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1.
Nat Immunol ; 23(2): 251-261, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35102343

RESUMO

Tumor necrosis factor (TNF) drives chronic inflammation and cell death in the intestine, and blocking TNF is a therapeutic approach in inflammatory bowel disease (IBD). Despite this knowledge, the pathways that protect the intestine from TNF are incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3s) protect the intestinal epithelium from TNF-induced cell death. This occurs independent of interleukin-22 (IL-22), and we identify that ILC3s are a dominant source of heparin-binding epidermal growth factor-like growth factor (HB-EGF). ILC3s produce HB-EGF in response to prostaglandin E2 (PGE2) and engagement of the EP2 receptor. Mice lacking ILC3-derived HB-EGF exhibit increased susceptibility to TNF-mediated epithelial cell death and experimental intestinal inflammation. Finally, human ILC3s produce HB-EGF and are reduced from the inflamed intestine. These results define an essential role for ILC3-derived HB-EGF in protecting the intestine from TNF and indicate that disruption of this pathway contributes to IBD.


Assuntos
Fator de Crescimento Semelhante a EGF de Ligação à Heparina/imunologia , Imunidade Inata/imunologia , Inflamação/imunologia , Intestinos/imunologia , Linfócitos/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Células Epiteliais/imunologia , Mucosa Intestinal/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/imunologia
2.
Gut Microbes ; 14(1): 2031696, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35130127

RESUMO

Obesity and type 2 diabetes (T2D) are growing burdens for individuals and the health-care system. Bariatric surgery is an efficient, but drastic treatment to reduce body weight, normalize glucose values, and reduce low-grade inflammation. The gut microbiome, which is in part controlled by intestinal antibodies, such as IgA, is involved in the development of both conditions. Knowledge of the effect of bariatric surgery on systemic and intestinal antibody response is limited. Here, we determined the fecal antibody and gut microbiome response in 40 T2D and non-diabetic (ND) obese individuals that underwent bariatric surgery (N = 40). Body weight, fasting glucose concentrations and inflammatory parameters decreased after bariatric surgery, whereas pro-inflammatory bacterial species such as lipopolysaccharide (LPS), and flagellin increased in the feces. Simultaneously, concentrations of LPS- and flagellin-specific intestinal IgA levels increased with the majority of pro-inflammatory bacteria coated with IgA after surgery. Finally, serum antibodies decreased in both groups, along with a lower inflammatory tone. We conclude that intestinal rearrangement by bariatric surgery leads to expansion of typical pro-inflammatory bacteria, which may be compensated by an improved antibody response. Although further evidence and mechanistic insights are needed, we postulate that this apparent compensatory antibody response might help to reduce systemic inflammation by neutralizing intestinal immunogenic components and thereby enhance intestinal barrier function after bariatric surgery.


Assuntos
Anticorpos Antibacterianos/sangue , Bactérias/imunologia , Diabetes Mellitus Tipo 2/imunologia , Microbioma Gastrointestinal , Intestinos/microbiologia , Obesidade/imunologia , Anticorpos Antibacterianos/imunologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Cirurgia Bariátrica , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/microbiologia , Diabetes Mellitus Tipo 2/cirurgia , Fezes/química , Fezes/microbiologia , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Intestinos/imunologia , Obesidade/sangue , Obesidade/microbiologia , Obesidade/cirurgia
3.
Science ; 375(6583): 859-863, 2022 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-35201883

RESUMO

Group 3 innate lymphoid cells (ILC3s) are innate immune effectors that contribute to host defense. Whether ILC3 functions are stably modified after pathogen encounter is unknown. Here, we assess the impact of a time-restricted enterobacterial challenge to long-term ILC3 activation in mice. We found that intestinal ILC3s persist for months in an activated state after exposure to Citrobacter rodentium. Upon rechallenge, these "trained" ILC3s proliferate, display enhanced interleukin-22 (IL-22) responses, and have a superior capacity to control infection compared with naïve ILC3s. Metabolic changes occur in C. rodentium-exposed ILC3s, but only trained ILC3s have an enhanced proliferative capacity that contributes to increased IL-22 production. Accordingly, a limited encounter with a pathogen can promote durable phenotypic and functional changes in intestinal ILC3s that contribute to long-term mucosal defense.


