RESUMO
The potential involvement of the gut microbiota in metabolic dysfunction-associated steatohepatitis (MASH) pathogenesis has garnered increasing attention. In this study, we elucidated the link between high-fat/cholesterol/cholate-based (iHFC)#2 diet-induced MASH progression and gut microbiota in C57BL/6 mice using antibiotic treatments. Treatment with vancomycin (VCM), which targets gram-positive bacteria, exacerbated the progression of liver damage, steatosis, and fibrosis in iHFC#2-fed C57BL/6 mice. The expression levels of inflammation- and fibrosis-related genes in the liver significantly increased after VCM treatment for 8 weeks. F4/80+ macrophage abundance increased in the livers of VCM-treated mice. These changes were rarely observed in the iHFC#2-fed C57BL/6 mice treated with metronidazole, which targets anaerobic bacteria. A16S rRNA sequence analysis revealed a significant decrease in α-diversity in VCM-treated mice compared with that in placebo-treated mice, with Bacteroidetes and Firmicutes significantly decreased, while Proteobacteria and Verrucomicrobia increased markedly. Finally, VCM treatment dramatically altered the level and balance of bile acid (BA) composition in iHFC#2-fed C57BL/6 mice. Thus, the VCM-mediated exacerbation of MASH progression depends on the interaction between the gut microbiota, BA metabolism, and inflammatory responses in the livers of iHFC#2-fed C57BL/6 mice.
Assuntos
Antibacterianos , Dieta Hiperlipídica , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Vancomicina , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Antibacterianos/farmacologia , Masculino , Vancomicina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/etiologia , Ácidos e Sais Biliares/metabolismoRESUMO
BACKGROUND: Tsumura-Suzuki non-obese (TSNO) mice exhibit a severe form of metabolic dysfunction-associated steatohepatitis (MASH) with advanced liver fibrosis upon feeding a high-fat/cholesterol/cholate-based (iHFC) diet. Another ddY strain, Tsumura-Suzuki diabetes obese (TSOD) mice, are impaired in the progression of iHFC diet-induced MASH. AIM: To elucidate the underlying mechanisms contributing to the differences in MASH progression between TSNO and TSOD mice. METHODS: We analyzed differences in the immune system, gut microbiota, and bile acid metabolism in TSNO and TSOD mice fed with a normal diet (ND) or an iHFC diet. RESULTS: TSOD mice had more anti-inflammatory macrophages in the liver than TSNO mice under ND feeding, and were impaired in the iHFC diet-induced accumulation of fibrosis-associated macrophages and formation of histological hepatic crown-like structures in the liver. The gut microbiota of TSOD mice also exhibited a distinct community composition with lower diversity and higher abundance of Akkermansia muciniphila compared with that in TSNO mice. Finally, TSOD mice had lower levels of bile acids linked to intestinal barrier disruption under iHFC feeding. CONCLUSIONS: The dynamics of liver macrophage subsets, and the compositions of the gut microbiota and bile acids at steady state and post-onset of MASH, had major impacts on MASH development.
Assuntos
Ácidos e Sais Biliares , Dieta Hiperlipídica , Microbioma Gastrointestinal , Fígado , Macrófagos , Animais , Ácidos e Sais Biliares/metabolismo , Fígado/patologia , Fígado/metabolismo , Dieta Hiperlipídica/efeitos adversos , Macrófagos/metabolismo , Macrófagos/imunologia , Masculino , Camundongos , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/microbiologia , Akkermansia , Progressão da Doença , Colesterol na Dieta/efeitos adversosRESUMO
The health benefits of young barley leaves, rich in dietary fiber, have been studied for several decades; however, their beneficial effects on the intestinal microenvironment remain to be elucidated. To investigate the effects of young barley leaf-derived dietary fiber (YB) on the gut microbiota and immunity, mice were fed an AIN-93G diet containing cellulose or YB and subjected to subsequent analysis. The population of MHC-II-positive conventional dendritic cells (cDCs) and CD86 expression in the cDCs of Peyer's patches were elevated in the YB-fed mice. MHC-II and CD86 expression was also elevated in the bone marrow-derived DCs treated with YB. 16S-based metagenomic analysis revealed that the gut microbiota composition was markedly altered by YB feeding. Among the gut microbiota, Lachnospiraceae, mainly comprising butyrate-producing NK4A136 spp., were overrepresented in the YB-fed mice. In fact, fecal butyrate concentration was also augmented in the YB-fed mice, which coincided with increased retinaldehyde dehydrogenase (RALDH) activity in the CD103+ cDCs of the mesenteric lymph nodes. Consistent with elevated RALDH activity, the population of colonic IgA+ plasma cells was higher in the YB-fed mice than in the parental control mice. In conclusion, YB has beneficial effects on the gut microbiota and intestinal immune system.
