Genistein Inhibits <i>Clostridioides difficile</i> Infection via Estrogen Receptors and Lysine-Deficient Protein Kinase 1

Xie, Ying; Fontenot, Lindsey; Estrada, Andrea Chupina; Nelson, Becca; Bullock, Ashlen; Faull, Kym F.; Feng, Hanping; Sun, Mingjun; Koon, Hon Wai

doi:10.1093/infdis/jiad008

Cited by 3 publications

(1 citation statement)

References 47 publications

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“…When the measured TEER reached 2,000 Ω, 10 ng/mL tumor necrosis factor-alpha (TNFα) and 10 ng/mL interferon-gamma (IFNγ) were added to the basolateral side and ADS024 sterile filtrate to both sides. TEER was measured at 0 and 4–6 h. The average value was recorded as the measured TEER using the calculation: TEER (Ω·cm 2 ) = (measured TEER–blank control TEER) × growth area ( Xie et al, 2023 ).…”

Section: Methodsmentioning

confidence: 99%

ADS024, a single-strain live biotherapeutic product of Bacillus velezensis alleviates dextran sulfate-mediated colitis in mice, protects human colonic epithelial cells against apoptosis, and maintains epithelial barrier function

Irwin,

Chupina Estrada,

Nelson

et al. 2024

Front. Microbiol.

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Epithelial cell apoptosis and compromised gut barrier function are features of inflammatory bowel disease. ADS024 is a single-strain live biotherapeutic product (LBP) of Bacillus velezensis under development for treating ulcerative colitis (UC). The cytoprotective effects of the sterile filtrate of ADS024’s secreted products on UC patient-derived colonic tissues, human primary colonic epithelial cells (HPEC), and human colonic epithelial T84 cells were evaluated. ADS024 filtrate significantly inhibited apoptosis and inflammation with reduced Bcl-2 Associated X-protein (BAX) and tumor necrosis factor (TNF) mRNA expression in fresh colonic explants from UC patients. Exposure to UC patient-derived serum exosomes (UCSE) induced apoptosis with increased cleaved caspase 3 protein expression in HPECs. ADS024 filtrate diminished the UCSE-mediated apoptosis by inhibiting cleaved caspase 3. TNFα and interferon-gamma (IFNγ) damaged epithelial barrier integrity with reduced transepithelial electrical resistance (TEER). ADS024 filtrate partially attenuated the TEER reduction and restored tight junction protein 1 (TJP1) expression. Oral live ADS024 treatment reduced weight loss, disease activity, colonic mucosal injury, and colonic expression of interleukin 6 (IL-6) and TNFα in dextran sodium sulfate (DSS)-treated mice with colitis. Thus, ADS024 may protect the colonic epithelial barrier in UC via anti-inflammatory, anti-apoptotic, and tight-junction protection mechanisms.

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Section: Methodsmentioning

confidence: 99%

ADS024, a single-strain live biotherapeutic product of Bacillus velezensis alleviates dextran sulfate-mediated colitis in mice, protects human colonic epithelial cells against apoptosis, and maintains epithelial barrier function

Irwin,

Chupina Estrada,

Nelson

et al. 2024

Front. Microbiol.

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Loratadine as an Anti-inflammatory Agent Against Clostridium difficile Toxin B

Xie,

Irwin,

Chupina Estrada

et al. 2024

The Journal of Infectious Diseases

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Background Clostridium difficile infection (CDI) is a debilitating nosocomial infection. C. difficile produces toxins A and B, which cause inflammation. Existing therapies have issues with recurrence, cost, and safety. We aim to discover a safe, effective, and economical non-microbiological therapeutic approach against CDI. Methods We included human primary peripheral blood mononuclear cells (PBMCs), fresh human colonic explants, and humanized HuCD34-NCG mice. Toxin A+B+ VPI10463 and A-B+ ribotype 017 C. difficile strains were used. We used single-cell RNA profiling and high-throughput screening to find actionable toxin B-dependent pathways in PBMCs. Results Histamine 1 receptor-related drugs were found among the hit compounds that reversed toxin-mediated macrophage inflammatory protein one alpha (MIP-1α) expression in PBMCs. We identified Loratadine as the safest representative antihistamine for therapeutic development. Loratadine inhibited toxin B-induced MIP-1α secretion in fresh human colonic tissues. Oral Loratadine (10 mg/kg/day) maintained survival, inhibited intestinal Ccl3 mRNA expression, and prevented vancomycin-associated recurrence in the VPI10463-infected mice and ribotype 017-infected hamsters. Splenocytes from Loratadine-treated mice conferred anti-inflammatory effects to the VPI10463-infected T/B cell-deficient Rag-/- mice. Oral Loratadine suppressed human MIP-1α expression in monocytes/macrophages in toxin B-expressing ribotype 017-infected humanized HuCD34-NCG mice. Conclusions Loratadine may be repurposed to optimize existing therapies against CDI.

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An Anti-inflammatory Approach to Drug Repurposing forClostridioides difficileInfection

Villafuerte Gálvez,

Kelly

2024

The Journal of Infectious Diseases

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Genistein Inhibits Clostridioides difficile Infection via Estrogen Receptors and Lysine-Deficient Protein Kinase 1

Abstract: Lay Summary Postmenopausal women may be subjected to an increased risk of CDI hospitalization. A deficiency of endogenous estrogen and dietary soy isoflavones increased the mortality of mice with CDI. The most prominent component of soy isoflavone, genistein, protects against CDI.

Cited by 3 publications

References 47 publications

ADS024, a single-strain live biotherapeutic product of Bacillus velezensis alleviates dextran sulfate-mediated colitis in mice, protects human colonic epithelial cells against apoptosis, and maintains epithelial barrier function

ADS024, a single-strain live biotherapeutic product of Bacillus velezensis alleviates dextran sulfate-mediated colitis in mice, protects human colonic epithelial cells against apoptosis, and maintains epithelial barrier function

Loratadine as an Anti-inflammatory Agent Against Clostridium difficile Toxin B

An Anti-inflammatory Approach to Drug Repurposing forClostridioides difficileInfection

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