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1.
Immunity ; 49(6): 1103-1115.e6, 2018 12 18.
Artículo en Inglés | MEDLINE | ID: mdl-30566883

RESUMEN

Retinoic acid (RA), a vitamin A metabolite, regulates transcriptional programs that drive protective or pathogenic immune responses in the intestine, in a manner dependent on RA concentration. Vitamin A is obtained from diet and is metabolized by intestinal epithelial cells (IECs), which operate in intimate association with microbes and immune cells. Here we found that commensal bacteria belonging to class Clostridia modulate RA concentration in the gut by suppressing the expression of retinol dehydrogenase 7 (Rdh7) in IECs. Rdh7 expression and associated RA amounts were lower in the intestinal tissue of conventional mice, as compared to germ-free mice. Deletion of Rdh7 in IECs diminished RA signaling in immune cells, reduced the IL-22-dependent antimicrobial response, and enhanced resistance to colonization by Salmonella Typhimurium. Our findings define a regulatory circuit wherein bacterial regulation of IEC-intrinsic RA synthesis protects microbial communities in the gut from excessive immune activity, achieving a balance that prevents colonization by enteric pathogens.


Asunto(s)
Disbiosis/metabolismo , Células Epiteliales/metabolismo , Interleucinas/metabolismo , Mucosa Intestinal/metabolismo , Tretinoina/metabolismo , Oxidorreductasas de Alcohol/genética , Oxidorreductasas de Alcohol/metabolismo , Animales , Bacterias/clasificación , Bacterias/genética , Disbiosis/microbiología , Células Epiteliales/microbiología , Interacciones Microbiota-Huesped , Mucosa Intestinal/citología , Mucosa Intestinal/microbiología , Linfocitos/metabolismo , Linfocitos/microbiología , Ratones Endogámicos C57BL , Ratones Noqueados , Microbiota/genética , Microbiota/fisiología , ARN Ribosómico 16S/genética , Salmonella typhimurium/genética , Salmonella typhimurium/fisiología , Simbiosis , Interleucina-22
2.
PLoS Pathog ; 16(4): e1008360, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32330185

RESUMEN

Intestinal epithelial cells (IECs) are at the forefront of host-pathogen interactions, coordinating a cascade of immune responses to protect against pathogens. Here we show that IEC-intrinsic vitamin A signaling restricts pathogen invasion early in the infection and subsequently activates immune cells to promote pathogen clearance. Mice blocked for retinoic acid receptor (RAR) signaling selectively in IECs (stopΔIEC) showed higher Salmonella burden in colonic tissues early in the infection that associated with higher luminal and systemic loads of the pathogen at later stages. Higher pathogen burden in stopΔIEC mice correlated with attenuated mucosal interferon gamma (IFNγ) production by underlying immune cells. We found that, at homeostasis, the intestinal epithelium of stopΔIEC mice produced significantly lower amounts of interleukin 18 (IL-18), a potent inducer of IFNγ. Regulation of IL-18 by vitamin A was also observed in a dietary model of vitamin A supplementation. IL-18 reconstitution in stopΔIEC mice restored resistance to Salmonella by promoting epithelial cell shedding to eliminate infected cells and limit pathogen invasion early in infection. Further, IL-18 augmented IFNγ production by underlying immune cells to restrict pathogen burden and systemic spread. Our work uncovers a critical role for vitamin A in coordinating a biphasic immune response to Salmonella infection by regulating IL-18 production by IECs.


Asunto(s)
Microbioma Gastrointestinal , Interleucina-18/metabolismo , Mucosa Intestinal/inmunología , Proteínas Asociadas a Microtúbulos/fisiología , Infecciones por Salmonella/prevención & control , Salmonella typhimurium/inmunología , Vitamina A/metabolismo , Animales , Interacciones Huésped-Patógeno , Interferón gamma/metabolismo , Mucosa Intestinal/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Ácido Retinoico/metabolismo , Infecciones por Salmonella/inmunología , Infecciones por Salmonella/microbiología , Infecciones por Salmonella/patología , Transducción de Señal
4.
Microorganisms ; 10(7)2022 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-35889102

