Tachykinin signaling defines distinct populations of glia in the enteric nervous system.

Targeted deletion of Cyp24a1 in the intestine reduces mucosal injury and preserves epithelial proliferation after 5-fluorouracil treatment.

ABSTRACT Salmonella is a food-borne zoonotic pathogen that causes human gastroenteritis and potentially fatal systemic infections. The invasion of intestinal epithelial cells and the survival and replication within host macrophages are essential for the intestinal and systemic infections caused by Salmonella, respectively. To precisely regulate the expression of virulence-related genes, Salmonella relies on a series of regulatory proteins. In this study, we identified STM1082, a putative AraC-type transcriptional regulator, as a new virulence activator in Salmonella. The expression of the STM1082 gene is up-regulated when Salmonella invades HeLa epithelial cells and replicates within RAW264.7 macrophages. Mutation of STM1082 impaired the ability of Salmonella to invade HeLa cells and replicate in RAW264.7 cells, and reduced its colonization in the mouse intestine, liver, and spleen. These results suggest that STM1082 facilitates Salmonella pathogenicity by promoting both its intestinal and systemic infections. Moreover, under intestinal-mimicking conditions, STM1082 increased the expression of genes related to 1,2-propanediol and ethanolamine metabolism, which are linked to Salmonella‘s intestinal survival. Under macrophage-mimicking conditions, it upregulated genes involved in purine biosynthesis, associated with Salmonella‘s systemic virulence. Together, these findings highlight the significant role of STM1082 in modulating the pathogenic mechanisms of Salmonella.

Magnetoacoustic tomography with magnetic induction (MAT-MI) is a promising noninvasive, radiation-free imaging technique capable of millimeter-level spatial resolution for mapping tissue conductivity. However, its application to luminal tissues (e.g., digestive tract, vasculature) is significantly hindered by low image quality due to acoustic wave attenuation and inherent tissue properties. This study aimed to overcome the image quality limitation in MAT-MI imaging of luminal structures by utilizing liquid metal (LM) as a novel conductive contrast agent and implementing M-sequence coded excitation to enhance signal strength and acquisition efficiency. The LM contrast agent used was a biocompatible Ga67In20.5Sn12.5 alloy (σ=3.1×10⁶ S/m). MAT-MI experiments were conducted on gel phantoms containing LM in various shapes and simulated luminal structures (PVC tubes, ex vivo mouse intestines), ex vivo mouse stomach tissues infused with LM or PBS (control), and in vivo mouse stomachs. The MAT-MI system employed 0.34 T static magnetic field, a pulsed excitation coil (1MHz center frequency), and an ultrasound transducer. We applied M-sequence coded excitation (up to 31-bit) and processed the signals using pulse compression followed by filtered back-projection reconstruction. Safety was assessed via long-term biocompatibility studies, blood elemental analysis, and histological examination (H&E staining) of gastrointestinal tissues. Integrating LM into the imaging target greatly increased the MAT-MI signal intensity. In vivo imaging of mouse stomachs demonstrated an approximate 28dB increase in image quality after LM infusion compared to pre-infusion imaging. LM enabled clear visualization within fine luminal structures (down to 0.5mm inner diameter) in phantoms and ex vivo tissues. M-sequence coding further improved image clarity and reduced total imaging time by approximately 84% relative to single-pulse excitation (from 6360s to 1020s for comparable image quality). High-resolution imaging (approximately 2mm spatial resolution) of LM distribution was achieved. The LM was safely excreted, with no significant toxicity observed in blood analysis or histology over 180 days. LM proved to be an effective and safe contrast agent for MAT-MI, significantly enhancing image quality and enabling high-quality imaging of luminal tissues, including the first successful in vivo visualization of the stomach in a live animal model. Combined with M-sequence coded excitation, this approach overcomes key limitations of conventional MAT-MI and could broaden its diagnostic utility in cardiovascular and gastrointestinal imaging.

