According to the World Allergy Organization (WAO), approximately 20% of the global population suffers from allergies. As per ongoing investigations, their pervasiveness is expanding comprehensively. Allergic diseases are significant because of the high prevalence and constant increase in their costs and adverse effects on human life. Probiotics are proposed as an intervention for the prevention and treatment of allergic diseases. Various mechanisms are considered for the anti-allergic effects of probiotic properties, like detecting related molecular patterns, including DNA motifs or lipopolysaccharides (LPS) of the bacteria, through interaction with host immune systems by Toll-like receptors. In this chapter, the microbiome, allergy, and the role of immunomodulatory probiotics against allergy are discussed.
In industrialized countries, more than 20% of the population has symptoms of allergies. The commonness of childhood asthma increased by 50% in the USA from 1980 to 2000. The allergy mechanism is an immune response to the allergen, which is often mediated by the immunoglobulin E (IgE) antibody . Allergies can be a serious risk for individuals. Allergens or pollens represent a small fraction of the proteins that humans are regularly exposed to. The importance of the topic in the uncertainty is the cause of the B and T cells’ responses to these proteins [2, 3]. Notably, some proteins that are structurally similar pollens may lead to immune response, known as cross-reactivity .
The human body microbiome has a diverse composition of bacteria, archaea, fungi, protozoa, and viruses, which are inhabited mainly in the different epidermal surfaces of the body—the skin and mucosal surface. Some of the species of these microbiotas are identified based on cultural techniques, but due to limitations of these techniques , it is suggested that the number of human microbiota exceeds 1000 species or 10 times the number of cells in the entire body with 30 times larger total genome than the human genome.
A majority of these microbiotas are in the gastrointestinal tract, the major source of microbial exposure, and live in symbiosis with their host cells [6, 7]. Given up genes necessary for the survival of the commensal microbiota in other microenvironments and retained genes beneficial for the host with no or little benefit to themselves  are the evidences of the symbiotic coevolution of the microbiota and human .
The interplay of the immune system with gut microbiota starts from the day of birth and even before that. Early exposure during plasticity and prenatal period seems to be beneficial to prevent the T helper cell type-2 (Th2)-mediated allergic disease . Th2 phenotype is the dominant one in newborns  to prevent rejection in utero. Skewing to Th2 in the immune system leads to the stimulated secretion of IgE by B cells and hence to allergies as seen in germ-free mice with the same condition that results in greater IgE responses to food antigens and failure in producing the proper amount of regulatory T cell (Treg) responses [12, 13, 14]. On the other hand, upsurge in the amount of T helper cell type-1 (Th1) also mediates the autoimmune disease [12, 15, 16, 17, 18, 19].
Restoring Th1/Th2 is the significant role of the microbiota . The association of microbiota and the immune system is mutual. This engagement results in different signaling pathways through the immune system’s molecules that increase immune responses . These regulations are crucial for maintaining the homeostasis of the host and for the prevention of different diseases by inducing secretion of IgA and regulatory T cell (Treg) and stimulation of tolerance in face of common antigens . So the formation, maintenance, and heterogeneity of microbiota are necessary during early life owing to their regulatory and tolerance properties in the immune system [23, 24], as it was confirmed that the lack of microflora during a short time in early life results in defection in immune regulation . The mechanisms of oral tolerance which are necessary to suppress excessive immune reactions to antigens are mediated by Foxp3þ Treg  and IgA, which is known as the most abundant immunoglobulin and is vital in establishing the composition of microbiota  and strengthening the mucosal barrier function .
Although, it is observed that abnormal IgA responses lead to allergy development . So the obligation of equilibrium of the allergy mediators is more sensible now.
Lack of genetic elements such as Toll-like receptors that cause enterocyte proliferation like TLR4 and CD14, which enhance the detection of bacterial LPS by TLR4, and TLR9, which identify the genetic molecules of the microorganisms, also increase susceptibility to allergies [29, 30].