Assuntos
Citrobacter rodentium/imunologia , Infecções por Enterobacteriaceae/imunologia , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Ativação Linfocitária , Linfócitos/imunologia , Imunidade Adaptativa , Animais , Proliferação de Células , Feminino , Imunidade Inata , Memória Imunológica , Interleucinas/metabolismo , Intestinos/imunologia , Listeria monocytogenes , Listeriose/imunologia , Linfócitos/metabolismo , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , Consumo de Oxigênio , RNA-Seq , Reinfecção/imunologia
4.
Sci Rep ; 12(1): 452, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013585

RESUMO

Macrophages are a heterogeneous population of mononuclear phagocytes abundantly distributed throughout the intestinal compartments that adapt to microenvironmental specific cues. In adult mice, the majority of intestinal macrophages exhibit a mature phenotype and are derived from blood monocytes. In the steady-state, replenishment of these cells is reduced in the absence of the chemokine receptor CCR2. Within the intestine of mice with colitis, there is a marked increase in the accumulation of immature macrophages that demonstrate an inflammatory phenotype. Here, we asked whether CCR2 is necessary for the development of colitis in mice lacking the receptor for IL10. We compared the development of intestinal inflammation in mice lacking IL10RA or both IL10RA and CCR2. The absence of CCR2 interfered with the accumulation of immature macrophages in IL10R-deficient mice, including a novel population of rounded submucosal Iba1+ cells, and reduced the severity of colitis in these mice. In contrast, the absence of CCR2 did not reduce the augmented inflammatory gene expression observed in mature intestinal macrophages isolated from mice lacking IL10RA. These data suggest that both newly recruited CCR2-dependent immature macrophages and CCR2-independent residual mature macrophages contribute to the development of intestinal inflammation observed in IL10R-deficient mice.


Assuntos
Colite/imunologia , Subunidade alfa de Receptor de Interleucina-10/imunologia , Intestinos/imunologia , Monócitos/imunologia , Receptores CCR2/imunologia , Animais , Colite/genética , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-10/genética , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Knockout , Receptores CCR2/genética
5.
J Gen Virol ; 103(1)2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35077345

RESUMO

Norovirus is the leading cause of epidemic and endemic acute gastroenteritis worldwide and the most frequent cause of foodborne illness in the United States. There is no specific treatment for norovirus infections and therapeutic interventions are based on alleviating symptoms and limiting viral transmission. The immune response to norovirus is not completely understood and mechanistic studies have been hindered by lack of a robust cell culture system. In recent years, the human intestinal enteroid/human intestinal organoid system (HIE/HIO) has enabled successful human norovirus replication. Cells derived from HIE have also successfully been subjected to genetic manipulation using viral vectors as well as CRISPR/Cas9 technology, thereby allowing studies to identify antiviral signaling pathways important in controlling norovirus infection. RNA sequencing using HIE cells has been used to investigate the transcriptional landscape during norovirus infection and to identify antiviral genes important in infection. Other cell culture platforms such as the microfluidics-based gut-on-chip technology in combination with the HIE/HIO system also have the potential to address fundamental questions on innate immunity to human norovirus. In this review, we highlight the recent advances in understanding the innate immune response to human norovirus infections in the HIE system, including the application of advanced molecular technologies that have become available in recent years such as the CRISPR/Cas9 and RNA sequencing, as well as the potential application of single cell transcriptomics, viral proteomics, and gut-on-a-chip technology to further elucidate innate immunity to norovirus.


Assuntos
Infecções por Caliciviridae/imunologia , Gastroenterite/imunologia , Intestinos/virologia , Organoides/imunologia , Gastroenterite/virologia , Humanos , Imunidade Inata , Intestinos/imunologia , Modelos Biológicos , Norovirus/patogenicidade , Norovirus/fisiologia , Organoides/virologia , Análise de Sequência de RNA , Replicação Viral
6.
Nutrients ; 14(2)2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35057454

RESUMO

It is well established that the diet, among other external influencing factors, also known as the exposome, has a key role in the prevention and management of different diseases [...].


