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1.
Cell Host Microbe ; 32(10): 1648-1650, 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39389028

RESUMO

Paneth cells located within intestinal crypts support epithelial stem cells and immunity through growth factors and antimicrobial peptides. In this issue of Cell Host & Microbe, Wallaeys et al. report that TNF sensing by Paneth cells disrupts the unfolded protein response and decreases antimicrobial peptides, causing bacterial translocation and sepsis.


Assuntos
Imunidade nas Mucosas , Celulas de Paneth , Celulas de Paneth/imunologia , Celulas de Paneth/metabolismo , Humanos , Animais , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Peptídeos Antimicrobianos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Resposta a Proteínas não Dobradas , Sepse/imunologia , Sepse/microbiologia , Translocação Bacteriana , Camundongos
2.
Cells ; 13(17)2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39273007

RESUMO

The small intestinal crypts harbor secretory Paneth cells (PCs) which express bactericidal peptides that are crucial for maintaining intestinal homeostasis. Considering the diverse environmental conditions throughout the course of the small intestine, multiple subtypes of PCs are expected to exist. We applied single-cell RNA-sequencing of PCs combined with deep bulk RNA-sequencing on PC populations of different small intestinal locations and discovered several expression-based PC clusters. Some of these are discrete and resemble tuft cell-like PCs, goblet cell (GC)-like PCs, PCs expressing stem cell markers, and atypical PCs. Other clusters are less discrete but appear to be derived from different locations along the intestinal tract and have environment-dictated functions such as food digestion and antimicrobial peptide production. A comprehensive spatial analysis using Resolve Bioscience was conducted, leading to the identification of different PC's transcriptomic identities along the different compartments of the intestine, but not between PCs in the crypts themselves.


Assuntos
Intestino Delgado , Celulas de Paneth , Celulas de Paneth/metabolismo , Animais , Intestino Delgado/metabolismo , Intestino Delgado/citologia , Camundongos , Camundongos Endogâmicos C57BL , Transcriptoma/genética , Análise de Célula Única
3.
Cell Host Microbe ; 32(10): 1725-1743.e7, 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39243761

RESUMO

The cytokine tumor necrosis factor (TNF) plays important roles in limiting infection but is also linked to sepsis. The mechanisms underlying these paradoxical roles are unclear. Here, we show that TNF limits the antimicrobial activity of Paneth cells (PCs), causing bacterial translocation from the gut to various organs. This TNF-induced lethality does not occur in mice with a PC-specific deletion in the TNF receptor, P55. In PCs, TNF stimulates the IFN pathway and ablates the steady-state unfolded protein response (UPR), effects not observed in mice lacking P55 or IFNAR1. TNF triggers the transcriptional downregulation of IRE1 key genes Ern1 and Ern2, which are key mediators of the UPR. This UPR deficiency causes a significant reduction in antimicrobial peptide production and PC antimicrobial activity, causing bacterial translocation to organs and subsequent polymicrobial sepsis, organ failure, and death. This study highlights the roles of PCs in bacterial control and therapeutic targets for sepsis.


Assuntos
Translocação Bacteriana , Celulas de Paneth , Sepse , Transdução de Sinais , Fator de Necrose Tumoral alfa , Animais , Celulas de Paneth/metabolismo , Sepse/microbiologia , Camundongos , Fator de Necrose Tumoral alfa/metabolismo , Resposta a Proteínas não Dobradas , Camundongos Endogâmicos C57BL , Camundongos Knockout , Endorribonucleases/metabolismo , Endorribonucleases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Peptídeos Antimicrobianos/metabolismo
4.
Am J Physiol Cell Physiol ; 327(3): C817-C829, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39099425