As the priority of the microbiome is proven, some factors are mentioned as follows, to support their presence and diversity in the body. Mode of birth; surgical or natural delivery, the process of contacting microflora in the first moment of the presence. Breast or formula feeding; the extension of contact with microflora. Nutritional patterns; the habit of food, based on people’s patterns to eat fatty and fast foods or healthy ones like prebiotics which are considered beneficial for even the microbiota of the host. Antibiotics; the matter of using antibiotics at an early age or the trouble of overuse of them in all ages which impair normal flora. Locality; living in urban areas with all of the stresses, less interaction with nature in contrast with living in rural areas results in losing ancient commensal microbiota. Environmental factors; contacting people or animals. Hygiene; the obsession behaviors or normal ones. Lifestyle; the matter of activity or sedentariness in someone’s lifestyle.
Natural delivery and breastfeeding are the first two initial and essential exposures when the immune system is not still mature and needs antigens to active oral tolerance [18, 25, 31]. Contravention of these simple factors grounds reformed patterns of early settlement which may result in the incidence of allergy . Food sensitization especially milk allergy and atopic eczema are examples of reduced gut microbial diversity [33, 34, 35, 36, 37].
2. The function of the intestinal microbiota
The microbiome is considered as an active organ because of manufacturing intrinsic signals for shifting postnatal development, inspiration of tolerance mechanisms and immunogenicity reduction, and resistance against invasive pathogens [38, 39, 40, 41, 42].
Consuming substrates of the microbiota containing fibers and mucins provides additional energy for the host as fatty acids . Amines, sulfides, and ammonia are the products of them, which are detrimental metabolites for the human.
The protective barrier function against the invasive microbes by their colonization in the intestine is another potential of the microbiota. Different mechanisms for the resistance colonization of the microbiota are considered, such as competition for nutrients and connection to the binding sites and secretion of the antimicrobial substances .
Stimulation of the innate signaling pathways through the straight cell-to-cell communications or secretion of short-chain fatty acids (SCFA) are the other regulatory actions of the microbiota. SCFAs produced by the microbiota can direct intestinal Treg cells and inhibit pro-inflammatory responses [45, 46, 47, 48].
3. The intestinal microbiota of allergic ones
The role of maternal microbiota in the process of preventing allergy has been proven. Infants from allergic parents are at least twice more likely to the risk of developing allergic diseases than nonallergic parents. Microbiota diversity exists between allergic and nonallergic persons. Reduction in the fecal diversity of the bacteroidetes in pregnancy is connected with the prevalence of atopic eczema in their young children . The microbiota of healthy infants with nonallergic parents frequently consists of healthy lactobacilli, representing the role of maternal microbiota in preventing allergic disorders. A decrease in the number of lactobacilli and bifidobacteria and an increase in the colonization of
4. Stabilizing intestinal bacterial flora
The intestine, the largest immune organ of the body, which is the source of the most antibody-producing cells  is the target of triggering maturation of the immune system or the restoration of the impaired commensal bacteria. Stimulation of the immune system is one of the most impressive functions of the resident microbiota of the intestine. Probiotic bacteria are considered as a safe solution for modulation of diminished commensal composition and also as influencer of the immune system in preventing allergic disorders . Lactic acid bacteria and bifidobacteria are good candidates as probiotics with an appropriate life span, no toxic or pathogenic properties, and no inflammatory induction. The selection of the bacteria as probiotics is mainly based on no harmful side effects during the history of their use for a long time. Consumption of these probiotics aid in balancing the ratio of the intestinal flora, avoiding the inhabiting of the pathogens by preventing the binding of them to the host cells, and suppressing the inflammation, which all are as the result of immune system regulation . The effects of probiotics vary with the dose, strain, and duration of consumption and timing.
But the problem of the probiotics is their longevity and residence in the body of the host, as it was seen that they only remain during the administration period and not after that, showing the transient colonization of the probiotics [61, 62, 63, 64, 65].
Long-term effects of probiotics in different periods of everyone’s life need to be more investigated in complementary studies.
