Abstract
Background and Aims
Patients with inflammatory bowel disease IBD, especially Crohn’s disease, often develop zinc deficiency. However, the precise mechanisms by which zinc deficiency affects ...IBD pathology, particularly intestinal macrophage function, remain unclear. We studied the effects of zinc deficiency on the development and progression of colitis in mice.
Methods
To induce colitis, mice were treated with 2,4,6-trinitrobenzene sulphonic acid. Rag1−/− mice were then given injections of naïve CD4+CD62L+ T cells. The respective degrees of mucosal injury of mice that had received a zinc chelator (TPEN; N,N,N′,N′-tetrakis 2-pyridylmethylethylenediamine) and of control mice were subsequently compared. Colonic lamina propria mononuclear cells were isolated by enzymatic digestion and were examined using flow cytometry. To generate mouse bone marrow-derived macrophages BMDMs, bone marrow cells were stimulated with mouse macrophage-colony stimulating factor.
Results
Zinc deficiency aggravates colonic inflammation through the activation of type 17 helper T Th17 cells in mice. Flow cytometric analysis revealed that zinc deficiency significantly increases the proportion of pro-inflammatory M1 macrophages in colonic lamina propria mononuclear cells obtained from inflamed colon. Interferon-γ plus lipopolysaccharide-mediated M1 skewing alters the expression of zinc transporters in BMDMs and thereby decreases the intracellular free zinc. TPEN treatment mimicking the effects of the M1 skewing up-regulates IL-23p19 expression, which is strongly related to Th17 development. Furthermore, the nuclear accumulation of interferon-regulatory factor 5 is closely involved in IL-23p19 induction in zinc-deficient macrophages.
Conclusions
Zinc deficiency aggravates colonic inflammation through activation of the IL-23/Th17 axis. This activation is controlled by subcellular distribution of interferon-regulatory factor 5.
A probiotic is considered a live microbial feed supplement that has beneficial effects on the host. In this study, the probiotic property by which Enterococcus faecium HS-08 strengthens the immune ...system was investigated. Using a murine model, we evaluated the abilities of this strain to increase intestinal short-chain fatty acid contents and to induce the production of mucosal immunoglobulin A (IgA), which are crucial for mucosal immune systems. Various amounts (0%, 0.0038%, 0.038%, or 0.38%) of strain HS-08 cells were administered to BALB/cAJcl mice, which resulted in a dose-dependent increase of fecal IgA levels. A qRT-PCR analysis of Peyer’s patch cells revealed that the gene expression of retinal-dehydrogenase, interleukin 6, B-cell-activating factor, and a proliferation-inducing ligand were increased, which leads to IgA secretion via a T-cell-independent mechanism. The administration of 0.038% and 0.38% of strain HS-08 cells also increased fecal acetate levels, which plays an important role for maintaining immune functions. This cecal floral analysis and the stability of strain HS-08 against gastrointestinal digestion suggest that this strain can inhabit the host intestine. In conclusion, the administration of E. faecium HS-08 increased intestinal acetate levels and enhanced IgA secretion, which may result in strengthening of the mucosal immune system.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
New Findings
What is the central question of this study?
Exercise for type 2 diabetes patients treated with insulin therapy involves the risk of hypoglycaemia. Dipeptidyl peptidase‐4 (DPP‐4) ...inhibitors can be effective in combination with exercise because they reduce the incidence of hypoglycaemia. We evaluated the effect of this combination of treatments on hepatic lipid metabolism in diabetic KK/Ta mice.
What is the main finding and its importance?
The combination of a DPP‐4 inhibitor and exercise, which lowers the risk of hypoglycaemia, is useful for improving insulin resistance by inhibiting excess insulin secretion and decreasing hepatic lipid accumulation, validated by downregulated CD36.