RESUMEN

The use of probiotics such as Lactobacillus and Bifidobacterium spp. as a therapeutic against inflammatory bowel disease (IBD) is of significant interest. Lactobacillus salivarus strain UCC118TM is a commensal that has been shown to possess probiotic properties in vitro and anti-infective properties in vivo. However, the usefulness of UCC118 TM as a therapeutic against colitis remains unclear. This study investigates the probiotic potential of Lactobacillus salivarius, UCC118™ in a mouse model of colitis. DSS-induced colitis was coupled with pre-treatment or post-treatment with UCC118TM by daily oral gavage. In the pre-treatment model of colitis, UCC118TM reduced the severity of the disease in the early stages. Improvement in disease severity was coupled with an upregulation of tissue IL-10 levels and increased expression of macrophage M2 markers. This anti-inflammatory activity of UCC118TM was further confirmed in vitro, using a model of LPS-treated bone marrow-derived macrophages. Taken together, these results suggest that UCC118TM may promote the resolution of inflammation. This was supported in a mouse model of established DSS-induced colitis whereby UCC118TM treatment accelerated recovery, as evidenced by weight, stool, histological markers and the recovery of microbiome-associated dysbiosis with an increased abundance of beneficial commensal species. These results demonstrate the potential of Lactobacillus salivarius UCC118TM as a probiotic-based therapeutic strategy to promote health through the upregulation of anti-inflammatory IL-10 and protect against dysbiosis during IBD.

5.
Nutrients ; 13(12)2021 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-34959809

RESUMEN

Inflammatory bowel disease (IBD) is a chronic inflammatory disease. The disease has a multifactorial aetiology, involving genetic, microbial as well as environmental factors. The disease pathogenesis operates at the host-microbe interface in the gut. The intestinal epithelium plays a central role in IBD disease pathogenesis. Apart from being a physical barrier, the epithelium acts as a node that integrates environmental, dietary, and microbial cues to calibrate host immune response and maintain homeostasis in the gut. IBD patients display microbial dysbiosis in the gut, combined with an increased barrier permeability that contributes to disease pathogenesis. Metabolites produced by microbes in the gut are dynamic indicators of diet, host, and microbial interplay in the gut. Microbial metabolites are actively absorbed or diffused across the intestinal lining to affect the host response in the intestine as well as at systemic sites via the engagement of cognate receptors. In this review, we summarize insights from metabolomics studies, uncovering the dynamic changes in gut metabolite profiles in IBD and their importance as potential diagnostic and prognostic biomarkers of disease. We focus on gut microbial metabolites as key regulators of the intestinal barrier and their role in the pathogenesis of IBD.


Asunto(s)
Disbiosis/microbiología , Microbioma Gastrointestinal/fisiología , Enfermedades Inflamatorias del Intestino/microbiología , Mucosa Intestinal/microbiología , Metabolómica , Biomarcadores/metabolismo , Humanos , Permeabilidad , Pronóstico
6.
Front Cell Infect Microbiol ; 11: 622491, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34350128

RESUMEN

The metabolite-rich environment that is the intestinal lumen contains metabolic by-products deriving from microbial fermentation and host cell metabolism, with resident macrophages being constantly exposed to this metabolic flux. Succinate, lactate and itaconate are three metabolites secreted by primed macrophages due to a fragmented tri-carboxylic acid (TCA) cycle. Additionally, succinate and lactate are known by-products of microbial fermentation. How these metabolites impact biological functioning of resident macrophages particularly in response to bacterial infection remains poorly understood. We have investigated the potential influence of these metabolites on macrophage phagocytosis and clearance of Escherichia coli (E. coli) infection. Treatment of murine bone-marrow-derived macrophages (BMDMs) with succinate reduced numbers of intracellular E. coli early during infection, while lactate-treated BMDMs displayed no difference throughout the course of infection. Treatment of BMDMs with itaconate lead to higher levels of intracellular E. coli early in the infection with bacterial burden subsequently reduced at later time-points compared to untreated macrophages, indicative of enhanced engulfment and killing capabilities of macrophages in response to itaconate. Expression of engulfment mediators MARCKS, RhoB, and CDC42 were reduced or unchanged following succinate or lactate treatment and increased in itaconate-treated macrophages following E. coli infection. Nitric oxide (NO) levels varied while pro- and anti-inflammatory cytokines differed in secretory levels in all metabolite-treated macrophages post-infection with E. coli or in response to lipopolysaccharide (LPS) stimulation. Finally, the basal phenotypic profile of metabolite-treated macrophages was altered according to marker gene expression, describing how fluid macrophage phenotype can be in response to the microenvironment. Collectively, our data suggests that microbe- and host-derived metabolites can drive distinct macrophage functional phenotypes in response to infection, whereby succinate and itaconate regulate phagocytosis and bactericidal mechanisms, limiting the intracellular bacterial niche and impeding the pathogenesis of infection.


Asunto(s)
Infecciones Bacterianas , Escherichia coli , Animales , Lipopolisacáridos , Macrófagos , Ratones , Fagocitosis
7.
Cell Host Microbe ; 19(2): 131-3, 2016 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-26867168

RESUMEN

Alcohol causes microbiota dysbiosis and breaches intestinal integrity, resulting in liver inflammation and ultimately cirrhosis. In this issue of Cell Host & Microbe, Wang et al. (2016) demonstrate that ethanol suppresses the intestinal anti-microbial response. This enables gut bacteria to trespass to the liver and thus exacerbates the disease progression.