As it was mentioned, immune tolerance is one of the necessary immune reactions to stop excessive inflammatory reactions. Preservation of this tolerance involves the integrity of the epithelial barrier that is heightened by commensal anaerobes, such as
5. Probiotics’ mechanisms of action in allergic disorders
Immune homeostasis develops in the gut as a relationship between the intestinal microbiota, the luminal antigens, and the epithelial barrier is established. Microbial intestinal colonization starts after conception. This happens when the newborn’s sterile gut is slowly colonized by environmental bacteria and by interaction with the mother’s intestinal flora and surroundings and probably by genetic factors [70, 71, 72]. Exposure to microbial flora early in life causes a transition in the T helper cell type-1 (Th1)/Th2 cytokine balance, promoting a Th1 cell response .
An infant’s immune system at birth is not completely formed and appears to be geared toward a Th2 phenotype to prevent in utero rejection . Nevertheless, the Th2 phenotype results in a stimulated production of IgE by B cells and therefore raises the risk of allergic reactions by mast cells activation [75, 76]. Early in life microbial stimulation will reverse the Th2 bias and promote the expansion of the Th1 phenotype and promote Th3 cell activity . In this way, their combined activity will lead to B-cells releasing IgA. IgA contributes to the elimination of allergens and hence would reduce the immune system’s response to antigens. Th1 phenotype-produced cytokines will also reduce inflammation and promote tolerance toward specific antigens .
The hygiene concept states that inadequate or aberrant exposure to environmental microbes is one of the triggers of allergy production and related diseases . As mentioned before, allergic diseases are associated with a change in the Th1/Th2 cytokine balance leading to Th2 cytokine activation and interleukin-4 (IL-4), IL-5, and IL-13 activation as well as IgE production [79, 80]. Probiotics significantly alter the gut microenvironment by encouraging a shift in local microflora and cytokine secretion  and can potentially modulate enterocyte Toll-like receptors and proteoglycan recognition proteins, resulting in dendritic cell (DC) activation and a Th1 response. The resulting stimulation of Th1 cytokines can suppress reactions to Th2 .
6. Probiotics in atopic dermatitis
Atopic dermatitis (AD) is a widespread chronic inflammatory skin condition with a prevalence of around 20% in children and 2–5% in adults worldwide . In recent years, the function of the intestinal microbiota in the aetiopathogenesis of AD has become increasingly important. Atopic dermatitis probiotic therapy is widely studied, with contradictory outcomes . Probiotics containing
7. Probiotics in asthma
Asthma, a chronic complex airway disease, is characterized by reversible airflow obstruction, bronchial hyper responsiveness, and underlying inflammation . In recent decades, the prevalence of asthma has risen. One possible mechanism behind this high prevalence is the microbial hypothesis, which suggests that less microbial exposure upregulates T helper cell type-2 (Th2) cytokine development, leading to a rise in allergic diseases . A meta-analysis found that while perinatal and early-life probiotic administration reduces children’s risk of atopic sensitization and total rates of immunoglobulin E (IgE), it may not reduce their risk of asthma . However, in addition to routine treatment, several studies have documented the advantage of using probiotics for treating children with asthma. A randomized, placebo-controlled trial for 7-week treatment with
8. Probiotics in allergic rhinitis
On these bases, probiotic bacteria are capable of altering immune responses through a range of mechanisms that could minimize allergic reactions to airborne allergens without the side effects of any current drugs, and these possible mechanisms, as shown in Figure 1, include regulatory T cells that dampen immune responses and suppress the production of IgE antibodies [92, 93]. There are contradictory studies about the effectiveness of probiotics in treating allergic rhinitis . It is reported that
9. Probiotics in food allergy
Food allergy (FA) is one of the pediatric age’s most common allergic disorders and has been considered a global health issue, particularly in the developed world.
Naturally, many subjects with FA outgrow this over time. Cow’s milk allergy (CMA), hen’s egg allergy, and wheat allergy resolve by 5–10 years in 50% of children. Many FAs (including peanuts, tree nuts, and fish) have low-resolution levels and are seen as persistent . Furthermore, certain types of FA may be correlated with the subsequent development of other allergic symptoms such as oculorhinitis, atopic dermatitis, asthma, and urticaria (the so-called “Atopic March”)  as well as other diseases such as functional gastrointestinal disorders (FGIDs), inflammatory intestinal diseases (IBD) , and psychiatric disorders such as attentive autistic spectrum disorders (ASD).
