Intestinal microbiota-derived metabolites have biological importance for the host. Polyamines, such as putrescine and spermidine, are produced by the intestinal microbiota and regulate multiple ...biological processes. Increased colonic luminal polyamines promote longevity in mice. However, no direct evidence has shown that microbial polyamines are incorporated into host cells to regulate cellular responses. Here, we show that microbial polyamines reinforce colonic epithelial proliferation and regulate macrophage differentiation. Colonisation by wild-type, but not polyamine biosynthesis-deficient, Escherichia coli in germ-free mice raises intracellular polyamine levels in colonocytes, accelerating epithelial renewal. Commensal bacterium-derived putrescine increases the abundance of anti-inflammatory macrophages in the colon. The bacterial polyamines ameliorate symptoms of dextran sulfate sodium-induced colitis in mice. These effects mainly result from enhanced hypusination of eukaryotic initiation translation factor. We conclude that bacterial putrescine functions as a substrate for symbiotic metabolism and is further absorbed and metabolised by the host, thus helping maintain mucosal homoeostasis in the intestine.
Antibiotics and dietary habits can affect the gut microbial community, thus influencing disease susceptibility. Although the effect of microbiota on the postnatal environment has been well ...documented, much less is known regarding the impact of gut microbiota at the embryonic stage. Here we show that maternal microbiota shapes the metabolic system of offspring in mice. During pregnancy, short-chain fatty acids produced by the maternal microbiota dictate the differentiation of neural, intestinal, and pancreatic cells through embryonic GPR41 and GPR43. This developmental process helps maintain postnatal energy homeostasis, as evidenced by the fact that offspring from germ-free mothers are highly susceptible to metabolic syndrome, even when reared under conventional conditions. Thus, our findings elaborate on a link between the maternal gut environment and the developmental origin of metabolic syndrome.
Abstract
Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is an intractable disease of the gastrointestinal tract. Multiple environmental factors, including food ...ingredients, have been implicated in the development of these diseases. For example, animal fat-rich diets are predisposing factors for ulcerative colitis, whereas n-3 unsaturated fatty acids such as docosahexaenoic acid (DHA) show protective effects in experimental colitis and are negatively correlated with the incidence of ulcerative colitis and Crohn's disease. Given that DHA exhibits agonistic activity on retinoid X receptor (RXR), activation of RXR could be a therapeutic strategy for IBD. However, conventional full RXR agonists are known to show considerable adverse effects. We therefore took advantage of a partial RXR agonist, CBt-PMN, to minimize the adverse effects, and evaluated its efficacy in dextran sodium sulfate-induced colitis. Administration of CBt-PMN efficiently ameliorated the symptoms of colitis. This effect was attributed to the down-regulation of pro-inflammatory cytokines such as Tnf and Il6 in colon-infiltrating monocytes. Down-regulation of pro-inflammatory cytokines by CBt-PMN was also evident in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs). Among many RXR-associated nuclear receptors, activation of peroxisome proliferator-activated receptor δ (PPARδ) and nuclear hormone receptor 77 (Nur77) suppressed cytokine production by BMDMs. These observations suggest that the activation of PPARδ/RXR and Nur77/RXR heterodimers by CBt-PMN through the permissive mechanism is responsible for diminishing the monocyte-mediated inflammatory response in the gut. Our data highlight the importance of RXR activation in the regulation of colitis.
A partial RXR agonist reduces side-effects while ameliorating colitis
Abstract
Background
Non-alcoholic liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and it can progress to non-alcoholic steatohepatitis (NASH). Alterations in the gut ...microbiome have been implicated in the development of NAFLD/NASH, although the underlying mechanisms remain unclear.
Results
We found that the consumption of the prebiotic inulin markedly ameliorated the phenotype of NAFLD/NASH, including hepatic steatosis and fibrosis, in mice. Inulin consumption resulted in global changes in the gut microbiome, including concomitant enrichment of the genera
Bacteroides
and
Blautia
, and increased concentrations of short-chain fatty acids, particularly acetate, in the gut lumen and portal blood. The consumption of acetate-releasing resistant starch protected against NAFLD development. Colonisation by
Bacteroides acidifaciens
and
Blautia producta
in germ-free mice resulted in synergetic effects on acetate production from inulin. Furthermore, the absence of free fatty acid receptor 2 (FFAR2), an acetate receptor, abolished the protective effect of inulin, as indicated by the more severe liver hypertrophy, hypercholesterolaemia and inflammation. These effects can be attributed to an exacerbation of insulin resistance in the liver, but not in muscle or adipose tissue.