Assuntos
Dieta Mediterrânea , Expossoma , Microbioma Gastrointestinal/fisiologia , Sistema Imunitário/fisiologia , Humanos , Intestinos/imunologia , Compostos Fitoquímicos/administração & dosagem , Polifenóis/farmacologia
7.
Elife ; 112022 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-35098923

RESUMO

N6-methyladenosine (m6A) is an abundant mRNA modification and affects many biological processes. However, how m6A levels are regulated during physiological or pathological processes such as virus infections, and the in vivo function of m6A in the intestinal immune defense against virus infections are largely unknown. Here, we uncover a novel antiviral function of m6A modification during rotavirus (RV) infection in small bowel intestinal epithelial cells (IECs). We found that rotavirus infection induced global m6A modifications on mRNA transcripts by down-regulating the m6a eraser ALKBH5. Mice lacking the m6A writer enzymes METTL3 in IECs (Mettl3ΔIEC) were resistant to RV infection and showed increased expression of interferons (IFNs) and IFN-stimulated genes (ISGs). Using RNA-sequencing and m6A RNA immuno-precipitation (RIP)-sequencing, we identified IRF7, a master regulator of IFN responses, as one of the primary m6A targets during virus infection. In the absence of METTL3, IECs showed increased Irf7 mRNA stability and enhanced type I and III IFN expression. Deficiency in IRF7 attenuated the elevated expression of IFNs and ISGs and restored susceptibility to RV infection in Mettl3ΔIEC mice. Moreover, the global m6A modification on mRNA transcripts declined with age in mice, with a significant drop from 2 weeks to 3 weeks post birth, which likely has broad implications for the development of intestinal immune system against enteric viruses early in life. Collectively, we demonstrated a novel host m6A-IRF7-IFN antiviral signaling cascade that restricts rotavirus infection in vivo.


Assuntos
Intestinos/imunologia , Infecções por Rotavirus/imunologia , Rotavirus/classificação , Homólogo AlkB 5 da RNA Desmetilase/genética , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Animais , Linhagem Celular , Testes Genéticos , Humanos , Fator Regulador 7 de Interferon/genética , Fator Regulador 7 de Interferon/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Carga Viral
8.
Sci Rep ; 12(1): 152, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34996983

RESUMO

The gut microbiota (GM) exerts a strong influence over the host immune system and dysbiosis of this microbial community can affect the clinical phenotype in chronic inflammatory conditions. To explore the role of the GM in lupus nephritis, we colonized NZM2410 mice with Segmented Filamentous Bacteria (SFB). Gut colonization with SFB was associated with worsening glomerulonephritis, glomerular and tubular immune complex deposition and interstitial inflammation compared to NZM2410 mice free of SFB. With SFB colonization mice experienced an increase in small intestinal lamina propria Th17 cells and group 3 innate lymphoid cells (ILC3s). However, although serum IL-17A expression was elevated in these mice, Th17 cells and ILC3s were not detected in the inflammatory infiltrate in the kidney. In contrast, serum and kidney tissue expression of the macrophage chemoattractants MCP-1 and CXCL1 were significantly elevated in SFB colonized mice. Furthermore, kidney infiltrating F4/80+CD206+M2-like macrophages were significantly increased in these mice. Evidence of increased gut permeability or "leakiness" was also detected in SFB colonized mice. Finally, the intestinal microbiome of SFB colonized mice at 15 and 30 weeks of age exhibited dysbiosis when compared to uncolonized mice at the same time points. Both microbial relative abundance as well as biodiversity of colonized mice was found to be altered. Collectively, SFB gut colonization in the NZM2410 mouse exacerbates kidney disease, promotes kidney M2-like macrophage infiltration and overall intestinal microbiota dysbiosis.


Assuntos
Bactérias/crescimento & desenvolvimento , Microbioma Gastrointestinal , Intestinos/microbiologia , Rim/imunologia , Nefrite Lúpica/microbiologia , Macrófagos/imunologia , Animais , Bactérias/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Disbiose , Feminino , Imunidade Inata , Mediadores da Inflamação/metabolismo , Intestinos/imunologia , Intestinos/metabolismo , Intestinos/patologia , Rim/metabolismo , Rim/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Fenótipo , Células Th17/imunologia , Células Th17/metabolismo
9.
Scand J Immunol ; 95(2): e13139, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34978077

