Effect And Mechanism Of Lactobacillus On Alleviation Of Respiratory Allergies

Respiratory allergies include Bronchial asthma(asthma)and Allergic rhinitis(AR).Clinically,asthma and AR are diagnosed and treated separately.So far,there is no cure for both diseases.Many studies have confirmed the link between respiratory allergies and the disorders of gut microbiota,and supplementations of Lactobacillus could affect the immune responses related to allergies.Therefore,this study will focus on selecting the most potential Lactobacillus strain based on Inflammation-immunity mechanisms shared by respiratory allergies.The effects and mechanisms on modulating gut microbiota,regulating immune responses,and alleviating inflammations by the Lactobacillus will be analyzed.Then,a human trial was conducted to evaluate the alleviation of respiratory allergies by Lactobacillus.The main outcomes are as follows:Six species of Lactobacillus that can be legally supplemented were comprehensively evaluated with their effects on inflammation of the respiratory tract,Th2,and Th17 immune responses,gut microbiota,and metabolisms.All of the six species could alleviate inflammation of the respiratory tract by lowering the cytokines and immunoglobulin related to Th2.But their effects on modulating Th17 related cytokines differ and none of them could increase the levels of immunoglobulin related to Th1.It was found that all of the six species of Lactobacillus could change the beta diversity of gut microbiota but not the alpha diversity.Bacteria that have positive effects on respiratory inflammation were increased in relative abundance,and negatively functioned bacteria were decreased.Lactobacillus reuteri(L.reuteri)was the best in improving the indicators mentioned above.It specifically regulated the relative abundance of Lactobacillus and Enterococcus,enriched pyruvate metabolic pathway,and promoted the production of short fatty chain acids(SFCA).This may be the reason why it has a better protective effect on respiratory tract inflammation compared to the rest.By analyzing the mechanisms of L.reuteri on alleviating respiratory tract inflammation,improving immune response,and modulating gut microbiota and metabolites,it was found to be strain-specific.Strain CCFM1072 and CCFM1040 could significantly lower the scores of respiratory inflammation by 50% and 58%,decrease the levels of Th2 and Th17 related cytokines.However,neither of these two strains affect increasing the Th1 immune responses in serum.By recovering the diversity of the imbalanced gut microbiota induced by the inflammation and promoting the growth of bacteria that produce SFCA,CCFM1072 could increase the numbers of Treg.At the same time,it could restrict Ig E-mediated Th2 and Th17 immune responses.Combing the effects of gut microbiota modulation and immune system regulation,CCFM1072 could achieve the results of inhibiting respiratory inflammation.In contrast,CCFM1040 does not work in the same mechanism.To understand the mechanisms of how CCFM1040 alleviates respiratory inflammations,dead cells of CCFM1040 were compared to alive CCFM1040 cells in animal models.It turns out that similar results were observed between the two on modulating gut microbiota and easing the symptoms of respiratory inflammation.Therefore,one or more components on the surface of/in the cells of CCFM1040 could be the key.Metagenomics and non-targeted metabolomics analysis showed that the live/dead bacteria enriched(P < 0.01)tryptophan metabolic genes and metabolites of gut microbiota.It is speculated that CCFM1040 enhances Treg response by promoting tryptophan metabolism in the gut microbiota,and indoleamine 2,3-dioxygenase(IDO)could be the mediator in the pathway.The results of animal experiments showed that both dead and living bacteria significantly(P < 0.01)promoted the expression of IDO in the colon and serum of mice and increased the content of kynurenine in serum.To conclude,cells of CCFM 1040 modulate the composition and metabolic functions of gut microbiota,stimulate the expression of IDO in host cells,activate the IDO kynurenine pathway,and then increase the level of Treg cells.Meanwhile,CCFM 1040 could suppress Th2 and Th17 immune responses to ultimately inhibit respiratory allergic inflammation.Finally,with a clinical trial,the effects of CCFM1040 on clinical symptoms and quality of life in adult subjects with asthma and AR were evaluated.CCFM1040 significantly improved clinical symptoms of asthmatic subjects,and significantly reduced the severities of sneezing and rhinorrhea,improved sleep and non-nasal and eye symptoms of allergic rhinitis subjects.Further analysis of the effect of CCFM1040 on the gut microbiota of AR subjects showed that CCFM1040 changed the diversity of gut microbe and significantly inhibited the growth of Proteobacteria and Intestinnibacter.It also regulated carbohydrate,energy,and lipid metabolism,heterogeneous biodegradation and metabolism,cofactor and vitamin metabolism,and 18 metabolic pathways involved in the immune system.These changes are helpful for CCFM1040 to improve the symptoms of adult subjects with AR.