The role of exercise training in prevention of diabetes and/or dyslipidaemia has been firmly established. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors improve insulin sensitivity and have attracted attention as therapeutics for hepatic lipid accumulation. The effect of a combination of DPP‐4 inhibitor and exercise training on the prevention and treatment of hepatic lipid accumulation is unclear. Here, we investigated whether alogliptin, a DPP‐4 inhibitor, enhances the preventive effect of exercise‐induced hepatic lipid accumulation in diabetic mice. Balb/c and KK/Ta mice were fed a high‐fat diet. Mice were divided into the following five groups: B, Balb/c mice; K, KK/Ta mice; K‐A, KK/Ta mice with alogliptin (0.01%); K‐Ex, KK/Ta mice with exercise training (3 days week−1, 15–20 m min−1 for 30 min); and K‐Ex+A, KK/Ta mice with alogliptin and exercise training (n = 8 or 9 mice per group). After 8 weeks, glucose, insulin and triglyceride concentrations in the blood and triglyceride levels in the liver were significantly lower in the K‐Ex+A group than in the K group. The liver expression level of PPAR‐γ in the K group was significantly higher than that in the other groups. Additionally, the liver CD36 expression level was significantly lower in the K‐Ex+A and B groups than in the K group. Thus, combined therapy of a DPP‐4 inhibitor with exercise training was effective against high‐fat diet‐induced hepatic lipid accumulation in KK/Ta mice. The results of this study provide useful support for the practice of safe exercise therapy even in diabetic patients who require treatment with a DPP‐4 inhibitor.
This study evaluated the immunostimulative effect on bone marrow-derived dendritic cells (DCs) of adjuvant-active exopolysaccharide (EPS) produced by Leuconostoc mesenteroides strain NTM048. EPS ...stimulation increased IL-6, IL-10, IL-12, and retinal dehydrogenase (RALDH) gene expression levels and induced retinoic acid-synthesizing RALDH-active DCs, which play a crucially important role in controlling adaptive immune responses in mucosa.
Consumption of yacon (Smallanthus sonchifolius) is associated with beneficial effects such as prevention of metabolic diseases. Yacon root is known to contain various bioactive components including ...indigestible carbohydrates, but the alteration of intestinal environment after treatment with yacon has not been fully investigated. This study investigated yacon-containing diet effects on the intestinal environment in mice, including microbial composition, short-chain fatty acid levels, and mucus content. After mice were administered yacon-containing diet for 4 weeks, 16S rRNA gene sequencing analyses revealed their fecal microbiota profiles. Organic acid concentrations in cecal contents were measured using an HPLC system. Compared to the control group, yacon-containing diet-received mice had significantly higher the concentrations of succinic acid, lactic acid, acetic acid, and propionic acid. The fecal mucin content was also higher in yacon-containing diet-received mice. Results of 16S rRNA gene sequencing analyses showed that the relative abundances of 27 taxa differed significantly in yacon-containing diet-received mice. Furthermore, results show effects of yacon administration on intestinal inflammation using 2,4,6-trinitrobenzene sulfonic acid induced colitis model in mice. Increased colonic damage and myeloperoxidase activity after 2,4,6-trinitrobenzene sulfonic acid treatment were suppressed in yacon-containing diet-received mice. Results suggest that oral intake of yacon root modulates the intestinal environment, thereby inhibiting intestinal inflammation.
