Biology subjects

Heredia, E.

Publications and source records attributed to Heredia, E..

4 recordsLinked to original sources

bioRxiv2026

Novel bile salt analogs reduce lipid accumulation in liver cells with potential to treat both metabolic dysfunction-associated steatotic liver disease and Clostridioides difficile infection

Metabolic dysfunction-associated steatotic liver disease (MASLD) and Clostridioides difficile (C. difficile) infection (CDI) are clinically associated, yet there is limited effective treatment for both diseases. Bile salt analogs (BSAs) have demonstrated potential in treating either MASLD or CDI. We screened a library of BSAs (n=112) previously synthesized as potential inhibitors of C. difficile spore germination, for their therapeutic potential in reducing intracellular accumulation of fatty acids in HepG2 cells as candidates for prevention and treatment of both MASLD and CDI. The screening was based on an in vitro model established by incubating HepG2 cells with free fatty acids, with obeticholic acid (OCA), a known BSA with anti-MASLD activity as a control. Gene and protein expressions were quantified to validate the treatment effect. We found that compounds C13, C24, C25, C74, C98, and C101 demonstrated significant effectiveness in both preventing the intracellular accumulation of lipids and removing pre-loaded cellular lipids. Gene expression analysis showed that C24, C25, and C74 produced a similar pattern characterized by a robust induction of FGF21 expression, while C13, C98, and C101 produced a transcription pattern that mirrors the effect of OCA. Structurally, while C13, C24, and C25 do not display drug-like properties, C74, C98, and C101 are drug-like and share a similar structure. Interestingly, C101 is a potent inhibitor of C. difficile spore germination. OCA shows a weak anti-gemination effect. Our study identified lead compound candidates for the development of novel therapeutics capable of treating both MASLD and CDI. Significance statementThe clinical association between MASLD and CDI remains an unmet need for dual acting therapeutic strategies. Given the reported potential of BSA, we screened 112 previously synthesized as potential inhibitors of C. difficile spore germination, for their therapeutic potential in reducing intracellular accumulation of fatty acids in HepG2 cells. Our study identified compounds that effectively reduce intracellular lipid accumulation and inhibit C. difficile spore germination. These results nominate lead candidates for developing dual-acting therapeutics targeting both MASLD and CDI.

pharmacology and toxicology↗

bioRxiv2025

Effects of sexual dimorphism and estrous cycle on C. difficile infections prophylaxis in two rodent models

Clostridioides difficile infection (CDI) is responsible for the majority of identifiable hospital-related antibiotic-associated diarrhea. Susceptibility to CDI and severity of disease varies depending on a variety of factors such as aggressive use of broad-spectrum antibiotics, age, and immune status. Epidemiological studies have consistently shown that female patients are more at risk for CDI than their male counterparts. C. difficile is spread by spores which can persist in the environment and in the intestines of patients. Spores do not cause disease but germinate in the antibiotic-altered gut of patients to generate toxin producing vegetative cells. The germination of C. difficile spores is mediated by the composition of bile salts in the gut with taurocholate facilitating germination and chenodeoxycholate inhibiting it.

microbiology↗

bioRxiv2025

Murine model of antibiotic-associated S. aureus gastrointestinal infections (SAGII) and colonization

BackgroundStaphylococcus aureus is an opportunistic pathogen that can both colonize the gastrointestinal tract and cause antibiotic associated diarrhea. MethodsTo develop a robust murine model for S. aureus gastrointestinal infection (SAGII) and colonization, mice were (a) treated with varying antibiotic regimes prior to infection, (b) infected with either a methicillin-sensitive S. aureus (MSSA) or a methicillin-resistant S. aureus (MRSA) strain, (c) challenged with different bacterial inocula, (d) tested for sexual dimorphism of SAGII virulence, and (e) tested for macronutrient effects on SAGII onset and virulence. ResultsWe found that antibiotic-treated male mice (but not female mice) were highly susceptible to even low inoculums of both an MSSA and an MRSA strains. Interestingly, male mice challenged with an MSSA strain showed more severe and more prolonged SAGII symptomatology than animals challenged with an MRSA strain. We also showed that for male mice a high-carbohydrate diet and a high-fat diet led to asymptomatic intestinal colonization followed by delayed SAGII sign onset. In contrast, male mice fed a high-protein diet started developing mild SAGII signs early but did not develop severe SAGII until two weeks post-challenge. Furthermore, only the high-protein diet sensitized female mice to SAGII, but their symptomatology remained less severe than in male mice. ConclusionsWe developed a robust murine model for antibiotic-associated S. aureus gastrointestinal infection and colonization. This model shows both sexual dimorphism and macronutrient preference for SAGII severity. Diet manipulation can also be used to establish S. aureus colonization of the GI tract.

microbiology↗

bioRxiv2023

Effects of sexual dimorphism and estrous cycle on C. difficile infections in rodent models

Clostridioides difficile infection (CDI) is responsible for the majority of identifiable antibiotic-associated diarrhea. Women are more susceptible to CDI than men. In this study, we show that female mice developed more severe CDI than males. Furthermore, females in estrus developed only mild CDI 1-2 days later, while females in proestrus developed deadly disease. Mirroring the delayed effect of the estrous cycle, pre-infection prolactin levels formed a complex network with immunoglobulins and cytokines that affected early CDI severity one day after challenge. Similarly, pre-infection progesterone and luteinizing hormone formed a network that affected CDI two days after challenge. As expected, immune effectors early in the infection formed a hormone-independent network that concurrently correlated with CDI severity. Interestingly, early infection follicular stimulating hormone levels created a network that affected the CDI recovery phase. In summary, murine sexual hormones affect CDI progression by affecting the immune system both before and during disease progression.

microbiology↗