| Author: | Zhang, Kexin |
| Title: | Impact of bifidobacterium and its metabolites on atopic dermatitis via modulation gut microbiota and host immunity |
| Advisors: | Chiou, Jiach Amber (FSN) |
| Degree: | Ph.D. |
| Year: | 2026 |
| Department: | Department of Food Science and Nutrition |
| Pages: | 170 pages : color illustrations |
| Language: | English |
| Abstract: | Bifidobacteria have garnered scientific interest since their discovery because of their extensive physiological benefits for the host. As persistent colonizers across the human lifespan, they perform important functions, such as modulating immune responses, enhancing intestinal barrier integrity, and competitively excluding pathogens. Their role as pivotal commensals is especially significant in early infancy, during which they dominate the gut microbiota and contribute fundamentally to immunological programming and tolerance development. The genus encompasses a wide diversity of species and strains, many uniquely adapted to metabolize human milk oligosaccharides (HMOs), reflecting a co-evolutionary relationship with humans. This integral niche within the microbiome, together with their ability to produce immunomodulatory metabolites like short-chain fatty acids (SCFAs), establishes bifidobacteria as promising therapeutic targets for immune-mediated diseases. Building on this foundation, they are considered as the key modulators of the Gut-Skin Axis. Their depletion or altered composition is mechanistically linked to the immune dysregulation and impaired tolerance observed in atopic dermatitis (AD). Consequently, strategies aimed at restoring or modulating bifidobacterial populations have become a major focus of contemporary research into this complex, chronic inflammatory skin disorder. Therefore, this study was structured into four distinct yet interconnected sections to investigate the relationship between bifidobacteria and AD. The first section presented a cohort study analyzing the correlation between AD and gut microbiota composition, with a focus on Bifidobacterium and its specific subspecies. It also examined the influence of delivery modes and feeding patterns on the development of the infant gut microbiome. Our data indicated that breastfeeding is the best source of high diversity of Bifidobacterium spp. to infant gut microbiota. A specific synbiotic mixture (B. breve M16-V with scGOS/lcFOS 9:1 prebiotic mixture) restored the delayed colonization of infant-type Bifidobacterium spp. and increased gut microbiota diversity in C-section born infants to levels closer to those observed in healthy, vaginal-born, breastfed infants. Besides, it helped the development of strict anaerobes in the C-section born infants' gut, which helps with digestion, nutrient absorption, SCFAs production and immune system development. The second section was designed to isolate, screen, and characterize bifidobacteria obtained from human breastmilk and feces. The biological functions of these isolates were examined through in cellulo and in vitro assays, with the focuses on gastrointestinal resilience, adhesion to intestinal epithelium, pathogen exclusion capability, antimicrobial activity, and anti-inflammatory effects. Our data showed that different species exhibited distinct capabilities that benefit host health through diverse mechanisms. Overall, B. longum AC15 demonstrated outstanding performance amongst all, especially the adhesion ability to enterocyte (6.0±1.1 bacteria/Caco-2 cell), tolerance to acid (Log (CFU/mL) decreased from 7.95 to 6.57), and anti-inflammatory on macrophage via suppressing the phosphorylation of p65 in the NF-κB signaling pathway. Those evidences suggested it might be a potential candidate in modulating immune responses and potentially serve as a therapeutic strategy to mitigate inflammatory diseases, which provided a potential option for the subsequent investigation of skin inflammatory disease. Different from the golden standard DNCB (2,4-Dinitrochlorobenzene) induction assay, AD animal model was established using Staphylococcus aureus-derived extracellular vesicles (SA-EVs) in section 3. SA-EVs created a thickened epidermis, enlarged skin draining lymph nodes (SDLNs), and increased level of total IgE in serum, which are comparable to the characteristics of DNCB-induced one. Data from the combinational analysis of transcriptome and proteome indicated that the underlying mechanisms between two disease models varied. SA-EVs mainly triggered immune responses via IL-17 signaling pathway, while DNCB influenced pathways related to parasites. Moreover, DNCB induced severe dysbiosis of skin microbiome, while SA-EVs led to over colonization of S. aureus but maintained overall skin microbiome diversity. Collectively, the SA-EVs model generates an AD phenotype more closely aligned with real-world disease pathology, providing a solid foundation for subsequent investigation into potential AD therapies. The last section evaluated the beneficial effects of the primary screened isolate, B. longum AC15, on AD mice induced by SA-EVs and its underlying mechanism. In this part, three forms of B. longum AC15, including live, heat-inactivated (HI), and EVs, were investigated. The most promising dosage was determined through preliminary titration experiments. Results from this study demonstrated that pre-treatment and co-treatment of 109 CFU of live/HI B. longum AC15 and 100 µg EVs of B. longum AC15 sufficiently alleviated the AD symptoms. Notably, the ameliorative effects were mediated through the suppression of Th17 cell differentiation and the downregulation of Th2- and Th17-related cytokines, subsequently modulating the immune system through SDLNs. Taken together, these results suggest that B. longum AC15 could be a promising candidate for the AD attenuation. |
| Rights: | All rights reserved |
| Access: | open access |
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