Hepatocyte nuclear factor 4A (HNF4A) is a transcription factor that regulates a diverse range of intestinal epithelial genes involved in tissue renewal, differentiation, and metabolism, among other functions. The HNF4A locus is associated with Inflammatory Bowel Diseases (IBD) susceptibility, and its deletion in the mouse intestine causes long-term chronic inflammation of the colon. However, it remains unclear whether HNF4A is part of the regulatory mechanisms involved in the inflammatory processes of the small intestine. Using a tamoxifen-inducible mouse intestinal knockout of Hnf4a, we observed a spontaneous increase in mucosal barrier permeability in the absence of HNF4A. However, when these mice were infected with the invasive-deficient Salmonella Typhimurium SB103, this increase in permeability did not result in an increase in liver and spleen bacterial colonization compared to undeleted mice. Interestingly, ileal secretory cell lineage differentiation was favored when HNF4A was depleted during the early stages of infection. This resulted in increased production of ileal goblet cells and the expression of Muc2, as well as the expression of specific antimicrobial peptides such as Reg3g and Rtnlb. We conclude that epithelial HNF4A is sensitive to Salmonella in the ileum and that its reduction in expression during the early phase of infection may contribute to rapidly reinforcing the chemical barrier response to elicit mucosal threat from pathogens.

Opioid-induced constipation is one of the most common and persistent side effect of opioid analgesics, yet the underlying neural mechanism(s) remain unclear. Here we show morphine-induced constipation is mediated by a neural circuit from glutamatergic neurons in the paraventricular nucleus of hypothalamus (PVNGlu) to acetylcholinergic neurons in the dorsal motor nucleus of the vagus (DMVAch), and subsequently to the small intestine in mice. Microendoscopic calcium imaging revealed morphine inhibits the PVNGlu→DMVAch→small intestine circuit, and this is accompanied by decreased small intestinal motility. Chemogenetic activation of this circuit, as well as pharmacological inhibition or knockdown of the μ-opioid receptor (MOR) in PVNGlu neurons alleviates morphine-induced constipation. Conversely, artificial inhibition of this circuit mimics morphine-induced constipation in naïve mice. Moreover, we show that morphine suppresses tonic NMDA receptor-mediated currents in DMVAch neurons. These findings reveal a brain-gut circuit underlying opioid-induced constipation and suggest potential therapeutic strategies to mitigate this debilitating side effect.

BackgroundHydroxyurea (HU) is an antitumor drug. However, HU exposure is associated with diminished ovarian reserve (DOR). Zi Chong granules, a Chinese Medicine, can protect against DOR, but little is known regarding its underlying mechanisms of DOR treatment, and thus the target of the present study.MethodsSeventy-two female Kunming (KM) mice (4–6 weeks old) were randomly divided into three groups: the control group (Con), the hydroxyurea group (HU), and the Zi Chong group (ZC). The Con group received saline, while the HU and ZC groups were administered hydroxyurea (400 mg/kg/d) by gavage for 21 days to induce diminished ovarian reserve (DOR). Subsequently, the Con and HU groups were given saline, while the ZC group was treated with Zi Chong granules (2.72 g/kg/d) for 15 days. Ovaries and uterus of mice were examined histologically by H&E. The levels of anti-Mullerian hormone (AMH), estradiol (E2), and progesterone (P) were quantified using ELISA kits. The number and quality of oocytes were assessed, and endometrial receptivity was evaluated by immunohistochemistry. 16 S rDNA gene sequencing was used to analyze the composition and abundance of gut microbiome in feces, and non-targeted metabolomics was performed to detect serum metabolite profiles. Correlation analysis was performed to explore the relationships between different gut microbiota and differential metabolites.ResultsZC granules increased the number of primordial follicles in the ovaries, reduced excessive follicular atresia, restored low AMH, upregulated estrogen and progesterone secretion, and increased the number of mature oocytes after ovulation promotion. It also increased thickness of uterine endometrium and the number of glands, resulting in increased endometrial microvessel density (MVD), enhanced endometrial blood supply, reduced CD138 expression levels and endometrial inflammation. HU decreased the abundance of Lactobacillus spp. in mouse intestines and decreased arachidonic acid metabolism, tryptophan metabolism, spermidine and spermine biosynthesis, steroidogenesis, and nicotinate and nicotinamide metabolism. Correlation analysis revealed that HU exerted its side effects by altering the gut microbiome and bacteria-derived metabolites, while ZC granules could reverse DOR partly depends on regulating gut microbiota and metabolites.ConclusionsZC granules may be a potential therapy for alleviating HU-induced DOR.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13048-025-01846-5.

