Abstract
The gut microbiota influences several biological functions including immune responses. Inflammatory bowel disease is favorably influenced by consumption of several dietary natural plant products such as pomegranate, walnuts, and berries containing polyphenolic compounds such as ellagitannins and ellagic acid. The gut microbiota metabolizes ellagic acid resulting in the formation of bioactive urolithins A, B, C, and D. Urolithin A (UA) is the most active and effective gut metabolite and acts as a potent anti-inflammatory and anti-oxidant agent. However, whether gut metabolite UA affects the function of immune cells remains incompletely understood. T cell proliferation is stimulated by store operated Ca2+ entry (SOCE) resulting from stimulation of Orai1 by STIM1/STIM2. We show here that treatment of murine CD4+ T cells with UA (10 μM, 3 days) significantly blunted SOCE in CD4+ T cells, an effect paralleled by significant downregulation of Orai1 and STIM1/2 transcript levels and protein abundance. UA treatment further increased miR-10a-5p abundance in CD4+ T cells in a dose dependent fashion. Overexpression of miR-10a-5p significantly decreased STIM1/2 and Orai1 mRNA and protein levels as well as SOCE in CD4+ T cells. UA further decreased CD4+ T cell proliferation. Thus, the gut bacterial metabolite UA increases miR-10a-5p levels thereby downregulating Orai1/STIM1/STIM2 expression, store operated Ca2+ entry, and proliferation of murine CD4+ T cells.
Highlights
Polyphenolic compounds are potential anti-inflammatory dietary agents [1, 2]
Orai1 channels are recruited after being stimulated by STIM1/2 and accomplish store operated Ca2+ entry (SOCE) into CD4+ T cells which is decisive for T cell activation [18]
CD4+ T cells were activated for 72 h in the presence of plate-bound anti-CD3 and antiCD28 (1:2 ratio) and in the presence or absence of Urolithin A (UA) (5– 50 μM) The activated cells were incubated with Fura-2 for 30 min in standard HEPES and washed once with standard HEPES. [Ca2+]i was measured first in standard HEPES, which was subsequently replaced by Ca2+-free HEPES
Summary
Polyphenolic compounds are potential anti-inflammatory dietary agents [1, 2]. Ellagitannin-rich food products and medicinal plants favorably influence inflammatory bowel disease [3]. In vivo studies from an animal model of colitis (inflammatory bowel disease) indicate that ellagitannincontaining food products can be especially effective in modulating intestinal inflammation [4]. Previous seminal studies have indicated that gut metabolites such as short chain fatty acids (SCFAs) derived from dietary fibers affect the development and function of regulatory T cells and effector T cells [13,14,15,16]. The characterization of these metabolites produced from polyphenols by gut microbiota is of great clinical interest due to their antioxidant and anti-inflammatory activities [5]. Gut metabolites in particular UA, which has an anti-inflammatory property in inflammatory bowel disease and, improves the gut permeability could modify function and activity of immune cells including adaptive immune T cells [4, 17]
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.
