TY - JOUR T1 - Targeted delivery of microbial metabolite, urolithin A protects from chemically (DSS or TNBS) induced colitis in pre-clinical models JF - The Journal of Immunology Y1 - 2017 A1 - Singh, Rajbir A1 - Hegde, Bindu A1 - Von Baby, Becca A1 - Sadeep, C A1 - Kotla, Niranjan A1 - Chandrasekar, Bhargavi A1 - Marepally, Srujan A1 - Bodduluri, Haribabu A1 - Vemula, Praveen K A1 - Jala, Venkatakrishna R AB -

Epidemiological data suggests that consumption of diets rich in phytochemicals are protective in inflammatory bowel diseases (IBDs). However, the beneficial effects are not uniform among individuals and attributed to variations in gut microbiota, and altered capacity to generate certain metabolites. Urolithin A (UroA) (3,8-dihydroxybenzo[c]chromen-6-one) is a microbial metabolite, derived from ellagic acid and ellagitannins, major poly phenolic components in berries and pomegranates. Here, we examined therapeutic applications of UroA and mechanisms of action in IBDs. Our studies suggested that UroA significantly reduced LPS induced inflammatory mediators (e.g., IL-6, TNF-alpha and IL-12) as well as ROS production in mouse bone marrow-derived macrophages (BMDMs), dendritic and THP1 cells. Most importantly, UroA also reduced LPS induced systemic inflammation in mouse models. Next, we examined therapeutic applications of UroA in dextran sodium sulphate (DSS)-induced, 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis models. Treatment with UroA significantly reduced both acute and chronic DSS-induced colitis as well as TNBS induced colitis in mouse models. Most importantly, delivery of UroA utilizing inflammation targeting oral nano-particles (single treatment regimen) effectively mitigated the colitis in both models. In summary, these results highlight even presence of single microbial metabolite at right location at right time will have significant beneficial effects to protect from adverse inflammatory activities.

VL - 198 UR - http://www.jimmunol.org/content/198/1_Supplement/65.6 ER - TY - JOUR T1 - Gut Microbiota Conversion of Dietary Ellagic Acid into Bioactive Phytoceutical Urolithin A Inhibits Heme Peroxidases. JF - PLoS One Y1 - 2016 A1 - Saha, Piu A1 - Yeoh, Beng San A1 - Singh, Rajbir A1 - Chandrasekar, Bhargavi A1 - Vemula, Praveen Kumar A1 - Haribabu, Bodduluri A1 - Vijay-Kumar, Matam A1 - Jala, Venkatakrishna R AB -

Numerous studies signify that diets rich in phytochemicals offer many beneficial functions specifically during pathologic conditions, yet their effects are often not uniform due to inter-individual variation. The host indigenous gut microbiota and their modifications of dietary phytochemicals have emerged as factors that greatly influence the efficacy of phytoceutical-based intervention. Here, we investigated the biological activities of one such active microbial metabolite, Urolithin A (UA or 3,8-dihydroxybenzo[c]chromen-6-one), which is derived from the ellagic acid (EA). Our study demonstrates that UA potently inhibits heme peroxidases i.e. myeloperoxidase (MPO) and lactoperoxidase (LPO) when compared to the parent compound EA. In addition, chrome azurol S (CAS) assay suggests that EA, but not UA, is capable of binding to Fe3+, due to its catechol-like structure, although its modest heme peroxidase inhibitory activity is abrogated upon Fe3+-binding. Interestingly, UA-mediated MPO and LPO inhibition can be prevented by innate immune protein human NGAL or its murine ortholog lipocalin 2 (Lcn2), implying the complex nature of host innate immunity-microbiota interactions. Spectral analysis indicates that UA inhibits heme peroxidase-catalyzed reaction by reverting the peroxidase back to its inactive native state. In support of these in vitro results, UA significantly reduced phorbol myristate acetate (PMA)-induced superoxide generation in neutrophils, however, EA failed to block the superoxide generation. Treatment with UA significantly reduced PMA-induced mouse ear edema and MPO activity compared to EA treated mice. Collectively, our results demonstrate that microbiota-mediated conversion of EA to UA is advantageous to both host and microbiota i.e. UA-mediated inhibition of pro-oxidant enzymes reduce tissue inflammation, mitigate non-specific killing of gut bacteria, and abrogate iron-binding property of EA, thus providing a competitive edge to the microbiota in acquiring limiting nutrient iron and thrive in the gut.

VL - 11 IS - 6 ER -