Lactococcus lactis sb. cremoris orchestrates signal events in the gut epithelium via TLR2 to promote tissue restitution

Naudin, C. R.; Owens, J. A.; Askew, L. C.; Khan, R. N.; Scharer, C. D.; Matthews, J. D.; Luo, L.; Kim, J.; Reedy, A. R.; Barbian, M. E.; Jones, R. M.

doi:10.1101/2021.12.02.471025

bioRxiv · 10.1101/2021.12.02.471025

Lactococcus lactis sb. cremoris orchestrates signal events in the gut epithelium via TLR2 to promote tissue restitution

Naudin, C. R.·Owens, J. A.·Askew, L. C.·Khan, R. N.·Scharer, C. D.·Matthews, J. D.·Luo, L.·Kim, J.·Reedy, A. R.·Barbian, M. E.·Jones, R. M.

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Abstract

The use of beneficial bacteria to promote gastrointestinal heath is widely practiced, however, the mechanisms whereby many of these microbes elicit their beneficial effects remain elusive. Previously, we conducted a screen for the discovery of novel beneficial microbes and identified the potent cytoprotective effects of a strain of Lactococcus lactis subsp. cremoris. Here, we show that dietary supplementation with L. lactis subsp. cremoris induced transcript enrichment of a set of genes within the colon whose functions are associated with host cell and microbe interactions. Specifically, L. lactis subsp. cremoris induced the expression of tlr2, which we show was required for L. lactis subsp. cremoris to elicit its beneficial effects on the intestine. L. lactis subsp. cremoris did not confer beneficial effects in mice deficient in TLR-2, or deficient in its adaptor protein Myd88 in chronic gut injury models. In addition to cytoprotection, culture supernatant from L. lactis subsp. cremoris accelerated epithelial migration in a cultured epithelial cell scratch wound assay; and effect that was abrogated by a TLR-2 antagonist. Furthermore, L. lactis subsp. cremoris accelerated epithelial tissue restitution following the infliction of a colonic wound biopsy in a TLR-2 and Myd88-dependent manner. Within colonic wounds, L. lactis subsp. cremoris induced the activation of signaling pathways that function in tissue restitution following injury, including the ERK signaling pathway, and of focal adhesion complex (FAC) proteins. Together, these data demonstrate that L. lactis subsp. cremoris signals via the TLR2/MyD88-axis to confer cytoprotection and accelarated tissue restituion in the gut epithelium. These data point to evolving adaptations where beneficial gut microbes moduate innate immune signaling to excert positive influnces on host physiology.

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Naudin, C. R., Owens, J. A., Askew, L. C., Khan, R. N., Scharer, C. D., Matthews, J. D., Luo, L., Kim, J., Reedy, A. R., Barbian, M. E., Jones, R. M.. 2021-12-03. Lactococcus lactis sb. cremoris orchestrates signal events in the gut epithelium via TLR2 to promote tissue restitution. https://doi.org/10.1101/2021.12.02.471025

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