Assuntos
Fibras na Dieta , Microbioma Gastrointestinal , Hordeum , Folhas de Planta , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Hordeum/química , Fibras na Dieta/farmacologia , Folhas de Planta/química , Camundongos , Retinal Desidrogenase/metabolismo , Butiratos/metabolismo , Fezes/microbiologiaRESUMO
The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain containing 3 (NLRP3) inflammasome contributes to the development of inflammatory diseases. Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory disease caused by NLRP3 gene mutations that results in excessive IL-1ß production. We previously identified isoliquiritigenin (ILG), a component of Glycyrrhiza uralensis extracts, as a potent inhibitor of the NLRP3 inflammasome. Here, we aimed to investigate whether ILG inhibits the activation of NLRP3 inflammasome caused by NLRP3 gene mutations. We demonstrated that ILG significantly inhibited NLRP3 inflammasome-mediated lactate dehydrogenase (LDH) release and IL-1ß production in two CAPS model THP-1 cell lines, NLRP3-D303N and NLRP3-L353P, in a dose-dependent manner. Interestingly, the NLRP3 inhibitor MCC950 inhibited LDH release and IL-1ß production in NLRP3-D303N cells, but not in NLRP3-L353P cells. Western blotting and caspase-1 activity assays showed that ILG, as well as caspase inhibitors, including Z-VAD and YVAD, suppressed caspase-1 activation. Notably, ILG prevented cryo-sensitive foci formation of NLRP3 without affecting the levels of intracellular Ca2+. We concluded that ILG effectively prevents the constitutive activation of the inflammasome associated with NLRP3 gene mutations by inhibiting the aggregation of cryo-sensitive mutated NLRP3.
Assuntos
Caspase 1 , Chalconas , Síndromes Periódicas Associadas à Criopirina , Inflamassomos , Mutação , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Chalconas/farmacologia , Humanos , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Caspase 1/metabolismo , Caspase 1/genética , Células THP-1 , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Síndromes Periódicas Associadas à Criopirina/metabolismo , Síndromes Periódicas Associadas à Criopirina/genética , Interleucina-1beta/metabolismoRESUMO
Macrophages are critical for the development of non-alcoholic steatohepatitis (NASH). Our previous findings in TSNO mouse livers showed that an iHFC (high-fat/cholesterol/cholate) diet induced liver fibrosis similar to human NASH and led to the accumulation of distinct subsets of macrophage: CD11c+/Ly6C- and CD11c-/Ly6C+ cells. CD11c+/Ly6C- cells were associated with the promotion of advanced liver fibrosis in NASH. On the other hand, CD11c-/Ly6C+ cells exhibited an anti-inflammatory effect and were involved in tissue remodeling processes. This study aimed to elucidate whether an iHFC diet with reduced cholic acid (iHFC#2 diet) induces NASH in C57BL/6 mice and examine the macrophage subsets accumulating in the liver. Histological and quantitative real-time PCR analyses revealed that the iHFC#2 diet promoted inflammation and fibrosis indicative of NASH in the livers of C57BL/6 mice. Cell numbers of Kupffer cells decreased and recruited macrophages were accumulated in the livers of iHFC#2 diet-fed C57BL/6 mice. Notably, the iHFC#2 diet resulted in the accumulation of three macrophage subsets in the livers of C57BL/6 mice: CD11c+/Ly6C-, CD11c-/Ly6C+, and CD11c+/Ly6C+ cells. However, CD11c+/Ly6C+ cells were not distinct populations in the iHFC-fed TSNO mice. Thus, differences in cholic acid content and mouse strain affect the macrophage subsets that accumulate in the liver.
