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Advanced Science (Weinheim,... Mar 2024Intervention of the gut microbiome is a promising adjuvant strategy in cancer immunotherapy. Chemotherapeutic agents are recognized for their substantial impacts on the...
Low-Dose Chemotherapy Preferentially Shapes the Ileal Microbiome and Augments the Response to Immune Checkpoint Blockade by Activating AIM2 Inflammasome in Ileal Epithelial Cells.
Intervention of the gut microbiome is a promising adjuvant strategy in cancer immunotherapy. Chemotherapeutic agents are recognized for their substantial impacts on the gut microbiome, yet their therapeutic potential as microbiome modulators remains uncertain, due to the complexity of microbiome-host-drug interactions. Here, it is showed that low-dose chemotherapy preferentially shapes the ileal microbiome to augment the extraintestinal immune response to anti-programmed death-1 (anti-PD-1) therapy without causing intestinal toxicity. Mechanistically, low-dose chemotherapy causes DNA damage restricted to highly-proliferative ileal epithelial cells, resulting in the accumulation of cytosolic dsDNA and the activation of the absent in melanoma 2 (AIM2) inflammasome. AIM2-dependent IL-18 secretion triggers the interplay between proximal Th1 cells and Paneth cells in ileal crypts, impairing the local antimicrobial host defense and resulting in ileal microbiome change. Intestinal epithelium-specific knockout of AIM2 in mice significantly attenuates CPT-11-caused IL-18 secretion, Paneth cell dysfunction, and ileal microbiome alteration. Moreover, AIM2 deficiency in mice or antibiotic microbial depletion attenuates chemotherapy-augmented antitumor responses to anti-PD1 therapy. Collectively, these findings provide mechanistic insights into how chemotherapy-induced genomic stress is transduced to gut microbiome change and support the rationale of applying low-dose chemotherapy as a promising adjuvant strategy in cancer immunotherapy with minimal toxicity.
Topics: Animals; Mice; Inflammasomes; Interleukin-18; Immune Checkpoint Inhibitors; Melanoma; DNA-Binding Proteins; Epithelial Cells; Microbiota
PubMed: 38189627
DOI: 10.1002/advs.202304781 -
Transplant Immunology Feb 2024Graft-versus-host disease (GVHD) is one of the most important cause of death in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). The... (Review)
Review
Graft-versus-host disease (GVHD) is one of the most important cause of death in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). The gastrointestinal tract is one of the most common sites affected by GVHD. However, there is no gold standard clinical practice for diagnosing gastrointestinal GVHD (GI-GVHD), and it is mainly diagnosed by the patient's clinical symptoms and related histological changes. Additionally, GI-GVHD causes intestinal immune system disorders, damages intestinal epithelial tissue such as intestinal epithelial cells((IEC), goblet, Paneth, and intestinal stem cells, and disrupts the intestinal epithelium's physical and chemical mucosal barriers. The use of antibiotics and diet alterations significantly reduces intestinal microbial diversity, further reducing bacterial metabolites such as short-chain fatty acids and indole, aggravating infection, and GI-GVHD. gut microbe diversity can be restored by fecal microbiota transplantation (FMT) to treat refractory GI-GVHD. This review article focuses on the clinical diagnosis of GI-GVHD and the effect of GVHD on intestinal flora and its metabolites.
Topics: Humans; Gastrointestinal Microbiome; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Epithelial Cells; Anti-Bacterial Agents
PubMed: 38184214
DOI: 10.1016/j.trim.2023.101977 -
Communications Biology Jan 2024Tumor tissues consist of heterogeneous cells that originate from stem cells; however, their cell fate determination program remains incompletely understood. Using...