RESUMO

Paneth cells at the bottom of small intestinal crypts secrete antimicrobial peptides, enzymes, and growth factors and contribute to pathogen clearance and maintenance of the stem cell niche. Loss of Paneth cells and their dysfunction occur commonly in various pathologies, but the mechanism underlying the control of Paneth cell function remains largely unknown. Here, we identified microRNA-195 (miR-195) as a repressor of Paneth cell development and activity by altering SOX9 translation via interaction with RNA-binding protein HuR. Tissue-specific transgenic expression of miR-195 (miR195-Tg) in the intestinal epithelium decreased the levels of mucosal SOX9 and reduced the numbers of lysozyme-positive (Paneth) cells in mice. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restored Paneth cell development ex vivo. miR-195 did not bind to Sox9 mRNA but it directly interacted with HuR and prevented HuR binding to Sox9 mRNA, thus inhibiting SOX9 translation. Intestinal mucosa from mice that harbored both Sox9 transgene and ablation of the HuR locus exhibited lower levels of SOX9 protein and Paneth cell numbers than those observed in miR-195-Tg mice. Inhibition of miR-195 activity by its specific antagomir improved Paneth cell function in HuR-deficient intestinal organoids. These results indicate that interaction of miR-195 with HuR regulates Paneth cell function by altering SOX9 translation in the small intestinal epithelium.NEW & NOTEWORTHY Our results indicate that intestinal epithelial tissue-specific transgenic miR-195 expression decreases the levels of SOX9 expression, along with reduced numbers of Paneth cells. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restores Paneth cell development ex vivo. miR-195 inhibits SOX9 translation by preventing binding of HuR to Sox9 mRNA. These findings suggest that interaction between miR-195 and HuR controls Paneth cell function via SOX9 in the intestinal epithelium.


Assuntos
Proteína Semelhante a ELAV 1 , Mucosa Intestinal , MicroRNAs , Celulas de Paneth , Fatores de Transcrição SOX9 , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Celulas de Paneth/metabolismo , Fatores de Transcrição SOX9/metabolismo , Fatores de Transcrição SOX9/genética , Mucosa Intestinal/metabolismo , Camundongos , Proteína Semelhante a ELAV 1/metabolismo , Proteína Semelhante a ELAV 1/genética , Camundongos Transgênicos , Humanos , Organoides/metabolismo , Biossíntese de Proteínas , Camundongos Endogâmicos C57BL
5.
Cancer Res ; 84(20): 3324-3326, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39186614

RESUMO

The origins of colorectal cancer have long been a subject of intense debate. Early observations noted cancer formation in the human gut slightly above the base of crypts, the structural and functional units of the regenerative compartment of the intestinal epithelium. This suggested that the cells of origin for colorectal cancer reside close to the crypt-villus junction, where more differentiated cells are located. However, the specific induction of early cancer-initiating mutations within differentiated cells failed to initiate cancer. The subsequent identification of long-lived Lgr5+ intestinal stem cells and investigations into their role in cancer development further shifted the earlier views, leading to the widely accepted theory that colorectal cancer arises from stem cells and progenitors located at the base of crypts. A recent study published in Nature Genetics by Mathijs P. Verhagen and colleagues challenges this paradigm, providing compelling evidence that differentiated nonstem cell lineages, particularly Paneth cells, can serve as a source of intestinal tumorigenesis, especially in the context of inflammation and the consumption of a Western-style diet. This work significantly advances our understanding of the colorectal cancer initiation process and provides a new paradigm that may explain the increasingly higher incidence of colorectal cancer in younger people.


Assuntos
Neoplasias Colorretais , Inflamação , Celulas de Paneth , Celulas de Paneth/patologia , Celulas de Paneth/metabolismo , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Animais , Inflamação/patologia , Transformação Celular Neoplásica/patologia , Transformação Celular Neoplásica/metabolismo , Mucosa Intestinal/patologia , Células-Tronco/patologia , Células-Tronco/metabolismo , Diferenciação Celular
6.
Dig Dis Sci ; 69(10): 3932-3941, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39110367

RESUMO

BACKGROUND: Paneth cells play multiple roles in maintaining intestinal homeostasis. However, the clinical role of Paneth cell metaplasia (PCM) in ulcerative colitis (UC) remains unclear. We aimed to investigate the relationship between PCM and relapse in patients with UC and compare the usefulness of PCM with other histological indexes, including mucin depletion (MD) and basal plasmacytosis (BP). METHODS: Patients with UC in clinical remission (CR) who underwent colonoscopy to confirm a Mayo endoscopic subscore (MES) ≦1 with biopsies from the distal colon were enrolled into this retrospective cohort study. Biopsy samples were evaluated for histological findings of PCM, MD, and BP. Clinical relapse was defined as partial Mayo score ≧3 or medication escalation. Multivariate analysis was performed to determine independent predictors of relapse among the three histological findings, MES, and patient background, and relapse prediction models were generated. RESULTS: Eighty-three patients were enrolled in this study (MES 0, n = 47; MES 1, n = 36). The number of PCM cases was significantly higher in patients with prolonged CR than that in those with relapse (p = 0.01). Multivariate analysis showed that the absence of PCM and MD were related to relapse in all the patients. In patients with MES 1, the absence of PCM was the only risk factor significantly and independently associated with relapse (hazard ratio, 4.51 [1.15-17.7]; p = 0.03). CONCLUSION: The absence of PCM was a histological risk factor for relapse in patients with MES 1, implying a protective role for PCM in remission and a new index for mucosal healing.