RESUMO
OBJECTIVE: Polyphenols have health-promoting effects, such as improving insulin resistance. Isoxanthohumol (IX), a prenylated flavonoid found in beer hops, has been suggested to reduce obesity and insulin resistance; however, the mechanism remains unknown. METHODS: High-fat diet-fed mice were administered IX. We analyzed glucose metabolism, gene expression profiles and histology of liver, epididymal adipose tissue and colon. Lipase activity, fecal lipid profiles and plasma metabolomic analysis were assessed. Fecal 16s rRNA sequencing was obtained and selected bacterial species were used for in vitro studies. Fecal microbiota transplantation and monocolonization were conducted to antibiotic-treated or germ-free (GF) mice. RESULTS: The administration of IX lowered weight gain, decreased steatohepatitis and improved glucose metabolism. Mechanistically, IX inhibited pancreatic lipase activity and lipid absorption by decreasing the expression of the fatty acid transporter CD36 in the small intestine, which was confirmed by increased lipid excretion in feces. IX administration increased markers of intestinal barrier function, including thickening the mucin layer and increasing caludin-1, a tight-junction related protein in the colon. In contrast, the effects of IX were nullified by antibiotics. As revealed using 16S rRNA sequencing, the microbial community structure changed with a significant increase in the abundance of Akkermansia muciniphila in the IX-treated group. An anaerobic chamber study showed that IX selectively promoted the growth of A. muciniphila while exhibiting antimicrobial activity against some Bacteroides and Clostridium species. To further explore the direct effect of A. muciniphila on lipid and glucose metabolism, we monocolonized either A. muciniphila or Bacteroides thetaiotaomicron to GF mice. A. muciniphila monocolonization decreased CD36 expression in the jejunum and improved glucose metabolism, with decreased levels of multiple classes of fatty acids determined using plasma metabolomic analysis. CONCLUSIONS: Our study demonstrated that IX prevents obesity and enhances glucose metabolism by inhibiting dietary fat absorption. This mechanism is linked to suppressing pancreatic lipase activity and shifts in microbial composition, notably an increase in A. muciniphila. These highlight new treatment strategies for preventing metabolic syndrome by boosting the gut microbiota with food components.
Assuntos
Resistência à Insulina , Animais , Camundongos , RNA Ribossômico 16S/genética , Obesidade/tratamento farmacológico , Obesidade/microbiologia , Verrucomicrobia/genética , Verrucomicrobia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta , Glucose/metabolismo , LipaseRESUMO
Polyethylene glycol (PEG) is a commonly used dispersant for oral administration of hydrophobic agents. PEG is partly absorbed in the small intestine, and the unabsorbed fraction reaches the large intestine; thus, oral administration of PEG may impact the gut microbial community. However, to the best of our knowledge, no study evaluated the effects of PEG on gut commensal bacteria. Herein, we aimed to determine whether oral administration of PEG modifies the gut microbiota. Administration of PEG400 and PEG4000 altered gut microbial diversity in a concentration-dependent manner. Taxonomic analysis revealed that Akkermansia muciniphila and particularly Parabacteroides goldsteinii were overrepresented in mice administered with 40% PEG. PEG400 administration ameliorated the high-fat diet (HFD)-induced obesity and adipose tissue inflammation. Fecal microbiome transplantation from PEG400-administered donors counteracted the HFD-induced body and epididymal adipose tissue weight gain, indicating that PEG400-associated bacteria are responsible for the anti-obesity effect. Conversely, carboxymethyl cellulose, also used as a dispersant, did not affect the abundance of these two bacterial species or HFD-induced obesity. In conclusion, we demonstrated that oral administration of a high concentration of PEG400 (40%) alters the gut microbiota composition and ameliorates HFD-induced obesity.
RESUMO
Radioprotective 105 (RP105) plays a key role in the development of high-fat diet (HFD)-induced metabolic disorders; however, the underlying mechanisms remain to be understood. Here, we aimed to uncover whether RP105 affects metabolic syndrome through the modification of gut microbiota. We confirmed that body weight gain and fat accumulation by HFD feeding were suppressed in Rp105-/- mice. Fecal microbiome transplantation from HFD-fed donor Rp105-/- mice into HFD-fed recipient wild-type mice significantly improved various abnormalities associated with metabolic syndrome, including body weight gain, insulin resistance, hepatic steatosis, macrophage infiltration and inflammation in the adipose tissue. In addition, HFD-induced intestinal barrier dysfunction was attenuated by fecal microbiome transplantation from HFD-fed donor Rp105-/- mice. A 16S rRNA sequence analysis indicated that RP105 modified gut microbiota composition and was involved in the maintenance of its diversity. Thus, RP105 promotes metabolic syndrome by altering gut microbiota composition and intestinal barrier function.