Tumor tissues consist of heterogeneous cells that originate from stem cells; however, their cell fate determination program remains incompletely understood. Using patient-derived organoids established from patients with advanced colorectal cancer (CRC), we evaluated the potential of olfactomedin 4 (OLFM4) stem cells to produce a bifurcated lineage of progenies with absorptive and secretory properties. In the early phases of organoid reconstruction, OLFM4 cells preferentially gave rise to secretory cells. Additionally, we found that Paneth-like cells, which do not exist in the normal colon, were induced in response to Notch signaling inhibition. Video recordings of single OLFM4 cells revealed that organoids containing Paneth-like cells were effectively propagated and that their selective ablation led to organoid collapse. In tumor tissues, Paneth-like cells were identified only in the region where tumor cells lost cell adhesion. These findings indicate that Paneth-like cells are directly produced by OLFM4 stem cells and that their interaction contributes to tumor formation by providing niche factors. This study reveals the importance of the cell fate specification program for building a complete tumor cellular ecosystem, which might be targeted with novel therapeutics.
Topics: Humans; Ecosystem; Stem Cells; Cell Proliferation; Colorectal Neoplasms; Organoids; Granulocyte Colony-Stimulating Factor
PubMed: 38182890
DOI: 10.1038/s42003-023-05504-8 -
Science Translational Medicine Jan 2024Environmental enteric dysfunction (EED) is a diffuse small bowel disorder associated with poor growth, inadequate responses to oral vaccines, and nutrient malabsorption...
Environmental enteric dysfunction (EED) is a diffuse small bowel disorder associated with poor growth, inadequate responses to oral vaccines, and nutrient malabsorption in millions of children worldwide. We identify loss of the small intestinal Paneth and goblet cells that are critical for innate immunity, reduced villous height, increased bile acids, and dysregulated nicotinamide adenine dinucleotide (NAD) synthesis signaling as potential mechanisms underlying EED and which also correlated with diminished length-for-age score. Isocaloric low-protein diet (LPD) consumption in mice recapitulated EED histopathology and transcriptomic changes in a microbiota-independent manner, as well as increases in serum and fecal bile acids. Children with refractory EED harbor single-nucleotide polymorphisms in key enzymes involved in NAD synthesis. In mice, deletion of , the gene encoding the rate-limiting enzyme in the NAD salvage pathway, from intestinal epithelium also reduced Paneth cell function, a deficiency that was further aggravated by LPD. Separate supplementation with NAD precursors or bile acid sequestrant partially restored LPD-associated Paneth cell defects and, when combined, fully restored all histopathology defects in LPD-fed mice. Therapeutic regimens that increase protein and NAD contents while reducing excessive bile acids may benefit children with refractory EED.
Topics: Humans; Child; Mice; Animals; NAD; Bile Acids and Salts; Cytokines
PubMed: 38170788
DOI: 10.1126/scitranslmed.abq4145 -
International Journal of Molecular... Dec 2023The number of people affected by cancer and antibiotic-resistant bacterial infections has increased, such that both diseases are already seen as current and future...
The number of people affected by cancer and antibiotic-resistant bacterial infections has increased, such that both diseases are already seen as current and future leading causes of death globally. To address this issue, based on a combined in silico and in vitro approach, we explored the anticancer potential of known antibacterials with a thiazolidinedione-thiosemicarbazone (TZD-TSC) core structure. A cytotoxicity assessment showed encouraging results for compounds -, with IC values against T98G and HepG2 cells in the low micromolar range. TZD-TSC proved to be most toxic to cancer cell lines, with IC values of 2.97 ± 0.39 µM against human hepatoma HepG2 cells and IC values of 28.34 ± 2.21 µM against human glioblastoma T98G cells. Additionally, compound induced apoptosis and showed no specific hemolytic activity. Furthermore, treatment using on cancer cell lines alters these cells' morphology and further suppresses migratory activity. Molecular docking, in turn, suggests that would have the capacity to simultaneously target HDACs and PPARγ, by the activation of PPARγ and the inhibition of both HDAC4 and HDAC8. Thus, the promising preliminary results obtained with TZD-TSC represent an encouraging starting point for the rational design of novel chemotherapeutics with dual antibacterial and anticancer activities.