The gut microbiome-immune system axis that influences the frequency of FA may be modulated by several genetic, environmental, and dietary factors . For example, increased family size, pet and/or rural exposure, balanced diet (full of fibers, fermented foods, antioxidants, omega-3), breastfeeding, and probiotic use are correlated with FA safety. Conversely, C-section, prenatal, and early-life exposure to antibiotics/gastric acid inhibitors/antiseptic agents, unhealthy diet (low fibers/high saturated fats, and junk foods) may increase the risk of developing FA. All these environmental factors mainly operate on a modulation of the structure and function of the gut microbiota, which may in effect be responsible for the epigenetic control of genes involved in immune tolerance.
The pathogenesis of these incidents also is largely unknown, but increasing evidence suggests the hypothesis that disturbance of intestinal microbiome, leading to alterations in the immune system and gut-brain axis, may affect the occurrence of FA and FA-related conditions later in life  (Figure 2).
Mediterranean diet (MD) is described as a healthy, balanced diet. It is associated with a high intake of assorted cereals, legumes, fruit, vegetables, olive oil, and nuts; moderate consumption of red wine, poultry, and fish; and a lower intake of red meat and sweets. MD has been shown to have a protective role against allergic illnesses in children during pregnancy and early life .
Elevated adherence to MD was associated with increased levels of Prevotella and other Firmicutes and production of short-chain fatty acids (SCFAs) . One of the strongest links between diet, gut microbiome, and allergic diseases is the immunomodulatory mechanisms elicited by SCFAs . Common SCFAs contain acetate, butyrate, propionate, and valerate. SCFA-producing bacteria include
The results of many studies have demonstrated that there is a strong relationship between modifications within the microbiome and many diseases. Much evidence proves that healthy microbiota affects and improves the immune system. It seems that probiotics can have an important role in the prevention of many diseases such as allergy. Microbiota diversity exists between allergic and nonallergic persons. Different mechanisms are considered for the anti-allergic impact of probiotics, like detecting related molecular patterns, including DNA motifs or LPS of the bacteria by Toll-like receptors. Probiotic mechanism against the allergen includes increasing regulatory T cells that damp down immune responses and suppress the production of IgE.
The authors are thankful to the National Institute of Genetic Engineering and Biotechnology (NIGEB), Iran, for providing the facilities.
Conflict of interest
The authors declare no conflict of interest.
Zhang L et al. SORTALLER: Predicting allergens using substantially optimized algorithm on allergen family featured peptides. Bioinformatics. 2012; 28(16):2178-2179
Goodman RE. Biosafety: Evaluation and regulation of genetically modified (GM) crops in the United States. Journal of Hauzhong Agricultural University. 2014; 33(6):85-114
Goodman RE et al. Allergenicity assessment of genetically modified crops—What makes sense? Nature Biotechnology. 2008; 26(1):73-81
Hayes M et al. In silico tools for exploring potential human allergy to proteins. Drug Discovery Today: Disease Models. 2015; 17:3-11
Zoetendal EG, Akkermans AD, De Vos WM. Temperature gradient gel electrophoresis analysis of 16S rRNA from human fecal samples reveals stable and host-specific communities of active bacteria. Applied and Environmental Microbiology. 1998; 64(10):3854-3859
Neish AS. Microbes in gastrointestinal health and disease. Gastroenterology. 2009; 136(1):65-80
Morelli L. Postnatal development of intestinal microflora as influenced by infant nutrition. The Journal of Nutrition. 2008; 138(9):1791S-1795S
McCutcheon JP, Moran NA. Extreme genome reduction in symbiotic bacteria. Nature Reviews Microbiology. 2012; 10(1):13-26