Assuntos
Microbioma Gastrointestinal , Síndrome Metabólica , Animais , Camundongos , Obesidade/metabolismo , Microbioma Gastrointestinal/fisiologia , RNA Ribossômico 16S/genética , Dieta Hiperlipídica/efeitos adversos , Aumento de Peso , Imunidade Inata , Camundongos Endogâmicos C57BLRESUMO
The health benefits of wheat-derived arabinoxylan, a commonly consumed dietary fiber, have been studied for decades. However, its effect on the gut microenvironment and inflammatory bowel disease remains unclear. The objective of this study was to understand the effect of wheat-derived arabinoxylan on gut microbiota, colonic regulatory T cells (Tregs), and experimental colitis. In this study, healthy and chronic colitis model mice were fed chow containing cellulose or wheat-derived arabinoxylan for 2-6 weeks and subjected to subsequent analysis. A 16S-based metagenomic analysis of the fecal DNA revealed that Lachnospiraceae, comprising butyrate-producing and Treg-inducing bacteria, were overrepresented in arabinoxylan-fed mice. In line with the changes in the gut microbiota, both the fecal butyrate concentration and the colonic Treg population were elevated in the arabinoxylan-fed mice. In a T cell transfer model of chronic colitis, wheat-derived arabinoxylan ameliorated body weight loss and colonic tissue inflammation, which may, in part, be mediated by Treg induction. Moreover, wheat-derived arabinoxylan suppressed TNFα production from type 1 helper T cells in this colitis model. In conclusion, wheat-derived arabinoxylans, by altering the gut microenvironment, may be a promising prebiotic for the prevention of colitis.
Assuntos
Colite , Microbioma Gastrointestinal , Animais , Camundongos , Linfócitos T Reguladores , Triticum , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Butiratos/farmacologia , Camundongos Endogâmicos C57BLRESUMO
The potential roles of the gut microbiota in the pathogenesis of non-alcoholic fatty liver disease, including non-alcoholic steatohepatitis (NASH), have attracted increased interest. We have investigated the links between gut microbiota and NASH development in Tsumura-Suzuki non-obese mice fed a high-fat/cholesterol/cholate-based (iHFC) diet that exhibit advanced liver fibrosis using antibiotic treatments. The administration of vancomycin, which targets Gram-positive organisms, exacerbated the progression of liver damage, steatohepatitis, and fibrosis in iHFC-fed mice, but not in mice fed a normal diet. F4/80+-recruited macrophages were more abundant in the liver of vancomycin-treated iHFC-fed mice. The infiltration of CD11c+-recruited macrophages into the liver, forming hepatic crown-like structures, was enhanced by vancomycin treatment. The co-localization of this macrophage subset with collagen was greatly augmented in the liver of vancomycin-treated iHFC-fed mice. These changes were rarely seen with the administration of metronidazole, which targets anaerobic organisms, in iHFC-fed mice. Finally, the vancomycin treatment dramatically modulated the level and composition of bile acid in iHFC-fed mice. Thus, our data demonstrate that changes in inflammation and fibrosis in the liver by the iHFC diet can be modified by antibiotic-induced changes in gut microbiota and shed light on their roles in the pathogenesis of advanced liver fibrosis.
Assuntos
Antibacterianos , Ácidos e Sais Biliares , Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Vancomicina , Animais , Camundongos , Antibacterianos/farmacologia , Ácidos e Sais Biliares/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Vancomicina/farmacologiaRESUMO
Soluble oat fibers, including ß-glucan, have been shown to alter the gut microbiome composition and ameliorate DSS-induced colitis; however, the beneficial effect of soluble oat fiber on colonic inflammation is not yet fully understood. In this study, we demonstrated that soluble oat fibers ameliorate T cell-dependent colitis through the induction of peripherally induced regulatory T cells (pTregs). Soluble oat fibers elevated colonic butyrate production dose-dependently, which coincided with the overrepresentation of Faecalibaculum rodentium (an analog of butyrate-producing Holdemanella biformis) in the gut microbiome. Soluble oat fibers promoted the growth of F. rodentium and H. biformis even in vitro, and increased the concentration of butyrate in the culture supernatant. These results indicate that soluble oat fibers are an energy source for butyrate-producing bacteria and are a fermentation substrate. Soluble oat fibers increased the percentage of colonic pTregs and ameliorated the weight loss and inflammation in acute 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis; this may in part be mediated by the increase in IL-10-producing T cells. In conclusion, our results suggest that the administration of soluble oat fibers is a promising prebiotic treatment for the prevention of colitis mediated via altered gut microbiota composition and elevated butyrate production.