Assuntos
Colite Ulcerativa , Colonoscopia , Mucosa Intestinal , Metaplasia , Celulas de Paneth , Recidiva , Humanos , Masculino , Feminino , Colite Ulcerativa/patologia , Estudos Retrospectivos , Adulto , Metaplasia/patologia , Celulas de Paneth/patologia , Pessoa de Meia-Idade , Mucosa Intestinal/patologia , Mucosa Intestinal/diagnóstico por imagem , Biópsia , Idoso , Fatores de Risco
7.
Tissue Cell ; 89: 102466, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38986346

RESUMO

The gut microbiota is responsible for several metabolic functions, producing various metabolites with numerous roles for the host. The gut microbiota plays a key role in constructing the microvascular network in the intestinal villus, depending on the Paneth cells, strategically positioned to coordinate the development of both the microbiota and the microvasculature. The gut microbiota secretes several molecules and chemokines involved in the induction of the secretion of pro-angiogenic factors.


Assuntos
Microbioma Gastrointestinal , Neovascularização Fisiológica , Microbioma Gastrointestinal/fisiologia , Humanos , Animais , Intestinos/microbiologia , Intestinos/irrigação sanguínea , Mucosa Intestinal/microbiologia , Mucosa Intestinal/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/microbiologia , Neovascularização Patológica/patologia , Celulas de Paneth/metabolismo , Angiogênese
8.
Gut Microbes ; 16(1): 2379624, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39042424

RESUMO

Symbiosis between the host and intestinal microbial communities is essential for human health. Disruption in this symbiosis is linked to gastrointestinal diseases, including inflammatory bowel diseases, as well as extra-gastrointestinal diseases. Unbalanced gut microbiome or gut dysbiosis contributes in multiple ways to disease frequency, severity and progression. Microbiome taxonomic profiling and metabolomics approaches greatly improved our understanding of gut dysbiosis features; however, the precise mechanisms involved in gut dysbiosis establishment still need to be clarified. The aim of this review is to present new actors and mechanisms underlying gut dysbiosis formation following parasitic infection or in a context of altered Paneth cells, revealing the existence of a critical crosstalk between Paneth and tuft cells to control microbiome composition.


Assuntos
Disbiose , Microbioma Gastrointestinal , Celulas de Paneth , Disbiose/microbiologia , Humanos , Animais , Celulas de Paneth/metabolismo , Simbiose , Bactérias/classificação , Bactérias/metabolismo , Bactérias/genética , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/metabolismo , Células em Tufo
9.
Nutrients ; 16(14)2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-39064679

RESUMO

The activation of the vitamin D receptor (VDR) in the ileum has been shown to regulate Paneth cell-specific defensins, a large family of antimicrobial peptides; hence, this may serve as a potential mechanism to maintain intestinal homeostasis. Previously, we have demonstrated that a combination of vitamin D3 (VD) and fructooligosaccharides (FOSs) upregulates colonic Vdr in mice. Here, we aim to examine the effect of VD, alone or in combination with FOSs, on intestinal barrier integrity and the secretion of antimicrobial peptides, as well as the gut microbial community. Male and female C57BL/6J mice at 6 weeks old were randomized into three groups to receive the following dietary regimens (n = 10/sex/group) for 8 weeks: (1) standard AIN-93G control diet (CTR), (2) CTR + 5000 IU vitamin D3 (VD), and (3) VD + 5% fructooligosaccharides (VF). VD and VF differentially regulated the mRNA expressions of tight junction proteins in the colon and ileum. VF suppressed the upregulation of colonic ZO-1 and occludin, which was induced by VD supplementation alone. In the ileum, occludin but not ZO-1 was upregulated 20-fold in the VF-treated mice. While VD did not alter the mRNA expressions of Vdr and defensins in the ileum, these targets were downregulated by VF. Microbial analysis further reveals a shift of microbial beta diversity and a reduction in Romboutsia ilealis, a pathobiont, in VF-treated mice. Though the implications of these phenotypical and microbial changes remain to be determined, the administration of FOSs in the presence of VD may serve as an effective dietary intervention for maintaining intestinal homeostasis.