RESUMO

The gastrointestinal tract is colonized by trillions of commensal microorganisms that collectively form the microbiome and make essential contributions to organism homeostasis. The intestinal immune system must tolerate these beneficial commensals, whilst preventing pathogenic organisms from systemic spread. Humoral immunity plays a key role in this process, with large quantities of immunoglobulin (Ig)A secreted into the lumen on a daily basis, regulating the microbiome and preventing bacteria from encroaching on the epithelium. However, there is an increasing appreciation of the role of IgG antibodies in intestinal immunity, including beneficial effects in neonatal immune development, pathogen and tumour resistance, but also of pathological effects in driving chronic inflammation in inflammatory bowel disease (IBD). These antibody isotypes differ in effector function, with IgG exhibiting more proinflammatory capabilities compared with IgA. Therefore, the process that leads to the generation of different antibody isotypes, class-switch recombination (CSR), requires careful regulation and is orchestrated by the immunological cues generated by the prevalent local challenge. In general, an initiating signal such as CD40 ligation on B cells leads to the induction of activation-induced cytidine deaminase (AID), but a second cytokine-mediated signal determines which Ig heavy chain is expressed. Whilst the cytokines driving intestinal IgA responses are well-studied, there is less clarity on how IgG responses are generated in the intestine, and how these cues might become dysfunctional in IBD. Here, we review the key mechanisms regulating class switching to IgA vs IgG in the intestine, processes that could be therapeutically manipulated in infection and IBD.


Assuntos
Imunoglobulina A/imunologia , Switching de Imunoglobulina/imunologia , Imunoglobulina G/imunologia , Intestinos/imunologia , Linfócitos B/imunologia , Células Cultivadas , Citidina Desaminase/metabolismo , Citocinas/metabolismo , Microbioma Gastrointestinal/imunologia , Humanos , Imunidade Humoral/imunologia
10.
Mucosal Immunol ; 15(1): 143-153, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34504311

RESUMO

Mechanisms linking ingested pollutants to increased incidence of allergy are poorly understood. We report that mice exposed to low doses of cadmium develop higher IgE responses following oral allergen sensitization and more severe allergic symptoms upon allergen challenge. The environmentally relevant doses of this pollutant also induced oxidative/inflammatory responses in the gut of SPF, but not germ-free mice. Interestingly, the increased IgE responses correlated with stimulation of the vitamin D3-metabolizing enzymes CYP27B1 and CYP24A1 in the gut and increased luminal levels of oxidized vitamin D3 metabolites that are not ligands of the vitamin D receptor. Inhibition of CYP27B1 and CYP24A1 via oral administration of pharmacological inhibitors reduced IgE responses induced in mice orally exposed to cadmium. Our findings identify local alteration of vitamin D signaling as a new mechanism for induction of IgE responses by environmental pollutants. They also identify vitamin D3-metabolizing enzymes as therapeutic targets for the treatment of allergy.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Cádmio/metabolismo , Poluentes Ambientais/metabolismo , Hipersensibilidade/imunologia , Intestinos/imunologia , Vitamina D3 24-Hidroxilase/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/antagonistas & inibidores , Alérgenos/imunologia , Animais , Modelos Animais de Doenças , Humanos , Imunização , Imunoglobulina E/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Transdução de Sinais , Vitamina D/metabolismo , Vitamina D3 24-Hidroxilase/antagonistas & inibidores
11.
Immunity ; 55(1): 145-158.e7, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-34879222

RESUMO

Children with autism spectrum disorders often display dysregulated immune responses and related gastrointestinal symptoms. However, the underlying mechanisms leading to the development of both phenotypes have not been elucidated. Here, we show that mouse offspring exhibiting autism-like phenotypes due to prenatal exposure to maternal inflammation were more susceptible to developing intestinal inflammation following challenges later in life. In contrast to its prenatal role in neurodevelopmental phenotypes, interleukin-17A (IL-17A) generated immune-primed phenotypes in offspring through changes in the maternal gut microbiota that led to postnatal alterations in the chromatin landscape of naive CD4+ T cells. The transfer of stool samples from pregnant mice with enhanced IL-17A responses into germ-free dams produced immune-primed phenotypes in offspring. Our study provides mechanistic insights into why children exposed to heightened inflammation in the womb might have an increased risk of developing inflammatory diseases in addition to neurodevelopmental disorders.


Assuntos
Transtorno do Espectro Autista/imunologia , Linfócitos T CD4-Positivos/imunologia , Cromatina/metabolismo , Microbioma Gastrointestinal/imunologia , Inflamação/imunologia , Interleucina-17/metabolismo , Intestinos/imunologia , Transtornos do Neurodesenvolvimento/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Transtorno do Espectro Autista/microbiologia , Criança , Modelos Animais de Doenças , Transplante de Microbiota Fecal , Feminino , Humanos , Imunização , Inflamação/microbiologia , Camundongos , Transtornos do Neurodesenvolvimento/microbiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/microbiologia
12.
Fish Shellfish Immunol ; 120: 82-91, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34780976