Abstract Every tissue-type has a specific rate of renewal that maintains its structural integrity throughout life. Our Aim is to understand how changes in the rate of tissue renewal underlie colon cancer development. For colon tumorigenesis, we measured kinetic changes that occur in human and murine intestinal crypts having different APC genotypes. Quantitative histologic mapping showed that transitions between the different cell phenotypes are progressively delayed along the axis of APC mutant crypts. The extent of this delay was greater in homozygous than in heterozygous APC-mutant crypts. In ApcMin/+ mouse intestine, clearance of BrdU from pre-labeled crypts was significantly slower than in wildtype-Apc mice. Kinetic modeling showed that retarded crypt renewal increases the number of cell divisions required for differentiation which causes incomplete differentiation and progressive expansion of the proliferative cell populations. Thus, our findings reveal that APC mutation-induced retardation of tissue renewal is a key driver mechanism in colon tumor initiation and development. Citation Format: Bruce Boman. APC Mutation-induced Retardation of Tissue Renewal is Fundamental to Colon Tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr C005.

Ketogenic diet influences the renin-angiotensin-aldosterone system components in the healthy and inflamed intestine of male mice.

Carbon dots from thermally processed Spirulina: Properties, biodistribution and cytotoxicity.

WGX-50, a previously reported drug candidate for Alzheimer's disease, is derived from Zanthoxylum bungeanum Maxim commonly called Sichuan pepper. Its pharmacological actions for the long run benefit of human health have been extensively investigated. However, in terms of its anti-aging effect, it totally remains unexplored. In this work, WGX-50 was first reported to promote healthy aging in Caenorhabditis elegans with insights from drug target prediction and molecular dynamics simulations. Further investigations have experimentally demonstrated that: Firstly, both daf-16 and skn-1 genes are causative to WGX-50 mediated longevity. WGX-50 failed to extend lifespan upon depletion of these genes in transgenic worms. Their orthologs Foxo1 and Nrf2 were also activated even in D-galactose (D-gal) induced aging and Zmpste24-/- progeria mice intestines. Secondly, WGX-50 inhibits IIS signaling via downregulating daf-2, and activating daf-16 and skn-1 genes, which thus enable downstream pro-longevity effectors increasing stress resistance and promoting healthier aging. WGX-50 increased expression levels of sod-3, ctl-1, gst-7/8/12/33, gsto-1, and heat shock protein genes such as hsp-12.2, hsp-90, F44E5.4/0.5, T05E11.9 and their inducer hsf-1. In addition, the accumulation of lipofuscin, fat, and reactive oxygen species levels with age was decreased significantly upon WGX-50 supplementation without physiological impairments. Thirdly, in progeria, D-gal and naturally aged mice, WGX-50 is incapable of inducing aging. Senescent genes and SASP factors were not produced at higher levels in livers and small intensities. No impact was observed on key organ indices, blood biochemistry parameters, and bone histomorphometry. WGX-50 perhaps prolongs lifespan through other mechanisms such as reducing fertility, inducing dietary restriction, and improving proteostasis with lowered levels of polyQ35 aggregates. Our findings thus provide primary insights for the potential medical use of WGX-50 in anti-aging and long-term healthcare.