Assuntos
Colecalciferol , Defensinas , Suplementos Nutricionais , Microbioma Gastrointestinal , Oligossacarídeos , Animais , Feminino , Masculino , Camundongos , Colecalciferol/farmacologia , Colo/metabolismo , Colo/efeitos dos fármacos , Defensinas/metabolismo , Defensinas/genética , Regulação para Baixo/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Íleo/metabolismo , Íleo/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Ocludina/metabolismo , Ocludina/genética , Oligossacarídeos/farmacologia , Oligossacarídeos/administração & dosagem , Celulas de Paneth/metabolismo , Celulas de Paneth/efeitos dos fármacos , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/genética , Proteína da Zônula de Oclusão-1/metabolismo , Proteína da Zônula de Oclusão-1/genética
10.
Sci Rep ; 14(1): 12879, 2024 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-38839896

RESUMO

Paneth cells (PCs), a subset of intestinal epithelial cells (IECs) found at the base of small intestinal crypts, play an essential role in maintaining intestinal homeostasis. Altered PCs function is associated with diverse intestinal pathologies, including ileal Crohn's disease (CD). CD patients with ileal involvement have been previously demonstrated to display impairment in PCs and decreased levels of anti-microbial peptides. Although the immunosuppressive drug Azathioprine (AZA) is widely used in CD therapy, the impact of AZA on IEC differentiation remains largely elusive. In the present study, we hypothesized that the orally administered drug AZA also exerts its effect through modulation of the intestinal epithelium and specifically via modulation of PC function. AZA-treated CD patients exhibited an ileal upregulation of AMPs on both mRNA and protein levels compared to non-AZA treated patients. Upon in vitro AZA stimulation, intestinal epithelial cell line MODE-K exhibited heightened expression levels of PC marker in concert with diminished cell proliferation but boosted mitochondrial OXPHOS activity. Moreover, differentiation of IECs, including PCs differentiation, was boosted in AZA-treated murine small intestinal organoids and was associated with decreased D-glucose consumption and decreased growth rates. Of note, AZA treatment strongly decreased Lgr5 mRNA expression as well as Ki67 positive cells. Further, AZA restored dysregulated PCs associated with mitochondrial dysfunction. AZA-dependent inhibition of IEC proliferation is accompanied by boosted mitochondria function and IEC differentiation into PC.


Assuntos
Azatioprina , Diferenciação Celular , Doença de Crohn , Mucosa Intestinal , Celulas de Paneth , Doença de Crohn/tratamento farmacológico , Doença de Crohn/patologia , Doença de Crohn/metabolismo , Azatioprina/farmacologia , Celulas de Paneth/metabolismo , Celulas de Paneth/efeitos dos fármacos , Celulas de Paneth/patologia , Humanos , Diferenciação Celular/efeitos dos fármacos , Animais , Camundongos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Feminino , Masculino , Íleo/efeitos dos fármacos , Íleo/metabolismo , Íleo/patologia , Adulto , Organoides/efeitos dos fármacos , Organoides/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Proliferação de Células/efeitos dos fármacos , Pessoa de Meia-Idade , Linhagem Celular , Índice de Gravidade de Doença
11.
Nat Genet ; 56(7): 1456-1467, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38902475

RESUMO

According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, has been shown to suppress intestinal stemness. Here, we used Paneth cells as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation in mice. Upon inflammation, Paneth cell-specific Apc mutations led to intestinal tumors reminiscent not only of those arising in patients with inflammatory bowel disease, but also of a larger fraction of human sporadic colon cancers. The latter is possibly because of the inflammatory consequences of western-style dietary habits, a major colon cancer risk factor. Machine learning methods designed to predict the cell-of-origin of cancer from patient-derived tumor samples confirmed that, in a substantial fraction of sporadic cases, the origins of colon cancer reside in secretory lineages and not in stem cells.