Topics: Humans; Structure-Activity Relationship; Cell Line, Tumor; Molecular Docking Simulation; Thiosemicarbazones; PPAR gamma; Drug Screening Assays, Antitumor; Antineoplastic Agents; Thiazolidinediones; Anti-Bacterial Agents; Molecular Structure; Cell Proliferation; Histone Deacetylases; Repressor Proteins
PubMed: 38139350
DOI: 10.3390/ijms242417521 -
Microorganisms Nov 2023Pouchitis is a common complication of restorative proctocolectomy and ileal pouch anal anastomosis (IPAA) for ulcerative colitis (UC), significantly affecting the...
BACKGROUND
Pouchitis is a common complication of restorative proctocolectomy and ileal pouch anal anastomosis (IPAA) for ulcerative colitis (UC), significantly affecting the postoperative quality of life. Paneth cells play an important role in the maintenance of gut homeostasis. This study aimed to investigate the role of Paneth cells in the pathogenesis of pouchitis.
METHOD
Endoscopic biopsies from the pouch body and terminal ileum of UC patients undergoing IPAA with or without pouchitis were obtained to analyze Paneth cell function. Acute pouchitis was induced with 5% dextran sulfate sodium (DSS) for seven consecutive days in a rat model of IPAA. The Paneth cell morphology was examined by immunofluorescence and electron microscopy. The effect of exogenous lysozyme supplementation on pouchitis was also investigated. The fecal microbiota profile after DSS and lysozyme treatment was determined by 16s rRNA ITS2 sequence analysis.
RESULT
Abnormal mucosal lysozyme expression was observed in patients with pouchitis. The rat model of pouchitis showed increased pouch inflammation, increased CD3+ and CD45+ T cell infiltration, and decreased tight junction proteins, including ZO-1 and Occludin. There is a significant deficiency of Paneth cell-derived lysozyme granules in the rat model of pouchitis. Supplementation with exogenous lysozyme significantly ameliorated pouchitis, lowering the levels of inflammatory cytokines such as TNF-α and IL-6 in the pouch tissue. 16s rRNA analysis revealed a higher Lachnospiraceae level after lysosome treatment.
CONCLUSIONS
Paneth cell dysfunction is prominent in patients and rat models of pouchitis and may be one of its causes. The decrease in Lachnospiraceae, a characteristic of dysbiosis in pouchitis, could be reserved by lysosome treatment. Lysozyme supplementation shows promise as a novel treatment strategy for pouchitis.
PubMed: 38137976
DOI: 10.3390/microorganisms11122832 -
World Journal of Clinical Cases Dec 2023Inflammatory bowel disease (IBD) is a disorder of the immune system and intestinal microecosystem caused by environmental factors in genetically susceptible people.... (Review)
Review
Inflammatory bowel disease (IBD) is a disorder of the immune system and intestinal microecosystem caused by environmental factors in genetically susceptible people. Paneth cells (PCs) play a central role in IBD pathogenesis, especially in Crohn's disease development, and their morphology, number and function are regulated by susceptibility genes. In the intestine, PCs participate in the formation of the stem cell microenvironment by secreting antibacterial particles and play a role in helping maintain the intestinal microecology and intestinal mucosal homeostasis. Moreover, PC proliferation and maturation depend on symbiotic flora in the intestine. This paper describes the interactions among susceptibility genes, PCs and intestinal microecology and their effects on IBD occurrence and development.
PubMed: 38130785
DOI: 10.12998/wjcc.v11.i34.8111 -
Clinics and Research in Hepatology and... Jan 2024Obesity is a global health crisis, with its prevalence steadily rising over the past few decades. One concerning consequence of obesity is its association with metabolic... (Review)
Review
Obesity is a global health crisis, with its prevalence steadily rising over the past few decades. One concerning consequence of obesity is its association with metabolic associated steatohepatitis [MASH], portal hypertension and liver cirrhosis. Cirrhosis is irreversible, but stages of liver disease before the development of cirrhosis are reversible with appropriate interventions. Studies have brought into light new entities that influences the pathophysiology of portal hypertension. This review provides evidence supporting that, Paneth cells[PCs] in the intestinal epithelium, which remained enigmatic for a century, are the maneuverer of pathophysiology of portal hypertension and obesity. PC dysfunction can cause perturbation of the intestinal microbiota and changes in intestinal permeability, which are the potential triggers of systemic inflammation. Thus, it can offer unique opportunities to understand the pathophysiology of portal hypertension for intervention strategies.