Introduction. Enteric viruses significantly impact morbidity, mortality, and healthcare. Transmission through wastewater is favoured in highly contaminated areas due to inadequate treatment.Objective. To determine the number of rotaviruses and their infectious capacity from wastewater samples used for irrigation in the western part of Bogotá.Materials and methods. Concentrations of group A rotavirus were monitored in wastewater using molecular methods. The infectivity of rotaviruses was evaluated in a mouse intestinal villi model. We assessed the feasibility of applying this approach for environmental health surveillance in Colombia, considering findings reported by other authors.Results. The research focused on the La Ramada irrigation network in the western part of Bogotá, specifically the Canal San José. We analysed eighteen wastewater samples using qRT-PCR and detected group A rotavirus in twelve of them. The positive samples contained infectious rotavirus, as confirmed through the mouse villi model.Conclusion. This study shows that contamination by group A rotavirus is frequent in wastewaters from the Canal San José in the La Ramada irrigation network in the western part of Bogotá and reveals high concentrations of rotavirus. The results suggest that villi from mouse intestines serve as a reliable model for isolating rotavirus from wastewaters. These findings provide a new approach for environmental health surveillance in Colombia, based on molecular epidemiology for waters highly contaminated with human enteric viruses.

Probiotic Limosilactobacillus reuteri DSM 17938 reduces autoimmunity in mouse models. Recently, a novel strain, L. reuteri DSM 32846 (BG-R46®), derived from DSM 17938 was found to have unique properties including bile acid tolerance and enhanced adenosine production. Human milk oligosaccharides (HMOs) help establish the intestinal microbiome and assist immune and neurodevelopment. The objective of the study was to explore the differential effects of each strain (with or without HMOs) with respect to innate and adaptive immunity in the intestine of mice during early development at postnatal d8 (early stage), d14 (rapid growth stage), and d21 (at weaning). C57BL/6J mice received intragastric DSM 17938 or DSM 32846 individually or in combination with HMOs, a mixture of 2`-FL and 6`-SL, daily from d7 to d20. We subsequently assessed circulating and intestinal immune cell markers at d8, d14 and d21. Both strains promoted development of intestinal macrophages, natural killer cells, and activated T and B cells. The cellular responses in the intestine of d8 mice were boosted within one day of treatment with DSM 17938, as opposed to 1-2weeks after treatment with DSM 32846. This delay could be reversed by supplementing HMOs along with DSM 32846. Both DSM 32846 and DSM 17938 facilitated dendritic cell maturation and enhanced regulatory T cell numbers in the intestines of these newborns. However, HMOs enhanced the effects of DSM 32846, but not DSM 17938. Therefore, an early-life boost of intestinal immune cells by probiotics was observed which could be essential to protection against neonatal inflammatory conditions. This novel difference between two strains of the same species in immune modulation could provide a rationale for co-administration in an HMO-rich environment.

Numerous G protein-coupled receptors (GPCRs) expressed in the gastrointestinal tract serve as crucial transducers to regulate a variety of physiological functions upon activation. Takeda G protein-coupled receptor 5 (TGR5), a prominent gastrointestinal GPCR expressed on enteroendocrine L cells, is activated by intestinal bile acids and plays a role in glucose utilization. However, the development of TGR5 agonists has been hindered by the hepatobiliary toxicity associated with long-term supplementation with exogenous agonists. Here, we designed and characterized a biomimetic receptor agonist, which we termed TGR5-targeted carrier-drug conjugate (TGR5-CaDC), that combined the TGR5-activating capabilities of deoxycholic acid, a TGR5 agonist, with the nonabsorbable properties of a carrier. Unlike traditional agonists or carrier-based drug delivery systems, nonabsorbable TGR5-CaDC remained localized in the intestines of mice and pigs, providing high surface concentrations of TGR5 agonists in addition to ensuring strong L cell specificity and TGR5 affinity. TGR5-CaDC treatment also promoted TGR5 cluster aggregation, signal amplification, and increased glucagon-like peptide 1 secretion. Notably, TGR5-CaDC demonstrated sustained glycemic effects with reduced toxicity compared with deoxycholic acid alone or liraglutide in diabetic mice and Bama minipigs. By targeting extracellular binding domains and mimicking native ligand-receptor binding patterns, the design concept underlying this carrier-drug conjugate has the potential for applications in a variety of GPCR-mediated gastrointestinal diseases.