The inhalation of carbon monoxide (CO) gas and the administration of CO-releasing molecules were shown to inhibit the development of intestinal inflammation in a murine colitis model. However, it ...remains unclear whether CO promotes intestinal wound healing. Herein, we aimed to evaluate the therapeutic effects of the topical application of CO-saturated saline enemas on intestinal inflammation and elucidate the underlying mechanism. Acute colitis was induced with trinitrobenzene sulfonic acid (TNBS) in male Wistar rats. A CO-saturated solution was prepared via bubbling 50% CO gas into saline and was rectally administrated twice a day after colitis induction; rats were sacrificed 3 or 7 days after induction for the study of the acute or healing phases, respectively. The distal colon was isolated, and ulcerated lesions were measured. In vitro wound healing assays were also employed to determine the mechanism underlying rat intestinal epithelial cell restitution after CO treatment. CO solution rectal administration ameliorated acute TNBS-induced colonic ulceration and accelerated ulcer healing without elevating serum CO levels. The increase in thiobarbituric acid-reactive substances and myeloperoxidase activity after induction of acute TNBS colitis was also significantly inhibited after CO treatment. Moreover, the wound healing assays revealed that the CO-saturated medium enhanced rat intestinal epithelial cell migration via the activation of Rho-kinase. In addition, the activation of Rho-kinase in response to CO treatment was confirmed in the inflamed colonic tissue. Therefore, the rectal administration of a CO-saturated solution protects the intestinal mucosa from inflammation and accelerates colonic ulcer healing through enhanced epithelial cell restitution. CO may thus represent a novel therapeutic agent for the treatment of inflammatory bowel disease.
•Rectal administration of CO-saturated solutions is safe and well tolerated.•Rectal topical administration of CO inhibits intestinal inflammation.•Rectal topical administration of CO solutions promotes colonic ulcer healing.•CO accelerates intestinal epithelial restitution through Rho-kinase activation.
Betalain pigments are mainly produced by plants belonging to the order of Caryophyllales. Betalains exhibit strong antioxidant activity and responds to environmental stimuli and stress in plants. ...Recent reports of antioxidant, anti-inflammatory and anti-cancer properties of betalain pigments have piqued interest in understanding their biological functions. We investigated the effects of betalain pigments (betanin and isobetanin) derived from red-beet on amyloid-
β
(A
β
) aggregation, which causes Alzheimer’s disease. Non-specific inhibition of A
β
aggregation against A
β
40 and A
β
42 by red-beet betalain pigments,
in vitro
was demonstrated using the thioflavin t fluorescence assay, circular dichroism spectroscopy analysis, transmission electron microscopy and nuclear magnetic resonance (NMR) analysis. Furthermore, we examined the ability of red-beet betalain pigments to interfere with A
β
toxicity by using the transgenic
Caenorhabditis elegans
model, which expresses the human A
β
42 protein intracellularly within the body wall muscle. It responds to A
β
-toxicity with paralysis and treatment with 50
μ
M red-beet betalain pigments significantly delayed the paralysis of
C. elegans
. These results suggest that betalain pigments reduce A
β
-induced toxicity.
Purpose
Agaro-oligosaccharides (AGO), hydrolysis products of agarose, is known to have antioxidant and anti-inflammatory properties. Speculating that AGO is effective for preventing aging, we ...investigated the longevity-supporting effects of AGO and their mechanisms using
Caenorhabditis elegans
.
Methods
Caenorhabditis elegans
were fed AGO from young adulthood. The lifespan, locomotory activity, lipofuscin accumulation, and heat stress resistance of the worms were examined. To elucidate mechanisms of AGO-mediated longevity, we conducted comprehensive expression analysis using microarrays. Moreover, we used quantitative real-time PCR (qRT-PCR) to verify the genes showing differential expression levels. Furthermore, we measured the lifespan of loss-of-function mutants to determine the genes related to AGO-mediated longevity.
Results
AGO extended the lifespan of
C. elegans
, reduced lipofuscin accumulation, and maintained vigorous locomotion. The microarray analysis revealed that the endoplasmic reticulum-unfolded protein response (ER-UPR) and insulin/insulin-like growth factor-1-mediated signaling (IIS) pathway were activated in AGO-fed worms. The qRT-PCR analysis showed that AGO treatment suppressed
sir-2.1
expression, which is a negative regulator of ER-UPR. In loss-of-function mutant of
sir-2.1
, AGO-induced longevity and heat stress resistance were decreased or cancelled completely. Furthermore, the pro-longevity effect of AGO was decreased in loss-of-function mutants of abnormal Dauer formation (
daf
)
-2
and
daf-16
, which are IIS pathway-related genes.
Conclusion
AGO delays the
C. elegans
aging process and extends their lifespan through the activations of ER-UPR and the IIS pathway.