RESUMO

Mitogen-activated protein kinase kinase kinase 4 (MAP3K4) is a multifunctional mediator of the conserved MAPK signaling pathway that plays essential roles in the regulation of immune responses in mammals. However, the function of teleost MAP3K4s in innate immunity, especially in the intestinal immune system, is still poorly understood. In the current study, we identified a fish MAP3K4 homolog (CiMAP3K4) in Ctenopharyngodon idella as well as its immune function in intestine following bacterial infection in vivo and in vitro. The open reading frame (ORF) of CiMAP3K4 encodes putative peptide of 1544 amino acids containing a predicted serine/threonine protein kinase (S_TKc) domain with high identity with other fish MAP3K4s. Phylogenetic analysis revealed the CiMAP3K4 belonged to the fish cluster and showed the closest relationship to Pimephales promelas. Quantitative real-time PCR (qRT-PCR) analysis revealed that CiMAP3K4 transcripts were widely distributed in all tested tissues, especially with high expression in the muscle and intestine of healthy grass carp. In vitro, CiMAP3K4 gene expression was upregulated by bacterial PAMPs (lipolysaccharide (LPS), peptidoglycan (PGN), L-Ala-γ-D-Glu-meso-diaminopimelic acid (Tri-DAP) and muramyl dipeptide (MDP)) and pathogens (Aeromonas hydrophila and Aeromonas veronii) in primary intestinal cells. In vivo, the mRNA expression levels of CiMAP3K4 in the intestine were significantly induced by bacterial MDP challenge in a time-dependent manner; however, this effect could be inhibited by the bioactive dipeptides ß-alanyl-l-histidine (carnosine) and alanyl-glutamine (Ala-Gln). Moreover, CiMAP3K4 was located primarily in the cytoplasm, and its overexpression increased the transcriptional activity of AP-1 in HEK293T cells. Collectively, these results suggested that CiMAP3K4 might play an important role in the intestinal immune response to bacterial infections, which paves the way for a better understanding of the intestinal immune system of grass carp.


Assuntos
Carpas , Doenças dos Peixes , Proteínas de Peixes , Infecções por Bactérias Gram-Negativas , MAP Quinase Quinase Quinase 4 , Aeromonas hydrophila , Animais , Carpas/genética , Carpas/imunologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Proteínas de Peixes/genética , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Células HEK293 , Humanos , Imunidade Inata/genética , Intestinos/imunologia , Intestinos/microbiologia , MAP Quinase Quinase Quinase 4/genética , Filogenia
13.
Mucosal Immunol ; 15(1): 40-50, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34465895

RESUMO

The intestine is constantly exposed to foreign antigens, which are mostly innocuous but can sometimes be harmful. Therefore, the intestinal immune system has the delicate task of maintaining immune tolerance to harmless food antigens while inducing tailored immune responses to pathogens and regulating but tolerating the microbiota. Intestinal dendritic cells (DCs) play a central role in these functions as sentinel cells able to prime and polarize the T cell responses. DCs are deployed throughout the intestinal mucosa but with local specializations along the gut length and between the diffuse effector sites of the gut lamina propria (LP) and the well-organized immune inductive sites comprising isolated lymphoid follicles (ILFs), Peyer's patches (PPs), and other species-specific gut-associated lymphoid tissues (GALTs). Understanding the specificities of each intestinal DC subset, how environmental factors influence DC functions, and how these can be modulated is key to harnessing the therapeutic potential of mucosal adaptive immune responses, whether by enhancing the efficacy of mucosal vaccines or by increasing tolerogenic responses in inflammatory disorders. In this review, we summarize recent findings related to intestinal DCs in steady state and upon inflammation, with a special focus on their functional specializations, highly dependent on their microenvironment.


Assuntos
Células Dendríticas/imunologia , Imunomodulação/imunologia , Mucosa Intestinal/imunologia , Intestinos/imunologia , Tecido Linfoide/imunologia , Animais , Humanos , Imunidade nas Mucosas
14.
J Sci Food Agric ; 102(3): 908-919, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34235749

RESUMO

BACKGROUND: Rhamnolipids (RLS), well known as glycolipid biosurfactants, display low toxicity, high biodegradability, and strong antibacterial properties. This study was carried out to evaluate the use of RLS supplementation as a substitute for antibiotics, and particularly to evaluate its effects on growth performance, immunity, intestinal barrier function, and metabolome composition in broilers. RESULTS: The RLS treatment improved the growth performance, immunity, and intestinal barrier function in broilers. The 16S rRNA sequencing revealed that the genus Alistipes was the dominant genus in broilers treated by RLS. An ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS)-based metabolomic analysis indicated that the sphingolipid metabolism, glycine, serine, and threonine metabolism, the gycerophospholipid metabolism, and the tryptophan metabolism were changed in broilers that were treated with RLS. CONCLUSION: l-Tryptophan may be the medium for RLS to regulate the growth and physiological metabolism. Rhamnolipids can be used as a potential alternative to antibiotics, with similar functions to antibiotics in the diet of broilers. The optimal level of supplemented RLS in the diet was 1000 mg kg-1 . © 2021 Society of Chemical Industry.