Assuntos
Carcinogênese , Linhagem da Célula , Neoplasias do Colo , Inflamação , Celulas de Paneth , Animais , Camundongos , Linhagem da Célula/genética , Celulas de Paneth/patologia , Humanos , Inflamação/genética , Inflamação/patologia , Carcinogênese/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Mutação , Células-Tronco/patologia , Diferenciação Celular/genética , Transformação Celular Neoplásica/genética , Proteína da Polipose Adenomatosa do Colo/genética , Camundongos Endogâmicos C57BL , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia
12.
Nat Commun ; 15(1): 3080, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38594251

RESUMO

Epithelial barrier dysfunction and crypt destruction are hallmarks of inflammatory bowel disease (IBD). Intestinal stem cells (ISCs) residing in the crypts play a crucial role in the continuous self-renewal and rapid recovery of intestinal epithelial cells (IECs). However, how ISCs are dysregulated in IBD remains poorly understood. Here, we observe reduced DHX9 protein levels in IBD patients, and mice with conditional DHX9 depletion in the intestinal epithelium (Dhx9ΔIEC) exhibit an increased susceptibility to experimental colitis. Notably, Dhx9ΔIEC mice display a significant reduction in the numbers of ISCs and Paneth cells. Further investigation using ISC-specific or Paneth cell-specific Dhx9-deficient mice demonstrates the involvement of ISC-expressed DHX9 in maintaining epithelial homeostasis. Mechanistically, DHX9 deficiency leads to abnormal R-loop accumulation, resulting in genomic instability and the cGAS-STING-mediated inflammatory response, which together impair ISC function and contribute to the pathogenesis of IBD. Collectively, our findings highlight R-loop-mediated genomic instability in ISCs as a risk factor in IBD.


Assuntos
Doenças Inflamatórias Intestinais , Estruturas R-Loop , Animais , Humanos , Camundongos , RNA Helicases DEAD-box/metabolismo , Células Epiteliais/metabolismo , Homeostase , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Proteínas de Neoplasias/metabolismo , Celulas de Paneth/metabolismo , Células-Tronco/metabolismo
13.
Neurogastroenterol Motil ; 36(5): e14780, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38462652

RESUMO

BACKGROUND: Different studies have shown the key role of endoplasmic reticulum (ER) stress in autoimmune and chronic inflammatory disorders, as well as in neurodegenerative diseases. ER stress leads to the formation of misfolded proteins which affect the secretion of different cell types that are crucial for the intestinal homeostasis. PURPOSE: In this review, we discuss the role of ER stress and its involvement in the development of inflammatory bowel diseases, chronic conditions that can cause severe damage of the gastrointestinal tract, focusing on the alteration of Paneth cells and goblet cells (the principal secretory phenotypes of the intestinal epithelial cells). ER stress is also discussed in the context of neurodegenerative diseases, in which protein misfolding represents the signature mechanism. ER stress in the bowel and consequent accumulation of misfolded proteins might represent a bridge between bowel inflammation and neurodegeneration along the gut-to-brain axis, affecting intestinal epithelial homeostasis and the equilibrium of the commensal microbiota. Targeting intestinal ER stress could foster future studies for designing new biomarkers and new therapeutic approaches for neurodegenerative disorders.


Assuntos
Estresse do Retículo Endoplasmático , Doenças Neurodegenerativas , Estresse do Retículo Endoplasmático/fisiologia , Humanos , Doenças Neurodegenerativas/metabolismo , Animais , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Celulas de Paneth/metabolismo , Inflamação/metabolismo
14.
Inflamm Bowel Dis ; 30(9): 1454-1466, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-38300738

RESUMO

BACKGROUND: Anti-Cluster of differentiation (CD)-40-induced colitis, driven by innate inflammatory responses in the intestine, is a potent animal model exhibiting IBD pathophysiology including diarrhea. However, the ion transport basis of diarrhea and some key mucosal pathways (Paneth cells, stem cell niche, and mechanosensory) in this model have not been investigated. METHODS: Mucosal scrapings and intestinal tissue from control and CD40 antibody (150 µg) treated Rag2-/- mice were examined for gut inflammation, Paneth cell numbers, expression of key transporters, tight/adherens junction proteins, stem cell niche, and mechanosensory pathway via hematoxylin and eosin staining, quantitative polymerase chain reaction, and western blotting. RESULTS: Compared with control, anti-CD40 antibody treatment resulted in a significant loss of body weight (P < .05) and diarrhea at day 3 postinjection. Distal colonic tissues of anti-CD40 mice exhibited increased inflammatory infiltrates, higher claudin-2 expression, and appearance of Paneth cell-like structures indicative of Paneth cell metaplasia. Significantly reduced expression (P < .005) of downregulated in adenoma (key Cl- transporter), P-glycoprotein/multidrug resistantance-1 (MDR1, xenobiotic transporter), and adherens junction protein E-cadherin (~2-fold P < .05) was also observed in the colon of anti-CD40 colitis mice. Interestingly, there were also marked alterations in the stem cell markers and upregulation of the mechanosensory YAP-TAZ pathway, suggesting the activation of alternate regeneration pathway post-tissue injury in this model. CONCLUSION: Our data demonstrate that the anti-CD40 colitis model shows key features of IBD observed in the human disease, hence making it a suitable model to investigate the pathophysiology of ulcerative colitis (UC).