Asunto(s)
Disbiosis/microbiología , Intestinos/microbiología , Etanol , Humanos , Hígado , Microbiota
8.
Expert Opin Investig Drugs ; 21(1): 67-81, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22149716

RESUMEN

INTRODUCTION: Extensive studies have gone into understanding the differential role of the innate and adaptive arms of the immune system in the context of various diseases. Receptor-ligand interactions are responsible for mediating cross-talk between the innate and adaptive arms of the immune system, so as to effectively counter the pathogenic challenge. While TLRs remain the best studied innate immune receptor, many other receptor families are now coming to the fore for their role in various pathologies. Research has focused on the discovery of novel agonists and antagonists for these receptors as potential therapeutics. AREAS COVERED: In this review, we present an overview of the recent advances in the discovery of drugs targeting important receptors such as G-protein coupled receptors, TRAIL-R, IL-1ß receptor, PPARs, etc. All these receptors play a critical role in the modulation of the immune response. We focus on the recent paradigms applied for the generation of specific and effective therapeutics for these receptors and their status in clinical trials. EXPERT OPINION: Non-specific activation by antagonist/agonist is a difficult problem to dodge. This demands innovation in ligand designing with the use of strategies such as allosterism and dual-specific ligands. Rigorous preclinical and clinical studies are required in transforming a compound to a therapeutic.


Asunto(s)
Sistema Inmunológico/efectos de los fármacos , Factores Inmunológicos/farmacología , Receptores Inmunológicos , Animales , Ensayos Clínicos como Asunto , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Sistema Inmunológico/metabolismo , Receptores de Superficie Celular/agonistas , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores Inmunológicos/agonistas , Receptores Inmunológicos/antagonistas & inhibidores
11.
Microbes Infect ; 12(11): 809-18, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20538070

RESUMEN

Salmonella, a Gram-negative facultative intracellular pathogen is capable of infecting vast array of hosts. The striking ability of Salmonella to overcome every hurdle encountered in the host proves that they are true survivors. In the host, Salmonella infects various cell types and needs to survive and replicate by countering the defense mechanism of the specific cell. In this review, we will summarize the recent insights into the cell biology of Salmonella infection. Here, we will focus on the findings that deal with the specific mechanism of various cell types to control Salmonella infection. Further, the survival strategies of the pathogen in response to the host immunity will also be discussed in detail. Better understanding of the mechanisms by which Salmonella evade the host defense system and establish pathogenesis will be critical in disease management.


Asunto(s)
Interacciones Huésped-Patógeno , Infecciones por Salmonella/inmunología , Infecciones por Salmonella/microbiología , Salmonella/inmunología , Salmonella/patogenicidad , Humanos , Evasión Inmune , Viabilidad Microbiana
12.
PLoS One ; 5(12): e15466, 2010 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-21151933

RESUMEN

Cationic amino acid transporters (mCAT1 and mCAT2B) regulate the arginine availability in macrophages. How in the infected cell a pathogen can alter the arginine metabolism of the host remains to be understood. We reveal here a novel mechanism by which Salmonella exploit mCAT1 and mCAT2B to acquire host arginine towards its own intracellular growth within antigen presenting cells. We demonstrate that Salmonella infected bone marrow derived macrophages and dendritic cells show enhanced arginine uptake and increased expression of mCAT1 and mCAT2B. We show that the mCAT1 transporter is in close proximity to Salmonella containing vacuole (SCV) specifically by live intracellular Salmonella in order to access the macrophage cytosolic arginine pool. Further, Lysosome associated membrane protein 1, a marker of SCV, also was found to colocalize with mCAT1 in the Salmonella infected cell. The intra vacuolar Salmonella then acquire the host arginine via its own arginine transporter, ArgT for growth. The argT knockout strain was unable to acquire host arginine and was attenuated in growth in both macrophages and in mice model of infection. Together, these data reveal survival strategies by which virulent Salmonella adapt to the harsh conditions prevailing in the infected host cells.


Asunto(s)
Sistemas de Transporte de Aminoácidos Básicos/fisiología , Arginina/química , Salmonella typhimurium/metabolismo , Animales , Arginina/metabolismo , Proteínas Bacterianas/metabolismo , Células Cultivadas , Citosol/metabolismo , Prueba de Complementación Genética , Macrófagos/citología , Ratones , Ratones Endogámicos BALB C , Mycobacterium bovis/metabolismo , Nitritos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Infecciones por Salmonella/metabolismo , Virulencia
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