Effects And Mechanisms Of Bifidobacterium On Alleviation Of Atopic Dermatitis

Atopic dermatitis is an inflammatory skin disease,which is characterized by itch and recurrent trouble.The prevalence of atopic dermatitis has been increased gradually,and the disease affects 15%-30% of children and 3% of adults worldwide.Glucocorticoid and antihistamine drugs are used to alleviate clinical symptoms of atopic dermatitis;however,the long-term use of these drugs has side effects on patients.Studies have been demonstrated that there is a close correlation between atopic dermatitis and gut microbiota.The diversity of gut microbiota in patients is lower than that in healthy cohorts.Furthermore,the relative abundances of Bifidobacterium and Lactobacillus are decreased but Staphylococcus aureus and Escherichia coli are increased in patients.The gut microbiota may be a target to alleviate atopic dermatitis.Based on these researches,this study aimed to screen Bifidobacterium strains with alleviation on atopic dermatitis and identify the mechanism.The effects of selected Bifidobacterium strain on patients was also explored in a pilot clinical trial.First,the effects of Bifidobacterium on the alleviation of atopic dermatitis were explored.The clinical symptoms of atopic dermatitis were induced using 2,4-dinitrofluorobenzene(DNFB)on the ear and dorsal skin in a mouse model.Based on changes in clinical symptoms and immune indicators,the effective strain was selected from a total of 32 Bifidobacterium strains from 6 species,and the differences in alleviation also needed to be found.The results showed that both B.longum CCFM1029 and B.bifidum BI1 significantly decreased inflammatory infiltration and suppressed Th2 immune responses,and thus contributed to alleviation for clinical symptoms of atopic dermatitis.However,B.breve BR1 and B.adolescentis Ad1 alleviated pathological symptoms through reducing tissue swelling and serum IgE,increasing IL-10.The other Bifidobacterium strains did not ameliorate atopic dermatitis.Collectively,the effects of Bifidobacterium on pathological symptoms and immune responses varied according to strains and had the different effects on the disease.Secondly,the role of gut microbiota in the alleviating effects of Bifidobacterium on mice with atopic dermatitis was evaluated.The 16 S rRNA amplicon sequencing was performed to study changes in gut microbial diversity and composition.Bifidobacterium increased the alpha diversity and regulated beta diversity of gut microbiota,and thus contributed to the improvement of gut microbial diversity and composition.Dorea,Sutterella,and Pseudomonas were the core microbiome in the DNFB group using linear discriminant analysis effect size(LEfSe)analysis,and these bacteria resulted in upregulating the gut microbial genes functions related to valine,leucine and isoleucine biosynthesis,lipopolysaccharide biosynthesis,bacterial invasion of the epithelial cell.However,Bifidobacterium increased the relative abundances of Lactobacillus,Bifidobacterium,Allobacullum,and Lachnospiraceae but decreased Bacteroidetes S24-7 and these changes in gut microbiota resulted in upregulating fatty acid biosynthesis,propanoate metabolism,butanoate metabolism,and linoleic acid metabolism.The results showed that Bifidobacterium interventions significantly regulated gut microbial diversity,composition,and metabolic functions and influenced the alleviation of atopic dermatitis.Based on metagenomic sequencing analysis and non-target metabonomics research,the mechanism of B.longum CCFM1029 on the alleviation of atopic dermatitis was demonstrated.The results showed that the interaction between live B.longum CCFM1029 and gut microbiota might be a way to alleviate atopic dermatitis because inactive B.longum CCFM1029 had no alleviating effect on pathological symptoms of mice.B.longum CCFM1029 increased the relative abundances of Lactobacillus,Clostridium,Staphylococcus,Lachnospiraceae,and Candidatus Saccharibacteria and lead to upregulating aminoacyl-t RNA biosynthesis,homologous recombination,and tryptophan metabolism.Using the enrichment analysis of fecal metabolome,tryptophan metabolism was identified as the acting path,and the aryl hydrocarbon receptor was required in the alleviation of B.longum CCFM1029 on atopic dermatitis.Indole-3-carbaldehyde was the ligand for the aryl hydrocarbon receptor and was increased through upregulating tryptophan metabolism after B.longum CCFM1029 intervention.Indole-3-carbaldehyde directly activated the aryl hydrocarbon receptor to block the expression of thymic stromal lymphopoietin,and thus contributed to decreases in IL-4 and IL-5,suppression for Th2 type immune response.These changes resulted in the improvement of skin inflammation in mice.Finally,the effects of B.longum CCFM1029 on patients with atopic dermatitis were evaluated in a pilot trial.B.longum CCFM1029 regulated the beta diversity of gut microbiota,reduced Escherichia-Shigella and Acinetobacter,increased Bifidobacterium and Anaerostipes,and enriched RuminococcaceaeUCG002 and Parabacteroides.These contributed to the suppression of overexpression of gut microbial genes relating to lipopolysaccharides biosynthesis and lipopolysaccharides biosynthesis proteins and lead to an increase in gut microbial genes relating to amino acid metabolism,lipid metabolism,vitamin metabolism,and immune system.The altered genes functions in patients were consistent with the results for prediction of gut microbial functional genes in mice.Changes in gut microbial metabolisms were conducive to a decrease in the DLQI(dermatology life quality index)to improve the life quality of patients.The decreased SCORAD(severity scoring of atopic dermatitis,improvement rate>25%,effective rate=65.2%)and serum IgE were closely associated with changes in immune responses that were beneficial for the alleviation of atopic dermatitis.