Our studies demonstrate the ion transport basis of diarrhea, downregulation of MDR1 and E-cadherin, Paneth cell metaplasia, and induction of claudin-2 and mechanosensory pathway in anti-CD40 colitis (innate immune-based model of IBD), similar to the human disease.


Assuntos
Colite , Diarreia , Modelos Animais de Doenças , Mucosa Intestinal , Metaplasia , Camundongos Knockout , Celulas de Paneth , Animais , Camundongos , Celulas de Paneth/metabolismo , Celulas de Paneth/patologia , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Metaplasia/metabolismo , Metaplasia/patologia , Diarreia/metabolismo , Diarreia/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Antígenos CD40/metabolismo , Regulação para Cima , Camundongos Endogâmicos C57BL , Mecanotransdução Celular
15.
J Vet Med Sci ; 86(3): 277-284, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38267031

RESUMO

The mechanism by which the neonicotinoid pesticide clothianidin (CLO) disrupts the intestinal microbiota of experimental animals is unknown. We focused on α-defensins, which are regulators of the intestinal microbiota. Subchronic exposure to CLO induced dysbiosis and reduced short-chain fatty acid-producing bacteria in the intestinal microbiota of mice. Levels of cryptdin-1 (Crp1, a major α-defensin in mice) in feces and cecal contents were lower in the CLO-exposed groups than in control. In Crp1 immunostaining, Paneth cells in the jejunum and ileum of the no-observed-adverse-effect-level CLO-exposed group showed a stronger positive signal than control, likely due to the suppression of Crp1 release. Our results showed that CLO exposure suppresses α-defensin secretion from Paneth cells as part of the mechanism underlying CLO-induced dysbiosis.


Assuntos
Microbioma Gastrointestinal , Guanidinas , Praguicidas , Doenças dos Roedores , Tiazóis , alfa-Defensinas , Camundongos , Animais , Praguicidas/toxicidade , Disbiose/induzido quimicamente , Disbiose/microbiologia , Disbiose/veterinária , Neonicotinoides/toxicidade , Celulas de Paneth/microbiologia
16.
Clin Res Hepatol Gastroenterol ; 48(1): 102259, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38070827

RESUMO

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.


Assuntos
Fígado Gorduroso , Hipertensão Portal , Humanos , Celulas de Paneth/metabolismo , Hipertensão Portal/complicações , Cirrose Hepática/complicações , Fígado Gorduroso/complicações , Obesidade/complicações , Obesidade/metabolismo
17.
Nat Commun ; 14(1): 7963, 2023 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-38042840

RESUMO

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.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Celulas de Paneth , Animais , Camundongos , Interleucina-9/genética , Imunidade Inata , Interleucina-33/genética , Linfócitos , Intestino Delgado , Metaplasia
18.
Sci Adv ; 9(47): eadh9673, 2023 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-38000028

RESUMO

The mammalian intestine is one of the most rapidly self-renewing tissues, driven by stem cells residing at the crypt bottom. Paneth cells form a major element of the niche microenvironment providing various growth factors to orchestrate intestinal stem cell homeostasis, such as Wnt3. Different Wnt ligands can selectively activate ß-catenin-dependent (canonical) or -independent (noncanonical) signaling. Here, we report that the Dishevelled-associated activator of morphogenesis 1 (Daam1) and its paralogue Daam2 asymmetrically regulate canonical and noncanonical Wnt (Wnt/PCP) signaling. Daam1/2 interacts with the Wnt inhibitor RNF43, and Daam1/2 double knockout stimulates canonical Wnt signaling by preventing RNF43-dependent degradation of the Wnt receptor, Frizzled (Fzd). Single-cell RNA sequencing analysis revealed that Paneth cell differentiation is impaired by Daam1/2 depletion because of defective Wnt/PCP signaling. Together, we identified Daam1/2 as an unexpected hub molecule coordinating both canonical and noncanonical Wnt, which is fundamental for specifying an adequate number of Paneth cells.


