Celiac disease (CeD) is an autoimmune disorder triggered by gluten. The only treatment for CeD is a gluten-free diet, hence, there is need for adjunctive therapies. The restoration of protease/anti-protease balance in chronic intestinal disorders has become a therapeutic target. We have previously demonstrated the efficacy of the human anti-protease, elafin, expressed transgenically by Lactococcus lactis, in attenuating gluten-induced pathology in mice. Here, we test the therapeutic potential of Bifidobacterium longum NCC 2705, a member of the commensal microbiota known to produce in vivo the serine protease inhibitor, serpin. NOD/DQ8 mice were sensitized with gliadin once per week for 3 weeks, then challenged with gliadin once per week for 2 weeks. During gliadin challenge, mice were gavaged with B. longum NCC 2705 (Bl WT), the same strain containing an engineered plasmid (pMDY25) over-expressing serpin (Bl serpin+), or another genetically modified version of NCC 2705 knocked out from its serpin gene NCC 9035 (Bl serpin KO). Intestinal pathology was evaluated by CD3+ intraepithelial lymphocyte (IEL) quantification and villus-crypt (V/C) ratios. Microbiota composition was determined via 16S rRNA sequencing on a MiSeq Illumina platform. Serpin-producing Bl WT protected against gluten-induced pathology to a similar degree as the previously tested recombinant L. lactis-elafin. Furthermore, gliadin-challenged mice treated with Bl WT had lower IEL counts compared with mice receiving Bl serpin KO. Treatment with Bl serpin+ resulted in even lower IEL counts, increased V/C ratios, and reduced paracellular intestinal permeability in the small intestine compared with mice treated with Bl serpin KO. No significant shifts in microbiota composition were revealed in small intestinal contents, however, we did observe shifts in fecal microbiota driven by gluten exposure and in the mice receiving the B. longum strains. B. longum strains expressing serpin ameliorated gluten-induced pathology in NOD/DQ8 mice, while Bl serpin KO did not achieve this protective effect. Thus, commensal strains expressing serpin, such as B. longum NCC 2705, represent a novel probiotic approach for gluten-related disorders. CIHR