Probiotic LB101 alleviates dry eye in mice by suppressing matrix metalloproteinase-9 expression through the regulation of gut microbiota-involved NF-κB signaling

PLoS One. 2024 Jun 17;19(6):e0303423. doi: 10.1371/journal.pone.0303423. eCollection 2024.

Abstract

Tear matrix metalloproteinase (MMP)-9 is an inflammatory signal in patients with dry eye (DE). In the present study, to understand the action mechanism of probiotic LB101 (Lactobacillus plantarum NK151 and Bifidobacterium bifidum NK175 [4:1] mix) against DE, we investigated its effect on tear amount and inflammatory marker expression levels in mice with unilateral exorbital lacrimal gland excision/atropine-benzalkonium chloride application (EB) or fecal microbiota transplantation from mice with EB (eFMT). Oral gavage of LB101 increased EB-suppressed tear amount and decreased EB-induced blinking number. Furthermore, LB101 decreased EB-induced TNF-α, IL-1β, and MMP-9 expression, TNF-α+ and NF-κB+CD11c+ cell populations, and edema in the conjunctiva, while EB-suppressed IL-10 and occludin expression increased. LB101 also decreased EB-induced TNF-α and IL-1β expression and NF-κB+CD11c+ cell population in the colon. eFMT also decreased tear amount and increased blinking number in the transplanted mice. eFMT increased TNF-α, IL-1β, and MMP-9 expression and TNF-α+ and NF-κB+CD11c+ cell populations in the conjunctiva and TNF-α and IL-1β expression and NF-κB+CD11c+ cell populations in the colon. Oral gavage of LB101 increased eFMT-suppressed tear amount and decreased eFMT-induced blinking number. Furthermore, LB101 decreased TNF-α, IL-1β, and MMP-9 expression, TNF-α+ and NF-κB+CD11c+ cell populations, and edema in the conjunctiva and TNF-α and IL-1β expression and NF-κB+CD11c+ cell population in the colon, while eFMT-suppressed IL-10 and occludin expression decreased. Furthermore, LB101 increased eFMT-suppressed Muribaculaceae, Prevotellaceae, and Lactobacillaceae populations in the gut microbiota, while eFMT-induced Bacteroidaceae population decreased. These findings suggest that DE may cause gut dysbiosis, which may be a risk factor for DE, and LB101 may alleviate DE with gut inflammation by suppressing the expression of MMP-9 and proinflammatory cytokines TNF-α and IL-1β with the regulation of gut microbiota-involved NF-κB signaling.

MeSH terms

  • Animals
  • Conjunctiva / metabolism
  • Conjunctiva / microbiology
  • Conjunctiva / pathology
  • Dry Eye Syndromes* / drug therapy
  • Dry Eye Syndromes* / metabolism
  • Fecal Microbiota Transplantation
  • Gastrointestinal Microbiome* / drug effects
  • Matrix Metalloproteinase 9* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B* / metabolism
  • Probiotics* / administration & dosage
  • Probiotics* / pharmacology
  • Signal Transduction* / drug effects
  • Tears / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Matrix Metalloproteinase 9
  • NF-kappa B
  • Mmp9 protein, mouse
  • Tumor Necrosis Factor-alpha

Grants and funding

This work was supported by the Technology Development Program (S3301743) funded by the Ministry of SMEs and Startups (MSS, Korea), the Ministry of Food and Drug Safety (22203MFDS539) funded by the Korea Healthy Industry Development Institute, and the Medical Research Program (2017R1A5A2014768) through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT, Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.