Assuntos
Celulas de Paneth , Via de Sinalização Wnt , Animais , Intestinos , Diferenciação Celular , Células-Tronco/metabolismo , Mamíferos
19.
Proc Natl Acad Sci U S A ; 120(47): e2312453120, 2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-37956278

RESUMO

To mediate critical host-microbe interactions in the human small intestine, Paneth cells constitutively produce abundant levels of α-defensins and other antimicrobials. We report that the expression profile of these antimicrobials is dramatically askew in human small intestinal organoids (enteroids) as compared to that in paired tissue from which they are derived, with a reduction of α-defensins to nearly undetectable levels. Murine enteroids, however, recapitulate the expression profile of Paneth cell α-defensins seen in tissue. WNT/TCF signaling has been found to be instrumental in the regulation of α-defensins, yet in human enteroids exogenous stimulation of WNT signaling appears insufficient to rescue α-defensin expression. By stark contrast, forkhead box O (FOXO) inhibitor AS1842856 induced the expression of α-defensin mRNA in enteroids by >100,000-fold, restoring DEFA5 and DEFA6 to levels comparable to those found in primary human tissue. These results newly identify FOXO signaling as a pathway of biological and potentially therapeutic relevance for the regulation of human Paneth cell α-defensins in health and disease.


Assuntos
Anti-Infecciosos , alfa-Defensinas , Humanos , Animais , Camundongos , alfa-Defensinas/genética , alfa-Defensinas/farmacologia , alfa-Defensinas/metabolismo , Intestinos , Intestino Delgado/metabolismo , Celulas de Paneth/metabolismo , Anti-Infecciosos/metabolismo , Organoides/metabolismo
20.
Microbiome ; 11(1): 256, 2023 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-37978573

RESUMO

BACKGROUND: Intestinal epithelial cell (IEC) mitochondrial dysfunction involvement in inflammatory bowel diseases (IBD), including Crohn's disease affecting the small intestine, is emerging in recent studies. As the interface between the self and the gut microbiota, IECs serve as hubs of bidirectional cross-talk between host and luminal microbiota. However, the role of mitochondrial-microbiota interaction in the ileum is largely unexplored. Prohibitin 1 (PHB1), a chaperone protein of the inner mitochondrial membrane required for optimal electron transport chain function, is decreased during IBD. We previously demonstrated that mice deficient in PHB1 specifically in IECs (Phb1i∆IEC) exhibited mitochondrial impairment, Paneth cell defects, gut microbiota dysbiosis, and spontaneous inflammation in the ileum (ileitis). Mice deficient in PHB1 in Paneth cells (epithelial secretory cells of the small intestine; Phb1∆PC) also exhibited mitochondrial impairment, Paneth cell defects, and spontaneous ileitis. Here, we determined whether this phenotype is driven by Phb1 deficiency-associated ileal microbiota alterations or direct effects of loss of PHB1 in host IECs. RESULTS: Depletion of gut microbiota by broad-spectrum antibiotic treatment in Phb1∆PC or Phb1i∆IEC mice revealed a necessary role of microbiota to cause ileitis. Using germ-free mice colonized with ileal microbiota from Phb1-deficient mice, we show that this microbiota could not independently induce ileitis without host mitochondrial dysfunction. The luminal microbiota phenotype of Phb1i∆IEC mice included a loss of the short-chain fatty acid butyrate. Supplementation of butyrate in Phb1-deficient mice ameliorated Paneth cell abnormalities and ileitis. Phb1-deficient ileal enteroid models suggest deleterious epithelial-intrinsic responses to ileal microbiota that were protected by butyrate. CONCLUSIONS: These results suggest a mutual and essential reinforcing interplay of gut microbiota and host IEC, including Paneth cell, mitochondrial health in influencing ileitis. Restoration of butyrate is a potential therapeutic option in Crohn's disease patients harboring epithelial cell mitochondrial dysfunction. Video Abstract.


Assuntos
Doença de Crohn , Microbioma Gastrointestinal , Ileíte , Doenças Inflamatórias Intestinais , Humanos , Animais , Camundongos , Ileíte/metabolismo , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Celulas de Paneth , Butiratos/metabolismo , Mitocôndrias/metabolismo , Mucosa Intestinal/metabolismo
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