (2014) Genomics of schizophrenia: time to consider the gut microbiome? Mol Psychiatry19: 1252-1257.
  42. Okusaga O, Yolken RH, Langenberg P, Sleemi A, Kelly DL, et al. (2013) Elevated gliadin antibody levels in individuals with schizophrenia. World J Biol Psychiatry14 (7): 509-515.
  43. Li Y, Webera NS, Fishera JA, Yolkenc RH, Cowana DN, et al. (2013) Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel. Schizophr Res 151(1-3): 36-42.
  44. Severance E, Alaedini A, Yang S, Halling M, Gressitt KL, et al. (2012) Gastrointestinal inflammation and associated immune activation in schizophrenia. Schizophr Res.138 (1): 48-53.
  45. Severance E G, Gressitt KL, Alaedini A, Rohleder C, Enning F, et al. (2015) IgG dynamics of dietary antigens point to cerebrospinal fluid barrier or flow dysfunction in first-episode schizophrenia. Brain Behav Immun44: 148-158.
  46. Vojdani A, O'Bryan T, Green JA, Mccandless J, Woeller KN, et al. (2004) Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutr Neurosci 7(3): 151-161.
  47. Fiorentino M, Sapone A, Senger S, Camhi SS, Kadzielski SM, et al. (2016) Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Mol Autism7: 49.
  48. De Magistris L, Picardi N, Siniscalco D, Pia Riccio M, Sapone A, et al. (2013) Antibodies against food antigens in patients with autistic spectrum disorders. Biomed Res Int: 729349.
  49. Trajkovski VE, Petlichkovski A, Mladenovska OE, Spiroski M, Arsov T, et al. (2008) Higher plasma concentration of food-specific antibodies in persons with autistic disorder in comparison to their siblings. Focus on Autism and Other Developmental Disabilities 23(3): 176-185.
  50. de Theije C, Bavelaar MB, Lopes da Silva S, Kraneveld AD, Olivier B, et al. (2014) Food allergy and food-based therapies in neuro developmental disorders. Pediatr Allergy Immunol 25(3): 218-226.
  51. Johnson N (2010) University of Bedfordshire, Autism Study (unpublished data).
  52. Ritz B, Lord R (2005) Case study: The effectiveness of a dietary supplement regimen in reducing IgG-mediated food sensitivity in ADHD. Altern Ther Health Med 11(3): 72-75.
  53. Scott KP, Antoine JM, Midtvedt T, van Hemert S (2015) Manipulating the gut micro biota to maintain health and treat disease. Microb Ecol Health Dis 26:10.3402.
  54. Bibbo S, Ianiro G, Giorgio V, Scaldaferri F, Masucci L, et al. (2016) The role of diet on gut micro biota composition. Eur Rev Med Pharmacol Sci 20(22): 4742-4749.