Assuntos
Galinhas/crescimento & desenvolvimento , Galinhas/imunologia , Glicolipídeos/administração & dosagem , Intestinos/imunologia , Metaboloma/efeitos dos fármacos , Ração Animal/análise , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Galinhas/metabolismo , Galinhas/microbiologia , Suplementos Nutricionais/análise , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/metabolismo , Intestinos/microbiologia , Metabolômica
15.
Cytokine ; 149: 155701, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34741881

RESUMO

The severity of chronic schistosomiasis has been mainly associated with the intensity and extension of the inflammatory response induced by egg-secreted antigens in the host tissue, especially in the liver and intestine. During acute schistosomiasis, eosinophils account for approximately 50% of the cells that compose the liver granulomas; however, the role of this cell-type in the pathology of schistosomiasis remains controversial. In the current study, we compared the parasite burden and liver immunopathological changes during experimental schistosomiasis in wild-type (WT) BALB/c mice and BALB/c mice selectively deficient for the differentiation of eosinophils (ΔdblGATA). Our data demonstrated that the absence of eosinophil differentiation did not alter the S. mansoni load or the liver retention of parasite eggs; however, there were significant changes in the liver immune response profile and tissue damage. S. mansoni infection in ΔdblGATA mice resulted in significantly lower liver concentrations of IL-5, IL-13, IL-33, IL-17, IL-10, and TGF-ß and higher concentrations of IFN-γ and TNF-α, as compared to WT mice. The changes in liver immune response observed in infected ΔdblGATA mice were accompanied by lower collagen deposition, but higher liver damage and larger granulomas. Moreover, the absence of eosinophils resulted in a higher mortality rate in mice infected with a high parasite load. Therefore, the data indicated that eosinophils participate in the establishment and/or amplification of liver Th-2 and regulatory response induced by S. mansoni, which is necessary for the balance between liver damage and fibrosis, which in turn is essential for modulating disease severity.


Assuntos
Eosinófilos/imunologia , Imunidade/imunologia , Hepatopatias/imunologia , Fígado/imunologia , Doenças Negligenciadas/imunologia , Esquistossomose mansoni/imunologia , Animais , Citocinas/imunologia , Modelos Animais de Doenças , Eosinófilos/parasitologia , Feminino , Fibrose/imunologia , Fibrose/parasitologia , Granuloma/imunologia , Granuloma/parasitologia , Intestinos/imunologia , Intestinos/parasitologia , Fígado/parasitologia , Hepatopatias/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Doenças Negligenciadas/parasitologia
16.
J Nutr Biochem ; 99: 108840, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34419569

RESUMO

Kaempferol, a flavonoid identified in a wide variety of dietary sources, has been reported to possess anti-obesity properties; however, its underlying mechanism was poorly understood. Chronic, low-grade gut inflammation and dysbacteria are proposed as underlying factors as well as novel treatment approaches for obesity-associated pathologies. This present study aims to investigate the benefits of experimental treatment with kaempferol on intestinal inflammation and gut microbial balance in animal model of obesity. High fat diet (HFD) was applied to C57BL/6J mice for 16 weeks, during which the supplement of kaempferol served as a variable. Clearly, HFD induced obesity, fat accumulation, glucose intolerance and adipose inflammation, the metabolic syndrome of which was the main finding. All these metabolic disorders can be alleviated through kaempferol supplementation. In addition, increased intestinal permeability, infiltration of immunocytes (macrophage, dendritic cells and neutrophils) and overexpression of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, monocyte chemoattractant protein-1) were also found in the HFD-induced mice. Kaempferol supplementation improved intestinal barrier integrity and inhibited gut inflammation, by reducing the activation of TLR4/NF-κB pathway. Furthermore, the characterization of the cecal microbiota by sequencing showed that kaempferol supplementation was able to counteract the dysbiosis associated to obesity. Our study delineated the multiple mechanism of action underlying the anti-obesity effect of kaempferol, and provide scientific evidence to support the development of kaempferol as a dietary supplement for obesity treatment.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/imunologia , Quempferóis/administração & dosagem , Obesidade/tratamento farmacológico , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/imunologia , Animais , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/imunologia , Humanos , Intestinos/microbiologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/imunologia , Obesidade/microbiologia
17.
J Nutr Biochem ; 99: 108855, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34517096

