S100B Inhibition Attenuates Intestinal Damage and Diarrhea Severity During Clostridioides difficile Infection by Modulating Inflammatory Response

Abstract

The involvement of the enteric nervous system, which is a source of S100B, in Clostridioides difficile (C. difficile) infection (CDI) is poorly understood although intestinal motility dysfunctions are known to occur following infection. Here, we investigated the role of S100B in CDI and examined the S100B signaling pathways activated in C. difficile toxin A (TcdA)- and B (TcdB)-induced enteric glial cell (EGC) inflammatory response. The expression of S100B was measured in colon tissues and fecal samples of patients with and without CDI, as well as in colon tissues from C. difficile-infected mice. To investigate the role of S100B signaling in IL-6 expression induced by TcdA and TcdB, rat EGCs were used. Increased S100B was found in colonic biopsies from patients with CDI and colon tissues from C. difficile-infected mice. Patients with CDI-promoted diarrhea exhibited higher levels of fecal S100B compared to non-CDI cases. Inhibition of S100B by pentamidine reduced the synthesis of IL-1β, IL-18, IL-6, GMCSF, TNF-α, IL-17, IL-23, and IL-2 and downregulated a variety of NFκB-related genes, increased the transcription (SOCS2 and Bcl-2) of protective mediators, reduced neutrophil recruitment, and ameliorated intestinal damage and diarrhea severity in mice. In EGCs, TcdA and TcdB upregulated S100B-mediated IL-6 expression via activation of RAGE/PI3K/NFκB. Thus, CDI appears to upregulate colonic S100B signaling in EGCs, which in turn augment inflammatory response. Inhibition of S100B activity attenuates the intestinal injury and diarrhea caused by C. difficile toxins. Our findings provide new insight into the role of S100B in CDI pathogenesis and opens novel avenues for therapeutic interventions.

Host Immune Responses to Clostridioides difficile: Toxins and Beyond

“…S100B was found to regulate cytokine synthesis. Mice treated with pentamidine also showed lower colonic concentrations of proinflammatory cytokines, including IL-6, IL-8, IL-1β, IL-23, and GM-CS, but not IL-33 and IL-22 levels were even found to be higher compared to untreated mice (Costa et al, 2021). More specifically, the addition of TcdA and TcdB to a rat EGC cell line (EGC PK060399) showed that stimulation with C. difficile toxins increased both S100B release and IL-6 expression by these cells (Costa et al, 2021).…”

“…inflammation [reduced histological colonic damage and reduced tumor necrosis factor α (TNF-α) levels, among others] (Hing et al, 2013). Beneath the intestinal epithelial layer lie enteric glial cells (EGCs) that release a number of mediators, such as interleukins, NO, and S100 calcium-binding protein (S100B) and seem to be involved in the immune responses to C. difficile (Cirillo et al, 2011;Macchioni et al, 2017;Costa et al, 2021). In colonic biopsies from both CDI patients and CDI mice increased S100B was observed compared to control subjects and uninfected mice respectively (Costa et al, 2021).…”

“…Beneath the intestinal epithelial layer lie enteric glial cells (EGCs) that release a number of mediators, such as interleukins, NO, and S100 calcium-binding protein (S100B) and seem to be involved in the immune responses to C. difficile (Cirillo et al, 2011;Macchioni et al, 2017;Costa et al, 2021). In colonic biopsies from both CDI patients and CDI mice increased S100B was observed compared to control subjects and uninfected mice respectively (Costa et al, 2021). Mouse experiments with a S100B inhibitor, pentamidine, revealed that, upon inhibition of this protein, disease severity and epithelial damage are decreased while C. difficile shedding remained unaffected.…”

Gut Microbiota-Related Inflammation Factors as a Potential Biomarker for Diagnosing Major Depressive Disorder

“…Inflammatory response is a very complex biological process, which has an important role in many diseases ( Costa et al., 2021 ; Li et al., 2021 ; Lu et al., 2021 ; Wang J. et al., 2021 ). Previous studies showed that inflammatory response played a critical role in the onset of depression, and the disturbance of inflammation levels could increase the incidence of depression ( Leonard, 2018 ; Colasanto et al., 2020 ).…”

Berberine reduces enteroglial-derived S100B production to alleviate gut vascular barrier damage

“…High concentration (µM) of S100B is proin ammatory. In a pathological condition, reactive EGCs can trigger, support and amplify gut in ammation via S100B protein [5][6][7][8] . Many studies have supported S100B may induce gut ora dysbiosis 7,9 , epithelial barrier disruption 5,9 and blood-brain barrier (BBB) impairment 10,11 .…”