ABSTRACT The host EnguLfment and cell MOtility protein 1 (ELMO1) is a cytosolic microbial sensor that binds bacterial effector proteins, including pathogenic effectors from Salmonella (Salmonella enterica serovar Typhimurium) and controls host innate immune signaling. To understand the ELMO1-regulated host pathways, we have performed liquid chromatography Multinotch MS3-Tandem Mass Tag (TMT) multiplexed proteomics to determine the global quantification of proteins regulated by ELMO1 in macrophages during Salmonella infection. Comparative proteome analysis of control and ELMO1-depleted murine J774 macrophages after Salmonella infection quantified more than 7000 proteins with a notable enrichment in mitochondrial-related proteins. Gene ontology enrichment analysis revealed 19 upregulated and 11 downregulated proteins exclusive to ELMO1-depleted cells during infection, belonging to mitochondrial functions, metabolism, vesicle transport, and the immune system. Seahorse analysis showed that Salmonella infection alters mitochondrial metabolism from oxidative phosphorylation to glycolysis-a shift significantly influenced by the depletion of ELMO1. Furthermore, ELMO1 depletion decreased the ATP rate index following Salmonella infection, indicating its importance in counteracting the effects of Salmonella on immunometabolism. Among the proteins involved in mitochondrial pathways, the mitochondrial fission protein DRP1 was significantly upregulated in ELMO1-depleted cells and ELMO1-KO mice intestine following Salmonella infection. Pharmacological inhibition of DRP1 identified the role of ELMO1-DRP1 pathway in the regulation of pro-inflammatory cytokine TNF-α following infection. The role of ELMO1 has been further characterized by a Proteome profiling of ELMO1-depleted macrophage infected with SifA mutant displayed the involvement of ELMO1-SifA in mitochondrial function, metabolism and host immune/defense responses. Collectively, these findings reveal a novel role for ELMO1 in modulating mitochondrial functions, potentially pivotal in modulating inflammatory responses.

Protocol for the quantification of mouse fecal IgM, IgG, and IgA utilizing standard curve-based enzyme-linked immunosorbent assays

Lactoferrin is a multifunctional protein mainly involved in the immune defense of organisms against various pathogens. It has been reported that intestinal inflammation was reduced by lactoferrin administration. However, the precise mechanism underlying lactoferrin's involvement in intestinal inflammation is not yet fully understood. In this study, we purified a mouse intestinal lactoferrin-binding protein with a molecular mass of ~ 400kDa that was expressed in the small intestine and colon. Sequence analysis revealed that the intestinal lactoferrin-binding protein represented an ortholog of rat immunoglobulin G fragment crystallizable gamma-binding protein (IgGFcγBP). N-linked glycans of lactoferrin were not necessary for binding to IgGFcγBP. After reduction, IgGFcγBP was separated into 120, 70, 65, 60, and 55kDa proteins, but these did not bind to lactoferrin. The expression of IgGFcγBP was lost in a mouse model of dextran sodium sulfate induced colitis and restored during the convalescence period of colitis, suggesting a role in mucosal protection and immune regulation. Furthermore, we discuss potential links between IgGFcγBP and mucin-associated microbiota which may contribute to lactoferrin's immunomodulatory effects. These findings provide new insights into the interaction between lactoferrin, mucosal immunity, and gut microbiota.

Enteral supplementation with a TGF-β-enriched polymeric diet mitigates gastrointestinal acute gvhd

Fecal Detection of Calprotectin Subunits Links Inflammatory Bowel Disease Activity With Chronicity of Intestinal Inflammation.

Microenvironmental TFPI2 in Hirschsprung Disease: Mechanisms in ENCC Development.