RESUMO

Patients with inflammatory bowel disease (IBD) have higher incidence of extraintestinal manifestations (EIM), including liver disorders, sarcopenia, and neuroinflammation. Fermented rice bran (FRB), generated from rice bran (RB), is rich in bioactive compounds, and exhibits anti-colitis activity. However, its role in EIM prevention is still unclear. Here, for the first time, we investigated whether EIM in female C57Bl/6N mice is attenuated by FRB supplementation. EIM was induced by repeated administration of 1.5% dextran sulfate sodium (DSS) in drinking water (4 d) followed by drinking water (12 d). Mice were divided into 3 groups-control (AIN93M), 10% RB, and 10% FRB. FRB ameliorated relapsing colitis and inflammation in muscle by significantly lowering proinflammatory cytokines Tnf-α and Il-6 in serum and advanced glycation end product-specific receptor (Ager) in serum and muscle when compared with the RB and control groups. As FRB reduced aspartate aminotransferase levels and oxidative stress, it might prevent liver disorders. FRB downregulated proinflammatory cytokine and chemokine transcripts responsible for neuroinflammation in the hippocampus and upregulated mRNA expression of G protein coupled receptors (GPRs), Gpr41 and Gpr43, in small and large intestines, which may explain the FRB-mediated protective mechanism. Hence, FRB can be used as a supplement to prevent IBD-associated EIM.


Assuntos
Colite/tratamento farmacológico , Colite/imunologia , Fibras na Dieta/administração & dosagem , Oryza/química , Preparações de Plantas/administração & dosagem , Animais , Quimiocinas/genética , Quimiocinas/imunologia , Doença Crônica/terapia , Colite/induzido quimicamente , Colite/genética , Sulfato de Dextrana/efeitos adversos , Fibras na Dieta/análise , Suplementos Nutricionais/análise , Modelos Animais de Doenças , Feminino , Hipocampo/imunologia , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Intestinos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/imunologia , Estresse Oxidativo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
18.
Am J Surg Pathol ; 46(1): 89-96, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34081038

RESUMO

Approximately 20% of patients with symptomatic syndrome-associated coronavirus-2 (SARS-CoV-2) infection have gastrointestinal bleeding and/or diarrhea. Most are managed without endoscopic evaluation because the risk of practitioner infection outweighs the value of biopsy analysis unless symptoms are life-threatening. As a result, much of what is known about the gastrointestinal manifestations of coronavirus disease-2019 (COVID-19) has been gleaned from surgical and autopsy cases that suffer from extensive ischemic injury and/or poor preservation. There are no detailed reports describing any other gastrointestinal effects of SARS-CoV-2 even though >3,000,000 people have died from COVID-19 worldwide. The purpose of this study is to report the intestinal findings related to SARS-CoV-2 infection by way of a small case series including one with evidence of direct viral cytopathic effect and 2 with secondary injury attributed to viral infection. Infection can be confirmed by immunohistochemical stains directed against SARS-CoV-2 spike protein, in situ hybridization for spike protein-encoding RNA, and ultrastructural visualization of viruses within the epithelium. It induces cytoplasmic blebs and tufted epithelial cells without inflammation and may not cause symptoms. In contrast, SARS-CoV-2 infection can cause gastrointestinal symptoms after the virus is no longer detected, reflecting systemic activation of cytokine and complement cascades rather than direct viral injury. Reversible mucosal ischemia features microvascular injury with hemorrhage, small vessel thrombosis, and platelet-rich thrombi. Systemic cytokine elaboration and dysbiosis likely explain epithelial cell injury that accompanies diarrheal symptoms. These observations are consistent with clinical and in vitro data and contribute to our understanding of the protean manifestations of COVID-19.