Assuntos
Avena , Colite , Animais , Ácido Trinitrobenzenossulfônico , Avena/química , Colite/microbiologia , Butiratos , Inflamação , Modelos Animais de DoençasRESUMO
Macrophages play critical roles in the pathogenesis of non-alcoholic steatohepatitis (NASH). However, it is unclear which macrophage subsets are critically involved in the development of inflammation and fibrosis in NASH. In TSNO mice fed a high-fat/cholesterol/cholate-based diet, which exhibit advanced liver fibrosis that mimics human NASH, we found that Kupffer cells (KCs) were less abundant and recruited macrophages were more abundant, forming hepatic crown-like structures (hCLS) in the liver. The recruited macrophages comprised two subsets: CD11c+/Ly6C- and CD11c-/Ly6C+ cells. CD11c+ cells were present in a mesh-like pattern around the lipid droplets, constituting the hCLS. In addition, CD11c+ cells colocalized with collagen fibers, suggesting that this subset of recruited macrophages might promote advanced liver fibrosis. In contrast, Ly6C+ cells were present in doughnut-like inflammatory lesions, with a lipid droplet in the center. Finally, RNA sequence analysis indicates that CD11c+/Ly6C- cells promote liver fibrosis and hepatic stellate cell (HSC) activation, whereas CD11c-/Ly6C+ cells are a macrophage subset that play an anti-inflammatory role and promote tissue repair in NASH. Taken together, our data revealed changes in liver macrophage subsets during the development of NASH and shed light on the roles of the recruited macrophages in the pathogenesis of advanced fibrosis in NASH.
Assuntos
Macrófagos , Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Antígeno CD11c , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fibrose , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
SCOPE: The purpose of this study is to compare the impact of four low-viscosity soluble dietary fibers (DFs) on the intestinal microenvironment, in terms of microbiota composition, short-chain fatty acid (SCFA) production, proportion of colonic peripherally induced regulatory T cells (pTregs), and experimental colitis in mice. METHODS AND RESULTS: Mice are administered 5% w/v low-viscosity soluble DFs in drinking water for 2 weeks. The gut microbiota composition is determined using 16S rRNA sequencing. Luminal SCFAs are quantified by gas chromatography, and colonic pTregs are analyzed using flow cytometry. All low-viscosity soluble DFs promote the growth of beneficial bacteria such as Akkermansia muciniphila and Bacteroides acidifaciens, while eliminating pathogenic bacteria such as Clostridium perfringens. Moreover, two low-viscosity soluble DFs significantly increase the abundance of commensal bacteria and promote the accumulation of propionate and butyrate, leading to marked induction of colonic pTregs. Consistently, these two fibers, in particular α-cyclodextrin, show remarkable anti-inflammatory properties in a colitis mouse model. CONCLUSION: Mice administered any low-viscosity soluble DF show comparable gut microbiota compositions, but differ in terms of bacterial abundance, SCFA concentration, pTreg population, and colitis development. This exploratory study suggests that administration of α-cyclodextrin may be a possible strategy for the prevention of colitis.
Assuntos
Colite , alfa-Ciclodextrinas , Camundongos , Animais , RNA Ribossômico 16S/genética , Viscosidade , Colite/microbiologia , Verrucomicrobia , Ácidos Graxos Voláteis/análise , Fibras na Dieta/farmacologia , Inflamação/prevenção & controle , Camundongos Endogâmicos C57BLRESUMO
Transforming growth factor (TGF)-ß1 and prostaglandin E2 (PGE2) are humoral factors critically involved in the induction of immunosuppression in the microenvironment of various types of tumors, including melanoma. In this study, we identified a natural compound that attenuated TGF-ß1- and PGE2-induced immunosuppression and examined its effect on B16 melanoma growth in mice. By screening 502 natural compounds for attenuating activity against TGF-ß1- or PGE2-induced suppression of cytolysis in poly(I:C)-stimulated murine splenocytes, we found that betulin was the most potent compound. Betulin also reduced TGF-ß1- and PGE2-induced downregulation of perforin and granzyme B mRNA expression and cell surface expression of NKG2D and CD69 in natural killer (NK) cells. Cell depletion and coculture experiments showed that NK cells, dendritic cells, B cells, and T cells were necessary for the attenuating effects of betulin. Structure-activity relationship analysis revealed that two hydroxyl groups at positions C3 and C28 of betulin, their cis-configuration, and methyl group at C30 played crucial roles in its attenuating activity. In a subcutaneous implantation model of B16 melanoma in mice, intratumor administration of betulin and LY2157299, a TGF-ß1 type I receptor kinase inhibitor, significantly retarded the growth of B16 melanoma. Notably, betulin increased significantly the number of CD69 positive NK cells in tumor sites at early stages of post-tumor cell injection. Our data suggest that betulin inhibits the growth of B16 melanoma by enhancing NK cell activity through attenuating the immunosuppressive tumor microenvironment.