Topics: Humans; Paneth Cells; Hypertension, Portal; Liver Cirrhosis; Fatty Liver; Obesity
PubMed: 38070827
DOI: 10.1016/j.clinre.2023.102259 -
Frontiers in Microbiology 2023The alleviating effects of in microencapsulation (LPM) on lipopolysaccharide (LPS)-induced intestinal inflammatory injury were investigated in layer chicks. A total of...
The alleviating effects of in microencapsulation (LPM) on lipopolysaccharide (LPS)-induced intestinal inflammatory injury were investigated in layer chicks. A total of 252 healthy Hy-Line Brown layer chicks were randomly divided into six groups. Birds were injected with saline or LPS except for the control, and the diets of birds subjected to LPS were supplemented with nothing, , LPM, and wall material of LPM, respectively. The viable counts of LPM reached 10 CFU/g, and the supplemental levels of , LPM, and WM were 0.02 g (10 CFU), 1.0 g, and 0.98 g, per kilogram feed, respectively. LPS administration caused intestinal damage in layer chicks, evidenced by increased proinflammatory factors accompanied by poor intestinal development and morphology ( < 0.05). LPM/LPS significantly increased body weight, small intestine weight and length, villus height, villus height/crypt depth, and mRNA relative expression of tight junction protein genes ( < 0.05) and performed better than free . These findings could be attributed to the significant increase in viable counts of in the small intestine ( < 0.05), as well as the enhanced levels of Actinobacteriota, Lactobacillaceae, and in intestinal microbiota ( < 0.05). Such results could further significantly increase goblet and PCNA+ cell percentage ( < 0.05); the mRNA relative expressions of epithelial cell, fast-cycling stem cell, quiescent stem cell, endocrine cell, and Paneth cell; and goblet and proliferative cell marker genes, including , , , , , , and ( < 0.05). Furthermore, the mRNA relative expressions of key genes involved in epithelial cell proliferation, namely, , , , and , exhibited significant upregulation compared with the LPS treatment, as well as the differentiating genes and ( < 0.05). To sum up, microencapsulated supplementation could alleviate intestinal injury in layer chicks induced by LPS by promoting the proliferation and differentiation of intestinal epithelial cells, which could be attributed to the increase in viable count of in the gut and optimization in intestinal microbial flora.
PubMed: 38053557
DOI: 10.3389/fmicb.2023.1287899 -
Nature Communications Dec 2023Paneth cell metaplasia (PCM) typically arises in pre-existing gastrointestinal (GI) diseases; however, the mechanistic pathway that induces metaplasia and whether PCM is...
Paneth cell metaplasia (PCM) typically arises in pre-existing gastrointestinal (GI) diseases; however, the mechanistic pathway that induces metaplasia and whether PCM is initiated exclusively by disorders intrinsic to the GI tract is not well known. Here, we describe the development of PCM in a murine model of chronic myelogenous leukemia (CML) that is driven by an inducible bcr-abl oncogene. Mechanistically, CML induces a proinflammatory state within the GI tract that results in the production of epithelial-derived IL-33. The binding of IL-33 to the decoy receptor ST2 leads to IL-9 production by type 2 innate lymphoid cells (ILC2) which is directly responsible for the induction of PCM in the colon and tissue remodeling in the small intestines, characterized by goblet and tuft cell hyperplasia along with expansion of mucosal mast cells. Thus, we demonstrate that an extra-intestinal disease can trigger an ILC2/IL-9 immune circuit, which induces PCM and regulates epithelial cell fate decisions in the GI tract.
Topics: Animals; Mice; Paneth Cells; Interleukin-9; Immunity, Innate; Interleukin-33; Lymphocytes; Intestine, Small; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Metaplasia
PubMed: 38042840
DOI: 10.1038/s41467-023-43248-5