Stein MM et al. Innate immunity and asthma risk in Amish and Hutterite farm children. New England Journal of Medicine. 2016; 375(5):411-421
West CE et al. Probiotics for treatment and primary prevention of allergic diseases and asthma: Looking back and moving forward. Expert Review of Clinical Immunology. 2016; 12(6):625-639
Zeiger RS. Food allergen avoidance in the prevention of food allergy in infants and children. Pediatrics. 2003; 111(Supplement 3):1662-1671
West CE, Jenmalm M, Prescott S. The gut microbiota and its role in the development of allergic disease: A wider perspective. Clinical & Experimental Allergy. 2015; 45(1):43-53
Wesemann DR et al. Microbial colonization influences early B-lineage development in the gut lamina propria. Nature. 2013; 501(7465):112-115
Rodriguez B et al. Infant gut microbiota is protective against cow’s milk allergy in mice despite immature ileal T-cell response. FEMS Microbiology Ecology. 2012; 79(1):192-202
Wesemann DR, Nagler CR. The microbiome, timing, and barrier function in the context of allergic disease. Immunity. 2016; 44(4):728-738
Stefka AT et al. Commensal bacteria protect against food allergen sensitization. Proceedings of the National Academy of Sciences. 2014; 111(36):13145-13150
Prescott SL, Björkstén B. Probiotics for the prevention or treatment of allergic diseases. Journal of Allergy and Clinical Immunology. 2007; 120(2):255-262
Blázquez AB, Berin MC. Microbiome and food allergy. Translational Research. 2017; 179:199-203
Björkstén B. Effects of intestinal microflora and the environment on the development of asthma and allergy. In: Springer Seminars in Immunopathology. Springer; 2004
Walker WA, Iyengar RS. Breast milk, microbiota, and intestinal immune homeostasis. Pediatric Research. 2015; 77(1-2):220-228
Nicholson JK et al. Host-gut microbiota metabolic interactions. Science. 2012; 336(6086):1262-1267
Kirjavainen PV, Gibson GR. Healthy gut microflora and allergy: Factors influencing development of the microbiota. Annals of Medicine. 1999; 31(4):288-292
Nagler-Anderson C et al. Mucosal antigen presentation and the control of tolerance and immunity. Trends in Immunology. 2001; 22(3):120-122
Nagler-Anderson C. Man the barrier! Strategic defences in the intestinal mucosa. Nature Reviews Immunology. 2001; 1(1):59-67
Yu W, Freeland DMH, Nadeau KC. Food allergy: Immune mechanisms, diagnosis and immunotherapy. Nature Reviews Immunology. 2016; 16(12):751
Pabst O, Cerovic V, Hornef M. Secretory IgA in the coordination of establishment and maintenance of the microbiota. Trends in Immunology. 2016; 37(5):287-296
Pabst O. New concepts in the generation and functions of IgA. Nature Reviews Immunology. 2012; 12(12):821-832
Dzidic M et al. Aberrant IgA responses to the gut microbiota during infancy precede asthma and allergy development. Journal of Allergy and Clinical Immunology. 2017; 139(3):1017-1025. e14
Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proceedings of the National Academy of Sciences. 2010; 107(27):12204-12209
Bashir MEH et al. Toll-like receptor 4 signaling by intestinal microbes influences susceptibility to food allergy. The Journal of Immunology. 2004; 172(11):6978-6987
Rodríguez JM et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microbial Ecology in Health and Disease. 2015; 26(1):26050
West CE et al. The gut microbiota and inflammatory noncommunicable diseases: Associations and potentials for gut microbiota therapies. Journal of Allergy and Clinical Immunology. 2015; 135(1):3-13
Wang M et al. Reduced diversity in the early fecal microbiota of infants with atopic eczema. Journal of Allergy and Clinical Immunology. 2008; 121(1):129-134
Ismail IH et al. Reduced gut microbial diversity in early life is associated with later development of eczema but not atopy in high-risk infants. Pediatric Allergy and Immunology. 2012; 23(7):674-681
Bunyavanich S et al. Early-life gut microbiome composition and milk allergy resolution. Journal of Allergy and Clinical Immunology. 2016; 138(4):1122-1130
