This article has been coauthored by Marina Pérez-Gordo, Cristobalina Mayorga and Mariona Pascal.

Allergic diseases include heterogenous inflammatory pathologies such as respiratory, cutaneous and food allergies. They are characterized by an immunological response with T lymphocytes as the main effector T cells, which promote the induction of other effector cells involved in allergic inflammation, such as mast cells, basophils, and eosinophils. These pathologies have dramatically increased in prevalence over the last few decades and recent research points to the microbiota’s central role.

It is well known that the microbiome modulates the body’s immune response, from cellular development to organ and tissue formation, exerting its effects through multiple interactions with both the innate and acquired branches of the immune system. In the late 1980s, Dr. Strachan proposed what is now referred to as the “hygiene hypothesis”, in which changes in environment and nutrition produce a dysbiosis in the skin, gut, or lung microbiome, inducing changes in composition and metabolic activity.

In each location on our body, such as mouth, skin, vagina, respiratory and digestive tract, complex microbial ecosystems, adapted to the particularities of each niche, can be found. These communities have a symbiotic and mutualistic behavior with human eukaryotic cells, maintaining an important dialogue with the immune system and featuring homeostatic functions that affect our health. Gut microbiota is the human body’s most complex, diverse and numerous ecosystem of all, particularly in the caecum, where the density of microorganisms is the highest.

Intestinal microbiota influences the mucosal immune system by training local immune cells. Most antigens in the gastrointestinal tract come from diet and gut microbiota. Constant exposure affects the acquisition of immunological tolerance, thus the mucosal immune system typically exists in a state of active tolerance to both food antigens and commensal bacteria. In this sense, the gastrointestinal tract plays an important role in the early stages of life because it develops both effector and tolerogenic responses to antigens, balancing the activities of Th1 and Th2 cells, as well as regulatory T cells. The induction of immunological tolerance has been related with humoral and cellular changes that include the reduction of sIgE and effector cells, Th2, Th9, and Th17 and inflammatory plasma cells, and the increase of IgG4 and Th1 and/or Treg cells.

Moreover, the complex interaction between food antigens, gut microbiota and cells at the epithelial barrier results in an environment that favors tolerance by the induction of IgA production, T CD4+ cells producing IFN-Y and IL-10, and regulatory T cells (Treg).

Alterations in the composition and diversity of bacteria present in the gastrointestinal tract can break the immunological tolerance of the mucosa and lead to the onset of food allergy and even asthma. Studies in pathogen-free mice (germ-free mice) confirm that tolerance to food antigens does not occur in the absence of intestinal microbiota. The stimulation of immune cells by gut microbiota lead to the secretion of cytokines and other effectors that can act either locally or systemically. This may explain why gut microbiota can distally affect the development of other pathologies such as respiratory and/or cutaneous allergies. Moreover, gut microbiota can generate metabolites, such as short-chain fatty acids (SCFAs), or alter the availability of micronutrients, which can act distally and modify pathogen growth in other organs and their immunity.

Associations between lung and gut microbiome and the risk of developing respiratory allergic disease have been found, indicating that both gut and lung mucosa may function as a single organ, sharing immunological functions and microorganisms. Madan et al studied a cohort of infants with cystic fibrosis and discovered a pattern of clusters of bacteria, including potential pathogens such as Enterococcus, which were present in early life in the gut and later in young life in the respiratory tract. In the same study, they showed that changes in diet affected patients’ respiratory microbiome, suggesting a link between nutrition and the development of microbial communities in the respiratory tract.

Song H et al described in 2016 that SCFA levels in the intestine were reduced in patients affected with atopic dermatitis, proving that the development of cutaneous allergic diseases was related to gut microbiota dysbiosis, although the underlying mechanisms are still unclear.

The microbiota can be considered a therapeutical target for treating allergy; moreover, certain species can be used to enhance tolerance response induction. In this sense, Tang ML et al described in 2015 that probiotic therapy with Lactobacillus rhamnosus GG (LGG) increases efficacy when co-administered with peanut oral immunotherapy in 62 peanut allergic children, producing desensitization in 82% of subjects. The beneficial effect of LGG in the prevention of atopic eczema was also described in 2010 in The Lancet, with a cohort of 62 babies who were administered LGG at 2.4 weeks and 6 months of life. The risk of suffering from atopic eczema in the group supplied with the probiotic was 5% versus 47% in the placebo group. Desensitization was also achieved when supplied together with extensively hydrolysed casein formula in cow’s milk-allergic patients, that is, as a symbiotic. It has been shown that supplying probiotics orally also has a beneficial effect on clinical symptoms in patients with rhinitis, while the nasal administration of a specific strain of Lactococcus lactis for 5 days (LLNZ9000) has protective effects against the effect of Streptococcus pneumoniae, increasing its clearance rate from the lungs and preventing dissemination into the blood.

In terms of prebiotics administration, fiber and oligosaccharides supplied during pregnancy in murine wheat allergy models increased the proportion of Lactobacillus and Clostridium leptum that protect against this type of food allergy. Studies related to asthma showed heterogeneous results, with one study reporting reduced wheezing while others reported no effect.

Further studies with larger numbers of well-characterized patients and controls are needed to elucidate the role of the microbiome in allergic diseases. Despite some limitations, interventions with probiotics, prebiotics and/or symbiotics are promising for the development of a preventive therapy, either by restoring altered microbiome functionality due to dysbiosis or as a boost to the immune system in specific immunotherapy. Detailed prospective, randomized, placebo-controlled studies will be essential for this purpose.

 

 

Reference:

Pascal M, Perez-Gordo M, Caballero T, et al. Microbiome and allergic diseases. Front Immunol. 2018; 9:1584. doi: 10.3389/fimmu.2018.01584.

Marina Pérez-Gordo
Marina Pérez-Gordo
Basic Medical Science Department, Faculty of Medicine, CEU San Pablo University, ARADyAL, Madrid, Spain. Institute of Applied and Molecular Medicine (IMMA), Faculty of Medicine, CEU San Pablo University, Madrid, Spain.