Biology subjects

Redinbo, M. R.

Publications and source records attributed to Redinbo, M. R..

4 recordsLinked to original sources

bioRxiv2025

Sex-Dependent Responses in Mice to Indomethacin-Induced Injury and Gut Microbiome-Targeted Alleviation

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used widely but produce gastrointestinal (GI) toxicities in both short- and long-term users. Previous studies have shown that the intestinal microbiota play an important role in gut damage and that gut microbial {beta}-glucuronidase (GUS) inhibitors can alleviate NSAID-induced injury in male mice by blocking the GI reactivation of NSAID-glucuronides. Here, in both male and female C57BL/6 mice, we examine the effects of indomethacin alone and with the GUS inhibitor UNC10201652. Oral delivery of 5 mg/kg body weight indomethacin over five days decreased body weight, induced colonic and hepatic inflammatory cytokine gene expression, and enlarged the spleens of both male and female mice. However, sex-specific inflammatory responses to indomethacin were observed, with males demonstrating more colonic injury while females presented greater splenic and hepatic toxic responses. Females also showed a unique indomethacin-induced bloom of fecal Verrucomicrobia as measured by 16S rRNA metagenomic sequencing. UNC10201652 alleviated aspects of these indomethacin-induced toxicities, including features of the male-specific colonic damage and the female-specific compositional changes and spleen and liver toxicities. Thus, GI and non-GI tissues in male and female mice respond distinctly to indomethacin-induced damage. These findings advance our understanding of how sex impacts systemic responses to xenobiotic exposure and may lead to improved therapeutic outcomes with these widely used drugs.

biochemistry↗

bioRxiv2022

Distinct bile salt hydrolase substrate preferences dictate C. difficile pathogenesis

Summary paragraphBile acids (BAs) mediate the crosstalk between human and microbial cells and influence intestinal diseases including Clostridioides difficile infection (CDI). While bile salt hydrolases (BSHs) shape the BA pool by deconjugating conjugated BAs, the basis for their substrate preferences and impact on C. difficile remain elusive. Here, we survey the diversity of Lactobacillus BSHs and unravel the structural basis of their substrate preference. We show that leveraging BSH activity and specificity is an effective strategy to prevent C. difficile growth in clinically relevant CDI models. A range of non-canonical conjugated BAs is also identified, comprising unique BSH substrates that also inhibit C. difficile spore germination. These findings establish BSHs as intestinal enzymes essential to BA homeostasis and colonization resistance against C. difficile. One sentence summaryBile salt hydrolase activity inhibits C. difficile by shaping the conventional and non-canonical conjugated bile acid pools

microbiology↗

bioRxiv2019

Targeting the Pregnane X Receptor Using Microbial Metabolite Mimicry

The human pregnane X receptor (PXR), a master regulator of drug metabolism, has important roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows to exploit previously unexplored parts of chemical space. Here we report functionalized indole-derivatives as first-in-class non-cytotoxic PXR agonists, as a proof-of-concept for microbial metabolite mimicry. The lead compound, FKK6, binds directly to PXR protein in solution, induces PXR specific target gene expression in, cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to mine underexploited regions of chemical space.

biochemistry↗

bioRxiv2019

Inhibition of Microbial Beta-Glucuronidase Does Not Prevent Breast Carcinogenesis in the Polyoma Middle T Mouse

PurposeTo demonstrate whether inhibition of intestinal microbial beta ({beta})-glucuronidase (BGUS) abrogates tumor formation in a MMTV-PyMT mouse breast cancer model.\n\nMethodsFemale MMTV-PyMT heterozygote mice (4 weeks old) were randomized to oral gavage with vehicle or UNC10201652 (20 g/day), a microbial BGUS inhibitor, for 9 weeks. The entire animal carcass was assessed for tumor deposits by histology and immunohistochemical staining for tumor (Ki67, PCNA) and breast specific (ER, PR, Cyclin D1, aSMA, Integrin {beta}1) markers.\n\nResultsThe MMTV-PyMT breast pathology in our study simulates prior published reports of tumor incidence and aggressiveness. There was no significant difference in the tumor histology, number of tumors (lesions), and patterns of spread of tumors in the UNC10201652 versus the vehicle treated mice. Similarly, there were no significant differences in the semi-quantitative scores for expression of ER, PR, Ki67, PCNA, or Integrin {beta}1. There were also no major differences seen in qualitative screening of Cyclin D1 and aSMA.\n\nConclusionsMMTV-PyMT mice administered UNC10201652, when compared to vehicle treated mice, show a similar abundance of breast tumor (and tumor initiating) lesions ranging from hyperplasia to frank carcinoma. There is a trend, however small, that the incidence of hyperplastic and adenomas may be decreased in UNC10201652 treated mice. Further refined dosing strategies in MMTV-PyMT are planned to clarify its biological significance. To our knowledge this is the first report of use of any BGUS inhibitor in chemoprevention of breast tumors using a genetic model simulating human breast cancer.

cancer biology↗