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Dinoprostona , Melanoma Experimental , Fator de Crescimento Transformador beta1 , Triterpenos , Animais , Dinoprostona/metabolismo , Células Matadoras Naturais , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Camundongos , Fator de Crescimento Transformador beta1/metabolismo , Triterpenos/farmacologia , Microambiente TumoralRESUMO
SCOPE: Isoliquiritigenin (ILG) has been reported to attenuate adipose tissue inflammation and metabolic disorder; however, the underlying mechanisms remain to be elucidated. The aim of this study is to elucidate whether ILG shows the anti-inflammatory and antimetabolic syndrome effects through gut microbiota modification. METHODS AND RESULTS: Mice are fed a high-fat diet (HFD) with or without ILG for up to 12 weeks. The effect of ILG on body weight, blood glucose level, adipose tissue inflammation, gut barrier function, and gut microbiota composition are investigated. ILG supplementation alleviates HFD-induced obesity, glucose tolerance, and insulin resistance and suppresses inflammatory gene expression in epididymal white adipose tissue (eWAT). Moreover, ILG supplementation modifies gut bacterial composition by increasing the abundance of antimetabolic disease-associated species (e.g., Parabacteroides goldsteinii and Akkemansia muciniphila) and up-regulated genes associated with gut barrier function. Fecal microbiome transplantation (FMT) from ILG-fed donors counteract HFD-induced body and eWAT weight changes, inflammation-related gene expression, glucose tolerance, and insulin resistance, thereby suggesting that ILG-responsive gut bacteria exerts anti-inflammatory and antimetabolic syndrome effects. CONCLUSION: Alterations in gut bacteria underly the beneficial effects of ILG against adipose tissue inflammation and metabolic disorders. ILG may be a promising prebiotic for the prevention and treatment of metabolic syndrome.
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Resistência à Insulina , Síndrome Metabólica , Tecido Adiposo/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Bactérias , Chalconas , Dieta Hiperlipídica/efeitos adversos , Glucose/metabolismo , Inflamação/metabolismo , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BLRESUMO
X-linked adrenoleukodystrophy (X-ALD) is a severe inherited metabolic disease with cerebral inflammatory demyelination and abnormal accumulation of very long chain fatty acid (VLCFA) in tissues, especially the brain. At present, bone marrow transplantation (BMT) at an early stage of the disease is the only effective treatment for halting disease progression, but the underlying mechanism of the treatment has remained unclear. Here, we transplanted GFP-expressing wild-type (WT) or Abcd1-deficient (KO) bone marrow cells into recipient KO mice, which enabled tracking of the donor GFP+ cells in the recipient mice. Both the WT and KO donor cells were equally distributed throughout the brain parenchyma, and displayed an Iba1-positive, GFAP- and Olig2-negative phenotype, indicating that most of the donor cells were engrafted as microglia-like cells. They constituted approximately 40% of the Iba1-positive cells. Unexpectedly, no decrease of VLCFA in the cerebrum was observed when WT bone marrow cells were transplanted into KO mice. Taken together, murine study suggests that bone marrow-derived microglia-like cells engrafted in the cerebrum of X-ALD patients suppress disease progression without evidently reducing the amount of VLCFA in the cerebrum.
