Abstract
Inflammatory bowel disease (IBD) is a chronic and relapsing intestinal inflammatory condition with no effective treatment. Probiotics have gained wide attention because of their outstanding advantages in intestinal health issues. In previous studies, a novel soluble protein, HM0539, which is derived from Lactobacillus rhamnosus GG (LGG), showed significant protective effects against murine colitis, but no clear precise mechanism for this effect was provided. In this study, we hypothesized that the protective function of HM0539 might be derived from its modulation of the TLR4/Myd88/NF-κB axis signaling pathway, which is a critical pathway widely involved in the modulation of inflammatory responses. To test this hypothesis, the underlying anti-inflammatory effects and associated mechanisms of HM0539 were determined both in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and in dextran sulfate sodium (DSS)-induced murine colitis. Our results showed that HM0539 inhibited the expression of cyclooxygenase-2 (COX-2) and the expression inducible nitric oxide synthase (iNOS) by down-regulating the activation of their respective promoter, and as a result this inhibited the production of prostaglandin E2 (PGE2) and nitric oxide (NO). Meanwhile, we demonstrated that HM0539 could ultimately modulate the activation of distal NF-κB by reducing the activation of TLR4 and suppressing the transduction of MyD88. However, even though the overexpression of TLR4 or MyD88 obviously reversed the effect of HM0539 on LPS-induced inflammation, HM0539 still retained some anti-inflammatory activity. Consistent with the in vitro findings, we found that HM0539 inhibited to a great extent the production of inflammatory mediators associated with the suppression of the TLR4/Myd88/NF-κB axis activation in colon tissue. In conclusion, HM0539 was shown to be a promising anti-inflammatory agent, at least in part through its down-regulation of the TLR4-MyD88 axis as well as of the downstream MyD88-dependent activated NF-κB signaling, and hence might be considered as a potential therapeutic option for IBD.
Highlights
In recent years, owing to the rapid development of microbiome research related to the interaction of microbes with the host, administering microbes into patients as well as modulating human microbiota have become a focus of new therapeutic strategies [1, 2]
In a comparison of these results for cells stimulated by LPS (1 mg/mL) (Figure 1B), these results indicated that treatment of HM0539 significantly improved cell viability
Inflammatory bowel disease (IBD) is a multifactorial immune disorder characterized by chronic inflammation and apoptosis of intestinal cells, which lead to intestinal mucosa damage, oxidative stress, and activation of immune cells with multiple inflammatory mediators [48,49,50,51]
Summary
In recent years, owing to the rapid development of microbiome research related to the interaction of microbes with the host, administering microbes into patients as well as modulating human microbiota have become a focus of new therapeutic strategies [1, 2]. Since the term “probiotics” was defined, they have been shown to act through cellular and molecular mechanisms involving antagonistic action on pathogens, and they have been shown to improve protective immunity, reduce inflammation induced by foreign antigens, and strengthen the mucosal barrier [2]. Evidence has been provided for probiotics inhibiting harmful bacteria from adhering to and invading intestinal mucosa, important since such adhesion and invasion play a key role in triggering the activation of immune response in IBD [3, 4], and subsequently enhancing the mucosal barrier and regulating the balance of intestinal flora, and restoring the function of its destruction [5, 6]. TLR4 signaling might play a critical role in intestinal tract injury and repair processes
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
