Novel Bacteroides Vulgatus strain protects against gluten-induced break of human celiac gut epithelial homeostasis: a pre-clinical proof-of-concept study

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2024年1月4日

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Tina Tran,
Stefania Senger,
Mariella Baldassarre,
Rachel A. Brosnan,
Fernanda Cristofori,
Marco Crocco,
Stefania De Santis,
Luca Elli,
Christina S. Faherty,
Ruggero Francavilla,
Isabella Goodchild-Michelman,
Victoria A. Kenyon,
Maureen M. Leonard,
Rosiane S. Lima,
Federica Malerba,
Monica Montuori,
Annalisa Morelli,
Lorenzo Norsa,
Tiziana Passaro,
Pasqua Piemontese,
James C. Reed,
Naire Sansotta,
Francesco Valitutti,
Ali R. Zomorrodi,
Alessio Fasano,
Maria Luisa Forchielli,
Adelaide Serretiello,
Corrado Vecchi,
Gemma Castillejo de Villasante,
Giorgia Venutolo,
Basilio Malamisura,
Angela Calvi,
Maria Elena Lionetti,
Mariella Baldassarre,
Chiara Maria Trovato,
Nicoletta Pietropaoli,
Michela Perrone,
Lidia Celeste Raguseo,
Carlo Catassi

摘要

Background and aims

We have identified a decreased abundance of microbial species known to have a potential anti-inflammatory, protective effect in subjects that developed Celiac Disease (CeD) compared to those who did not. We aim to confirm the potential protective role of one of these species, namely Bacteroides vulgatus, and to mechanistically establish the effect of bacterial bioproducts on gluten-dependent changes on human gut epithelial functions.

Methods

We identified, isolated, cultivated, and sequenced a unique novel strain (20220303-A2) of B. vulgatus found only in control subjects. Using a human gut organoid system developed from pre-celiac patients, we monitored epithelial phenotype and innate immune cytokines at baseline, after exposure to gliadin, or gliadin plus B. vulgatus cell free supernatant (CFS).

Results

Following gliadin exposure, we observed increases in epithelial cell death, epithelial monolayer permeability, and secretion of pro-inflammatory cytokines. These effects were mitigated upon exposure to B. vulgatus 20220303-A2 CFS, which had matched phenotype gene product mutations. These protective effects were mediated by epigenetic reprogramming of the organoids treated with B. vulgatus CFS.

Conclusions

We identified a unique strain of B. vulgatus that may exert a beneficial role by protecting CeD epithelium against a gluten-induced break of epithelial tolerance through miRNA reprogramming.

Impact

Gut dysbiosis precedes the onset of celiac disease in genetically at-risk infants.

This dysbiosis is characterized by the loss of protective bacterial strains in those children who will go on to develop celiac disease.

The paper reports the mechanism by which one of these protective strains, B. vulgatus, ameliorates the gluten-induced break of gut epithelial homeostasis by epigenetically re-programming the target intestinal epithelium involving pathways controlling permeability, immune response, and cell turnover.