Azad MB et al. Infant gut microbiota and food sensitization: Associations in the first year of life. Clinical & Experimental Allergy. 2015; 45(3):632-643
Abrahamsson TR et al. Low diversity of the gut microbiota in infants with atopic eczema. Journal of Allergy and Clinical Immunology. 2012; 129(2):434-440. e2
Olszak T et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science. 2012; 336(6080):489-493
Iweala OI, Nagler CR. Immune privilege in the gut: The establishment and maintenance of non-responsiveness to dietary antigens and commensal flora. Immunological Reviews. 2006; 213(1):82-100
Iannitti T, Palmieri B. Therapeutical use of probiotic formulations in clinical practice. Clinical Nutrition. 2010; 29(6):701-725
Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science. 2001; 292(5519):1115-1118
Brandtzaeg P. Development of the mucosal immune system in humans. In: Recent developments in infant nutrition. Springer-Verlag GmbH Germany, part of Springer Nature; 1996. pp. 349-376
Ouwehand AC et al. Prebiotics and other microbial substrates for gut functionality. Current Opinion in Biotechnology. 2005; 16(2):212-217
Adlerberth MC, Poilane I, Wold A, Collignon A, Ingegerd. Mechanisms of colonisation and colonisation resistance of the digestive tract part 1: Bacteria/host interactions. Microbial Ecology in Health and Disease. 2000; 12(2):223-239
Smith PM et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013; 341(6145):569-573
Furusawa Y et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013; 504(7480):446-450
Chang PV et al. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proceedings of the National Academy of Sciences. 2014; 111(6):2247-2252
Arpaia N, Rudensky AY. Microbial metabolites control gut inflammatory responses. Proceedings of the National Academy of Sciences. 2014; 111(6):2058-2059
West CE et al. Gut microbiome and innate immune response patterns in Ig E-associated eczema. Clinical & Experimental Allergy. 2015; 45(9):1419-1429
Sepp E et al. Intestinal microbiota and immunoglobulin E responses in 5-year-old estonian children. Clinical & Experimental Allergy. 2005; 35(9):1141-1146
Kalliomäki M et al. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. Journal of Allergy and Clinical Immunology. 2001; 107(1):129-134
Ouwehand AC et al. Differences in Bifidobacterium flora composition in allergic and healthy infants. Journal of Allergy and Clinical Immunology. 2001; 108(1):144-145
Murray C et al. Fecal microbiota in sensitized wheezy and non-sensitized non-wheezy children: A nested case–control study. Clinical & Experimental Allergy. 2005; 35(6):741-745
He F et al. Intestinal Bifidobacteriumspecies induce varying cytokine production. Journal of Allergy and Clinical Immunology. 2002; 109(6):1035-1036
Morita H et al. Adhesion of lactic acid bacteria to Caco-2 cells and their effect on cytokine secretion. Microbiology and Immunology. 2002; 46(4):293-297
He F et al. Comparison of mucosal adhesion and species identification of bifidobacteria isolated from healthy and allergic infants. FEMS Immunology and Medical Microbiology. 2001; 30(1):43-47
Norin E, Midtvedt T, Björkstén B. Development of faecal short-chain fatty acid pattern during the first year of life in Estonian and Swedish infants. Microbial Ecology in Health and Disease. 2004; 16(1):8-12
Brandtzaeg P. Current understanding of gastrointestinal immunoregulation and its relation to food allergy. Annals of the New York Academy of Sciences. 2002; 964(1):13-45
Saavedra J, Tschernia A. Human studies with probiotics and prebiotics: Clinical implications. British Journal of Nutrition. 2002; 87(S2):S241-S246
Salinas I et al. Monospecies and multispecies probiotic formulations produce different systemic and local immunostimulatory effects in the gilthead seabream ( Sparus aurataL.). Fish & Shellfish Immunology. 2008; 25(1-2):114-123
Wickens K et al. A differential effect of 2 probiotics in the prevention of eczema and atopy: A double-blind, randomized, placebo-controlled trial. Journal of Allergy and Clinical Immunology. 2008; 122(4):788-794
