Biology subjects

Jala, V. R.

Publications and source records attributed to Jala, V. R..

4 recordsLinked to original sources

bioRxiv2026

Dietary Sodium Restriction Reprograms Gut Microbial Fermentation and Reduces Host Energy Harvest

Diet is a major determinant of gut microbiome structure and function, yet the role of dietary electrolytes--particularly sodium--remains poorly defined. Here, we identify dietary sodium availability as a key regulator of gut microbial fermentation and host energy harvest. Using a controlled sodium-sufficient versus sodium-deprived dietary intervention in rats, we integrated shotgun metagenomic sequencing, functional pathway analysis, targeted short-chain fatty acid (SCFA) quantification, and host physiological phenotyping. Sodium deprivation induced a coordinated restructuring of the gut microbiome, characterized by depletion of classical saccharolytic Firmicutes, including multiple Lactobacillus species, and enrichment of stress-tolerant, metabolically flexible taxa. Functional profiling revealed a shift away from growth-associated metabolic programs toward stress-adaptive and nutrient-scavenging pathways. Consistent with these changes, fecal concentrations of key SCFAs--including acetate, butyrate, hexanoate, and valerate--were significantly reduced, indicating impaired microbial fermentative capacity. These microbiome-level alterations translated into measurable host phenotypes, including reduced cecal mass and attenuated weight gain, consistent with decreased microbial energy harvest. Together, these findings establish a functional link between luminal sodium availability, microbial metabolic efficiency, and host energy balance, extending the framework of diet-microbiome interactions beyond macronutrients to include dietary electrolytes. This work identifies sodium as a previously underappreciated ecological constraint shaping gut microbial metabolism and suggests that modulation of dietary sodium intake may influence host metabolic outcomes through microbiome-mediated mechanisms.

microbiology↗

bioRxiv2025

NRF2-Dependent Anti-Inflammatory Activity of Indole via Cell Surface Receptor Signaling in Murine Macrophages

In this study, we report indoles anti-inflammatory effects to be AhR-independent in RAW 264.7 macrophages. To explore the possibility of indoles surface-receptor mediated signaling, we developed an indole-bovine serum albumin conjugate (I3B), which primarily engage cell surface receptors and has limited intracellular engagement. Treatment with 10 M of I3B led to a comparable reduction of TNF- production in LPS-stimulated RAW 264.7 macrophages to that observed with 500 M of free indole. Transcriptome profiling of I3B-treated LPS-stimulated RAW 264.7 macrophages revealed, I3B blunts pro-inflammatory response and induces gene signatures consistent with NRF2 activation. LPS-stimulated NRF2-/- Bone Marrow-derived Macrophages (BMM) treated with I3B, showed higher levels of pro-inflammatory cytokine production relative to non-treated BMM. To define the upstream pathways responsible for this NRF2-depedent response, we examined GPCR-mediated signaling and found that I3B engages a Gq-coupled receptor to induce PKC{delta} phosphorylation, and subsequent NRF2 phosphorylation. Our results suggest I3B signals through a surface-receptor in a NRF2-dependent manner to reduce inflammation in murine macrophages. TeaserA cell-impermeant indole conjugate inhibits inflammatory signaling in macrophages through an NRF2-dependent mechanism.

cell biology↗

bioRxiv2025

The Nox2 NADPH oxidase regulates neutrophilic inflammation in the oral cavity

The leukocyte NADPH oxidase 2 (NOX2) is an important regulator of inflammatory responses, independent of its antimicrobial activity. Inactivating mutations in NOX2 cause chronic granulomatous disease (CGD), a severe immunodeficiency associated with recurrent infections and dysregulated neutrophilic inflammation. Recurrent oral ulcers, stomatitis, gingivitis, and other inflammatory issues affecting the oral mucosa have been observed in patients with CGD; however, the underlying mechanisms are not known. Here, we present evidence that the extensive inflammatory destruction of oral mucosal tissues observed in Nox2-deficient or CybbKOmice was not caused by impaired antimicrobial surveillance against oral pathobionts but instead resulted from a cell-intrinsic dysregulation of neutrophil inflammatory responses. Transcriptional and cellular profiling of oral tissues isolated from wild-type and CybbKO mice showed a dominant neutrophil signature, which was accompanied by a significant upregulation of several bone-resorbing, tissue-degrading inflammatory cytokines and a reduced expression of nuclear factor erythroid 2-related factor 2 (Nrf2) regulated genes. Mechanistically, hyperinflammatory responses were mitigated by restoring Nrf2 transcriptional activity using a synthetic agonist. Thus, our studies show that Nox2 oxidase and its derived reactive oxygen species are crucial for balanced recruitment and cell-intrinsic regulation of neutrophil inflammatory responses within oral tissues in an Nrf2-dependent manner.

immunology↗

bioRxiv2023

The microbial metabolite Urolithin A reduces C. difficile toxin expression and repairs toxin-induced epithelial damage.

Clostridioides difficile is a gram-positive, anaerobic, spore-forming bacterium that is responsible for antibiotic-associated pseudomembranous colitis. Clostridioides difficile infection (CDI) symptoms can range from diarrhea to life-threatening colon damage. Toxins produced by C. difficile (TcdA and TcdB) cause intestinal epithelial injury and lead to severe gut barrier dysfunction, stem cell damage, and impaired regeneration of the gut epithelium. Current treatment options for intestinal repair are limited. In this study, we demonstrate that treatment with the microbial metabolite urolithin A (UroA) attenuates CDI-induced adverse effects on the colon epithelium in a preclinical model of CDI-induced colitis. Moreover, our analysis suggests that UroA treatment protects against C. difficile-induced inflammation, disruption of gut barrier integrity, and intestinal tight junction proteins in the colon of CDI mice. Importantly, UroA treatment significantly reduced the expression and release of toxins from C. difficile, without inducing bacterial cell death. These results indicate the direct regulatory effects of UroA on bacterial gene regulation. Overall, our findings reveal a novel aspect of UroA activities, as it appears to act at both the bacterial and host levels to protect against CDI-induced colitis pathogenesis. This research sheds light on a promising avenue for the development of novel treatments for C. difficile infection. ImportanceTherapy for C. difficile infections includes the use of antibiotics, immunosuppressors, and fecal microbiota transplantation (FMT). However, these treatments have several drawbacks, including the loss of colonization resistance, promotion of autoimmune disorders, and the potential for unknown pathogens in donor samples. To date, the potential benefits of microbial metabolites in CDI-induced colitis have not been fully investigated. Here, we report for the first time that the microbial metabolite Urolithin A has the potential to block toxin production from C. difficile and enhance gut barrier function to mitigate CDI-induced colitis.

microbiology↗