Biology subjects

Reddivari, L.

Publications and source records attributed to Reddivari, L..

4 recordsLinked to original sources

bioRxiv2026

Impaired Fermentation in the Absence of Gut Microbiota Promotes Inulin-Induced Intestinal Inflammation

Background and aims: Inflammatory bowel diseases (IBD) are characterized by altered gut microbiota composition and impaired dietary fiber fermentation, which can complicate symptom management. Although inulin is a well-established prebiotic fiber, it can exacerbate gut inflammation under certain conditions. We hypothesized that impaired microbial fermentation leaves intact inulin in the gut to activate epithelial immune receptors and promote inflammation, whereas effective fermentation reduces this pro-inflammatory signaling. Methods: We used germ-free (GF) and conventional (CONV) interleukin-10 knockout (Il10-/-) and wild-type (WT) C57BL/6J mice to assess the role of microbial fermentation and host genetic susceptibility in IBD. GF Il10-/- mice were colonized with fecal microbiota from ulcerative colitis (UC) patients or healthy individuals with fiber intolerance (FI). Mice were fed inulin or structurally distinct, physicochemically matched fiber analogs. Colonic inflammatory and barrier-related gene expression and protein levels were assessed by qPCR and ELISA. Results: In GF Il10-/- mice, inulin, but not cellulose, induced weight loss, diarrhea, and rectal prolapse. Increased colonic toll-like receptor expression (TLR2, TLR4) as well as elevated serum amyloid A (SAA) and lipocalin-2 levels indicated immune activation by unfermented inulin in GF mice. Colonization with dysbiotic microbiota attenuated these effects. {beta}-fructan fibers including fructooligosaccharides and chicory-derived inulin elicited marked inflammatory responses, whereas agave-derived inulin did not, highlighting the influence of fiber composition in inflammation associated with IBD. Conclusions: Effective microbial fermentation is essential for host tolerance to fermentable fibers. These findings underscore the need of personalized nutrition when recommending fiber supplementation in immune-compromised individuals or those with gut dysbiosis.

immunology↗

bioRxiv2026

LAP-TLR2 Axis Drives Inflammatory Pathology during Listeria monocytogenes Gastroenteritis

Listeria monocytogenes (Lm) causes acute gastroenteritis that precedes systemic invasive listeriosis, yet the molecular mechanisms coordinating bacterial virulence with host inflammatory responses during the enteric phase remain poorly understood. We show that Lm-associated gastroenteritis is dose-dependent, and a high infectious dose (~1x10^10 CFU/mouse), reflecting epidemic cases, recapitulates hallmark features of gastroenteritis in a mouse model, including early onset, epithelial erosion, and profound inflammatory cell infiltration. We identify Listeria adhesion protein (LAP), rather than classical virulence factors such as internalin A and listeriolysin O, as the primary mediator of enteric pathology, driving epithelial cell death and neutrophil recruitment. Transcriptomic (mRNA-seq) profiling implicates LAP-driven engagement of the TLR2-MyD88 pathway. Using the HEK-Dual hTLR2 (NF-kB) reporter cell line and TLR2 knockout mice, we show that LAP engages TLR2 to activate TNFalpha; NF-kB signaling and compromises the gut epithelial barrier. Disease severity correlates with myeloid hyperactivation and intestinal ion channel dysregulation, as CD11b-; mice exhibit attenuated diarrhea despite elevated bacterial tissue loads. Finally, studies in MLCK knock-out mice confirm that this myeloid-driven pathology requires MLCK-dependent tight junction opening for paracellular neutrophil migration, which works in concert with LAP-TLR2 signaling during Lm-induced gastroenteritis.

microbiology↗

bioRxiv2024

Understanding disease-associated metabolic changes in human colon epithelial cells using iColonEpithelium metabolic reconstruction

The colon epithelium plays a key role in the host-microbiome interactions, allowing uptake of various nutrients and driving important metabolic processes. To unravel detailed metabolic activities in the human colon epithelium, our present study focuses on the generation of the first cell-type specific genome-scale metabolic model (GEM) of human colonic epithelial cells, named iColonEpithelium. GEMs are powerful tools for exploring reactions and metabolites at systems level and predicting the flux distributions at steady state. Our cell-type-specific iColonEpithelium metabolic reconstruction captures genes specifically expressed in the human colonic epithelial cells. The iColonEpithelium is also capable of performing metabolic tasks specific to the cell type. A unique transport reaction compartment has been included to allow simulation of metabolic interactions with the gut microbiome. We used iColonEpithelium to identify metabolic signatures associated with inflammatory bowel disease. We integrated single-cell RNA sequencing data from Crohns Diseases (CD) and ulcerative colitis (UC) samples with the iColonEpithelium metabolic network to predict metabolic signatures of colonocytes between CD and UC compared to healthy samples. We identified reactions in nucleotide interconversion, fatty acid synthesis and tryptophan metabolism were differentially regulated in CD and UC conditions, which were in accordance with experimental results. The iColonEpithelium metabolic network can be used to identify mechanisms at the cellular level, and our network has the potential to be integrated with gut microbiome models to explore the metabolic interactions between host and gut microbiota under various conditions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/619644v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@77e2deorg.highwire.dtl.DTLVardef@cf7de2org.highwire.dtl.DTLVardef@51c178org.highwire.dtl.DTLVardef@174e2c9_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2024

A gnotobiotic mouse model with divergent equol-producing phenotype: potential for determining microbial-driven health impacts of soy isoflavone daidzein

The implications of soy consumption on human health have been a subject of debate, largely due to the mixed evidence regarding its benefits and potential risks. The variability in responses to soy has been partly attributed to differences in the metabolism of soy isoflavones, compounds with structural similarities to estrogen. Approximately one-third of humans possess gut bacteria capable of converting soy isoflavone daidzein into equol, a metabolite produced exclusively by gut microbiota with significant estrogenic potency. In contrast, lab-raised rodents are efficient equol producers, except for those raised germ-free. This discrepancy raises concerns about the applicability of traditional rodent models to humans. Herein, we designed a gnotobiotic mouse model to differentiate between equol producers and non-producers by introducing synthetic bacterial communities with and without the capacity into female and male germ-free mice. These gnotobiotic mice display equol-producing phenotypes consistent with the capacity of the gut microbiota received. Our findings confirm the models efficacy in mimicking human equol production capacity, offering a promising tool for future studies to explore the relationship between endogenous equol production and health outcomes like cardiometabolic and fertility. This approach aims to refine dietary guidelines by considering individual microbiome differences.

microbiology↗