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Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/deficiência , Adrenoleucodistrofia/terapia , Transplante de Medula Óssea , Encéfalo/metabolismo , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/genética , Adrenoleucodistrofia/metabolismo , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Células Cultivadas , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , Fator de Transcrição 2 de Oligodendrócitos/metabolismoRESUMO
Obesity and insulin resistance are associated with dysbiosis of the gut microbiota and impaired intestinal barrier function. Herein, we report that Bofutsushosan (BFT), a Japanese herbal medicine, Kampo, which has been clinically used for constipation in Asian countries, ameliorates glucose metabolism in mice with diet-induced obesity. A 16S rRNA sequence analysis of fecal samples showed that BFT dramatically increased the relative abundance of Verrucomicrobia, which was mainly associated with a bloom of Akkermansia muciniphila (AKK). BFT decreased the gut permeability as assessed by FITC-dextran gavage assay, associated with increased expression of tight-junction related protein, claudin-1, in the colon. The BFT treatment group also showed significant decreases of the plasma endotoxin level and expression of the hepatic lipopolysaccharide-binding protein. Antibiotic treatment abrogated the metabolic effects of BFT. Moreover, many of these changes could be reproduced when the cecal contents of BFT-treated donors were transferred to antibiotic-pretreated high fat diet-fed mice. These data demonstrate that BFT modifies the gut microbiota with an increase in AKK, which may contribute to improving gut barrier function and preventing metabolic endotoxemia, leading to attenuation of diet-induced inflammation and glucose intolerance. Understanding the interaction between a medicine and the gut microbiota may provide insights into new pharmacological targets to improve glucose metabolism.
Assuntos
Glicemia/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Obesidade/tratamento farmacológico , Akkermansia/classificação , Akkermansia/efeitos dos fármacos , Akkermansia/genética , Akkermansia/isolamento & purificação , Animais , Medicamentos de Ervas Chinesas/farmacologia , Endotoxinas/sangue , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos , Obesidade/sangue , Obesidade/induzido quimicamente , Permeabilidade , RNA Ribossômico 16S/genética , Análise de Sequência de DNARESUMO
Chronic activation of the IL-1ß system in adipose tissue on metabolic disorders is well demonstrated. However, a mechanism for its expression and activation in the tissue has remained unexplored. Here, we demonstrate that IL-1ß transcript was enriched in neutrophils of white adipose tissue (WAT) from lean mice. Mechanistically, the interaction of neutrophils with adipocytes induced IL-1ß expression via NF-κB pathway. Lipolysis of adipocytes accumulated neutrophils prior to macrophages in WAT and produced high levels of IL-1ß via an inflammasome pathway. Leukotriene B4 (LTB4) production in WAT also contributed to neutrophil accumulation. Furthermore, an LTB4-inflammasome axis contributed to the expression of chemotactic molecules involved in high-fat diet-induced macrophage infiltration into WAT. We have identified previously unappreciated roles for neutrophils in the development of adipose tissue inflammation: robust IL-1ß production and infiltration of macrophages to initiate chronic inflammation.-Watanabe, Y., Nagai, Y., Honda, H., Okamoto, N., Yanagibashi, T., Ogasawara, M., Yamamoto, S., Imamura, R., Takasaki, I., Hara, H., Sasahara, M., Arita, M., Hida, S., Taniguchi, S., Suda, T., Takatsu, K. Bidirectional crosstalk between neutrophils and adipocytes promotes adipose tissue inflammation.
Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Inflamação/metabolismo , Neutrófilos/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Inflamassomos/metabolismo , Lipólise/fisiologia , Macrófagos/metabolismo , Camundongos Transgênicos , Obesidade/metabolismoRESUMO
Dual X-ray absorptiometry (DXA) is used to diagnose osteoporosis. On the other hand, quantitative ultrasound (QUS) is widely used to assess bone density as part of medical screening as it is relatively inexpensive and easy to perform. Current QUS devices do not share precise ultrasound-related parameters, such as frequency, waveform, beam pattern, transient response, definition of propagation time, definition of degree of attenuation, and precise measurement site, resulting in different measurements across models. The Japan Osteoporosis Society established a QUS Standardization Committee in 2007 to investigate standardization of speed of sound (SOS) and broadband ultrasonic attenuation (BUA) measurements to resolve this issue. The committee came up with a formula to convert SOS and BUA values yielded by each model available in Japan. This has made it possible to convert QUS measurements from different models into standardized values, greatly improving the effectiveness of QUS measurements.
Assuntos
Densidade Óssea , Osso e Ossos/diagnóstico por imagem , Osteoporose/diagnóstico por imagem , Ultrassonografia/normas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Padrões de Referência , Valores de Referência , Ondas Ultrassônicas , Ultrassonografia/instrumentação , Ultrassonografia/métodos , Adulto JovemRESUMO
In the original version of the article, the third author name was incorrectly published. The correct name is Kosei Yoh.