West CE, Hammarström ML, Hernell O. Probiotics in primary prevention of allergic disease–follow-up at 8-9 years of age. Allergy. 2013; 68(8):1015-1020
West CE et al. Effects of feeding probiotics during weaning on infections and antibody responses to diphtheria, tetanus and Hib vaccines. Pediatric Allergy and Immunology. 2008; 19(1):53-60
Rutten N et al. Long term development of gut microbiota composition in atopic children: impact of probiotics. PLoS One. 2015; 10(9):e0137681
Dotterud CK et al. Does maternal perinatal probiotic supplementation alter the intestinal microbiota of mother and child? Journal of Pediatric Gastroenterology and Nutrition. 2015; 61(2):200-207
Atarashi K et al. Induction of colonic regulatory T cells by indigenous Clostridiumspecies. Science. 2011; 331(6015):337-341
Atarashi K et al. T reg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature. 2013; 500(7461):232-236
Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nature Reviews Immunology. 2009; 9(5):313-323
Sabat R, Ouyang W, Wolk K. Therapeutic opportunities of the IL-22–IL-22R1 system. Nature Reviews Drug Discovery. 2014; 13(1):21-38
Strachan DP. Family size, infection and atopy: The first decade of the’hygiene hypothesis’. Thorax. 2000; 55(Suppl 1):S2
Noverr MC, Huffnagle GB. The ‘microflora hypothesis’ of allergic diseases. Clinical & Experimental. Allergy. 2005; 35(12):1511-1520
Tang R-B. Risk factors associated with the development of asthma. Journal of the Chinese Medical Association. 2005; 68(5):199-201
Winkler P et al. Molecular and cellular basis of microflora-host interactions. Journal of Nutrition. 2007; 137(3):756S-772S
Simon AK, Hollander GA, McMichael A. Evolution of the immune system in humans from infancy to old age. Proceedings of the Royal Society B: Biological Sciences. 2015; 282(1821):20143085
Ouwehand AC. Antiallergic effects of probiotics. Journal of Nutrition. 2007; 137(3):794S-797S
Tang R-B, Chang J-K, Chen H-L. Can probiotics be used to treat allergic diseases? Journal of the Chinese Medical Association. 2015; 78(3):154-157
Paibomesai MA. Epigenetic influences on bovine T-helper 1 and T-helper 2 cytokines (interferon-gamma and Interleukin-4) in high and low immune responders around the peripartum period [Diss.]; 2017
Daley D. The evolution of the hygiene hypothesis: The role of early-life exposures to viruses and microbes and their relationship to asthma and allergic diseases. Current Opinion in Allergy and Clinical Immunology. 2014; 14(5):390-396
Deo SS et al. Role played by Th2 type cytokines in IgE mediated allergy and asthma. Lung India: Official Organ of Indian Chest Society. 2010; 27(2):66
Ngoc LP et al. Cytokines, allergy, and asthma. Current Opinion in Allergy and Clinical Immunology. 2005; 5(2):161-166
Jae LB, Bak Y-T. Irritable bowel syndrome, gut microbiota and probiotics. Neurogastroenterology & Motility. 2011; 17(3):252
Rabia A, Shah NP. Immune system stimulation by probiotic microorganisms. Critical Reviews in Food Science and Nutrition. 2014; 54(7):938-956
Stephanie W et al. Effects of probiotics on atopic dermatitis: A randomised controlled trial. Archives of Disease in Childhood. 2005; 90(9):892-897
Perceval C et al. Prophylactic use of probiotics for gastrointestinal disorders in children. The Lancet Child & Adolescent Health. 2019; 3(9):655-662
Sofia R et al. Gut microbiota profile in children affected by atopic dermatitis and evaluation of intestinal persistence of a probiotic mixture. Scientific Reports. 2019; 9(1)
Fang Z et al. Strain-specific ameliorating effect of Bifidobacterium longumon atopic dermatitis in mice. Journal of Functional Foods. 2019; 60:103426
Hamdan AL-J et al. Asthma control and predictive factors among adults in Saudi Arabia: Results from the epidemiological study on the Management of Asthma in asthmatic Middle East adult population study. Annals of Thoracic Medicine. 2019; 14(2):148