Gut microbiota are deeply associated with the prevalence of obesity. Agarose is hydrolyzed easily to yield oligosaccharides, designated as agaro-oligosaccharides (AGO). This study evaluated the ...effects of AGO on obese phenotype and gut microbial composition in mice. Mice were administered AGO in drinking water (AGO-receiving mice). 16S rRNA gene sequencing analyses revealed their fecal microbiota profiles. Serum bile acids were ascertained using a LC-MS/MS system. Compared to the control group, AGO administration significantly reduced epididymal adipose tissue weights and serum non-esterified fatty acid concentrations, but the cecal content weights were increased. Data from the serum bile acid profile show that concentrations of primary bile acids (cholic acid and chenodeoxycholic acid), but not those of secondary bile acids (deoxycholic acid, lithocholic acid, and ursodeoxycholic acid), tended to increase in AGO-receiving mice. 16S rRNA gene sequencing analyses showed that the relative abundances of 15 taxa differed significantly in AGO-receiving mice. Of these, the relative abundances of Rikenellaceae and Lachnospiraceae were found to be positively correlated with epididymal adipose tissue weight. The relative abundances of Bacteroides and Ruminococcus were correlated negatively with epididymal adipose tissue weight. Although the definitive role of gut microbes of AGO-received mice is still unknown, our data demonstrate the possibility that AGO administration affects the gut microbial composition and inhibits obesity in mice.
BACKGROUNDThe gut-liver axis has attracted much interest in the context of chronic liver disease pathogenesis. Prebiotics such as dietary fibers were shown to attenuate non-alcoholic fatty liver ...disease (NAFLD) by modulating gut microbiota. Partially hydrolyzed guar gum (PHGG), a water-soluble dietary fiber, has been reported to alleviate the symptoms of various intestinal diseases and metabolic syndromes. However, its effects on NAFLD remain to be fully elucidated.AIMTo determine whether treatment with PHGG attenuates NAFLD development in mice through the gut-liver axis.METHODSSeven-week-old male C57BL/6J mice with increased intestinal permeability were fed a control or atherogenic (Ath) diet (a mouse model of NAFLD) for 8 wk, with or without 5% PHGG. Increased intestinal permeability was induced through chronic intermittent administration of low-dose dextran sulfate sodium. Body weight, liver weight, macroscopic findings in the liver, blood biochemistry aspartate aminotransferase (AST) and alanine aminotransferase (ALT), total cholesterol, triglyceride, free fatty acids, and glucose levels, liver histology, myeloperoxidase activity in liver tissue, mRNA expression in the liver and intestine, serum endotoxin levels in the portal vein, intestinal permeability, and microbiota and short-chain fatty acid (SCFA) profiles in the cecal samples were investigated.RESULTSMice with increased intestinal permeability subjected to the Ath diet showed significantly increased serum AST and ALT levels, liver fat accumulation, liver inflammatory (tumor necrosis factor-α and monocyte chemotactic protein-1) and fibrogenic (collagen 1a1 and α smooth muscle actin) marker levels, and liver myeloperoxidase activity, which were significantly attenuated by PHGG treatment. Furthermore, the Ath diet combined with increased intestinal permeability resulted in elevated portal endotoxin levels and activated toll-like receptor (TLR) 4 and TLR9 expression, confirming that intestinal permeability was significantly elevated, as observed by evaluating the lumen-to-blood clearance of fluorescein isothiocyanate-conjugated dextran. PHGG treatment did not affect fatty acid metabolism in the liver. However, it decreased lipopolysaccharide signaling through the gut-liver axis. In addition, it significantly increased the abundance of cecal Bacteroides and Clostridium subcluster XIVa. Treatment with PHGG markedly increased the levels of SCFAs, particularly, butyric acid, acetic acid, propionic acid, and formic acid, in the cecal samples.CONCLUSIONPHGG partially prevented NAFLD development in mice through the gut-liver axis by modulating microbiota and downstream SCFA profiles.
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