Assuntos
COVID-19/patologia , Enteropatias/patologia , Enteropatias/virologia , Intestinos/patologia , Intestinos/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Biópsia , COVID-19/diagnóstico , COVID-19/imunologia , Citocinas/metabolismo , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/imunologia , Hemorragia Gastrointestinal/patologia , Hemorragia Gastrointestinal/virologia , Humanos , Enteropatias/diagnóstico , Enteropatias/imunologia , Intestinos/imunologia , Isquemia/diagnóstico , Isquemia/imunologia , Isquemia/patologia , Isquemia/virologia , Masculino , Trombose/diagnóstico , Trombose/imunologia , Trombose/patologia , Trombose/virologia
19.
Cell ; 184(26): 6281-6298.e23, 2021 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-34875227

RESUMO

While intestinal Th17 cells are critical for maintaining tissue homeostasis, recent studies have implicated their roles in the development of extra-intestinal autoimmune diseases including multiple sclerosis. However, the mechanisms by which tissue Th17 cells mediate these dichotomous functions remain unknown. Here, we characterized the heterogeneity, plasticity, and migratory phenotypes of tissue Th17 cells in vivo by combined fate mapping with profiling of the transcriptomes and TCR clonotypes of over 84,000 Th17 cells at homeostasis and during CNS autoimmune inflammation. Inter- and intra-organ single-cell analyses revealed a homeostatic, stem-like TCF1+ IL-17+ SLAMF6+ population that traffics to the intestine where it is maintained by the microbiota, providing a ready reservoir for the IL-23-driven generation of encephalitogenic GM-CSF+ IFN-γ+ CXCR6+ T cells. Our study defines a direct in vivo relationship between IL-17+ non-pathogenic and GM-CSF+ and IFN-γ+ pathogenic Th17 populations and provides a mechanism by which homeostatic intestinal Th17 cells direct extra-intestinal autoimmune disease.


Assuntos
Autoimunidade , Intestinos/imunologia , Células-Tronco/metabolismo , Células Th17/imunologia , Animais , Movimento Celular , Células Clonais , Encefalomielite Autoimune Experimental/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Homeostase , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , RNA/metabolismo , RNA-Seq , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores CXCR6/metabolismo , Receptores de Interleucina/metabolismo , Reprodutibilidade dos Testes , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Análise de Célula Única , Baço/metabolismo
20.
Commun Biol ; 4(1): 1359, 2021 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-34862463

RESUMO

Salmonella enterica persist in the chicken gut by suppressing inflammatory responses via expansion of intestinal regulatory T cells (Tregs). In humans, T cell activation is controlled by neurochemical signaling in Tregs; however, whether similar neuroimmunological signaling occurs in chickens is currently unknown. In this study, we explore the role of the neuroimmunological axis in intestinal Salmonella resistance using the drug reserpine, which disrupts intracellular storage of catecholamines like norepinephrine. Following reserpine treatment, norepinephrine release was increased in both ceca explant media and Tregs. Similarly, Salmonella killing was greater in reserpine-treated explants, and oral reserpine treatment reduced the level of intestinal Salmonella Typhimurium and other Enterobacteriaceae in vivo. These antimicrobial responses were linked to an increase in antimicrobial peptide and IL-2 gene expression as well as a decrease in CTLA-4 gene expression. Globally, reserpine treatment led to phosphorylative changes in epidermal growth factor receptor (EGFR), mammalian target of rapamycin (mTOR), and the mitogen-associated protein kinase 2(MEK2). Exogenous norepinephrine treatment alone increased Salmonella resistance, and reserpine-induced antimicrobial responses were blocked using beta-adrenergic receptor inhibitors, suggesting norepinephrine signaling is crucial in this mechanism. Furthermore, EGF treatment reversed reserpine-induced antimicrobial responses, whereas mTOR inhibition increased antimicrobial activities, confirming the roles of metabolic signaling in these responses. Finally, MEK1/2 inhibition suppressed reserpine, norepinephrine, and mTOR-induced antimicrobial responses. Overall, this study demonstrates a central role for MEK1/2 activity in reserpine induced neuro-immunometabolic signaling and subsequent antimicrobial responses in the chicken intestine, providing a means of reducing bacterial colonization in chickens to improve food safety.


Assuntos
Galinhas , Resistência à Doença/efeitos dos fármacos , Infecções por Enterobacteriaceae/veterinária , Enterobacteriaceae/fisiologia , Doenças das Aves Domésticas/microbiologia , Reserpina/farmacologia , Transdução de Sinais , Animais , Infecções por Enterobacteriaceae/microbiologia , Intestinos/imunologia , Intestinos/microbiologia , Salmonelose Animal/microbiologia , Salmonella typhimurium/fisiologia
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