Ahanchian H et al. Probiotics for the treatment of asthma: A systematic review and meta-analysis of randomized trials. International Journal of Pediatrics. 2020; 8(5):11271-11285
Johnson C. Asthma flare-ups in children returning to school: New blood screening device developed: More bowel cancer cases for under 50s. Australian Medicine. 2019; 31(2):25
Wei X et al. Association between probiotic supplementation and asthma incidence in infants: A meta-analysis of randomized controlled trials. The Journal of Asthma. 2020; 57(2):167-178
Wu C-T et al. Effect of Lactobacillus rhamnosusGG immunopathologic changes in chronic mouse asthma model. Journal of Microbiology, Immunology and Infection. 2019; 52(6):911-919
Schaefer M, Enck P. Effects of a probiotic treatment ( Enterococcus faecalis) and open-label placebo on symptoms of allergic rhinitis: Study protocol for a randomised controlled trial. BMJ Open. 2019; 9:e031339. doi: 10.1136/bmjopen-2019-031339
Dehnavi S et al. A significant decrease in the gene expression of interleukin-17 following the administration of synbiotic in patients with allergic rhinitis who underwent immunotherapy: A placebo-controlled clinical trial. Journal of Research in Medical Sciences: The Official Journal of Isfahan University of Medical Sciences. 2019; 24:1-7
Sadeghi-Shabestari M et al. Effect of probiotics on allergic rhinitis: A randomized, controlled, clinical trial. Galen Medical Journal. 2020; 9:1918
Giovannini M, Agostoni C, Riva E, Salvini F, Ruscitto A, Zuccotti GV, et al. A randomized prospective double blind controlled trial on effects of long-term consumption of fermented milk containing Lactobacillus caseiin pre-school children with allergic asthma and/or rhinitis. Pediatric Research. 2007; 62:215-220
Helin T, Haahtela S, Haahtela T. No effect of oral treatment with an intestinal bacterial strain, Lactobacillus rhamnosus(ATCC 53103), on birch-pollen allergy: A placebo-controlled double-blind study. Allergy. 2002; 57:243-246
Yang G, Liu ZG, Yang PC. Treatment of allergic rhinitis with probiotics; an alternative approach. North American Journal of Medical Sciences. 2013; 5:465-468
Das RR, Singh M, Shafiq N. Probiotics in treatment of allergic rhinitis. World Allergy Organization Journal. 2010; 3:239-244
Marcello G et al. A randomized prospective double blind controlled trial on effects of long-term consumption of fermented milk containing Lactobacillus caseiin pre-school children with allergic asthma and/or rhinitis. Pediatric Research. 2007; 62(2):215-220
Miguel S, Lu P, Bonilla S. Cow’s-milk allergy is a risk factor for the development of FGIDs in children. Journal of Pediatric Gastroenterology and Nutrition. 2011; 52(2):166-169
Virta LJ, Kautiainen H, Kolho K-L. Symptoms suggestive of cow’s milk allergy in infancy and pediatric inflammatory bowel disease. Pediatric Allergy and Immunology. 2016; 27(4):361-367
Filippis D, Francesca, et al. High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut. 2016; 65(11):1812-1821
Roberto BC et al. Gut microbiome as target for innovative strategies against food allergy. Frontiers in Immunology. 2019; 10:191
Castro-Rodriguez JA, Garcia-Marcos L. What are the effects of a Mediterranean diet on allergies and asthma in children? Frontiers in Pediatrics. 2017; 5:72
Craig MK et al. The nutrition-gut microbiome-physiology axis and allergic diseases. Immunological Reviews. 2017; 278(1):277-295
Louis P, Flint HJ. Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiology Letters. 2009; 294(1):1-8
Schauber J et al. Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes: Relevance of signalling pathways. Gut. 2003; 52(5):735-741
Luying P et al. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. Journal of Nutrition. 2009; 139(9):1619-1625
Brown AJ et al. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. The Journal of Biological Chemistry. 2003; 278(13):11312-11319
Nilsson NE et al. Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochemical and Biophysical Research Communications. 2003; 303(4):1047-1052