Conclusion
These findings demonstrated that the commensal microbiome–acetate–FFAR2 molecular circuit improves insulin sensitivity in the liver and prevents the development of NAFLD/NASH.
Middle-carbon martensite steels are vital materials for mechanical components and their mechanical properties have attracted significant interest. However, the decrease in the elastic limit of the ...as-quenched materials is one of the remaining puzzles. Herein, we quantitatively characterized the dislocation density and its structure in the as-quenched and tempered martensite steel by neutron diffraction line profile analysis and discussed their impact on the yield stress. The dislocation density in the as-quenched specimen was the highest at 9.7 × 1015 m−2, while it decreased with an increase in the tempering temperature. In addition, the component ratios of edge and screw dislocations decreased and increased, respectively, depending on the increase in the tempering temperature. The dislocation arrangement parameter (M) varied between the tempering temperatures of 220 and 290°C. Although there was a large difference between the yield stress obtained from the tensile test and that estimated from the dislocation density, the experimental results could be explained by correcting them with the inverse of M value as an index showing the effective dislocation density ratio.
Chitinases are enzymes that hydrolyze chitin, a polymer of β-1, 4-linked N-acetyl-D-glucosamine (GlcNAc). Chitin has long been considered as a source of dietary fiber that is not digested in the ...mammalian digestive system. Here, we provide evidence that acidic mammalian chitinase (AMCase) can function as a major digestive enzyme that constitutively degrades chitin substrates and produces (GlcNAc)
fragments in the mouse gastrointestinal environment. AMCase was resistant to endogenous pepsin C digestion and remained active in the mouse stomach extract at pH 2.0. The AMCase mRNA levels were much higher than those of four major gastric proteins and two housekeeping genes and comparable to the level of pepsinogen C in the mouse stomach tissues. Furthermore, AMCase was expressed in the gastric pepsinogen-synthesizing chief cells. The enzyme was also stable and active in the presence of trypsin and chymotrypsin at pH 7.6, where pepsin C was completely degraded. Mouse AMCase degraded polymeric colloidal and crystalline chitin substrates in the gastrointestinal environments in presence of the proteolytic enzymes. Thus, AMCase can function as a protease-resistant major glycosidase under the conditions of stomach and intestine and degrade chitin substrates to produce (GlcNAc)
, a source of carbon, nitrogen and energy.
Middle-carbon martensite steels are vital materials for mechanical components and their mechanical properties have attracted significant interest. However, the decrease in the elastic limit of the ...as-quenched materials is one of the remaining puzzles. Herein, we quantitatively characterized the dislocation density and its structure in the as-quenched and tempered martensite steel by neutron diffraction line profile analysis and discussed their impact on the yield stress. The dislocation density in the as-quenched specimen was the highest at 9.7 × 1015 m-2, while it decreased with an increase in the tempering temperature. In addition, the component ratios of edge and screw dislocations decreased and increased, respectively, depending on the increase in the tempering temperature. The dislocation arrangement parameter (M) varied between the tempering temperatures of 220 and 290°C. Although there was a large difference between the yield stress obtained from the tensile test and that estimated from the dislocation density, the experimental results could be explained by correcting them with the inverse of M value as an index showing the effective dislocation density ratio.
The crystallization of phenytoin occurring after its dilution with infusion fluid is a major concern in the clinical use of injectable phenytoin. To gain further understanding of the crystallization, ...this study assessed details of the involvement of glucose in this action. For sample preparation, phenytoin crystals were created by diluting the injectable phenytoin with infusion fluids with different glucose concentrations at different temperature, and then the characteristics of the crystallization (e.g., crystal size in the long direction, accumulated amount over 24 h, and crystallization rate constant) were measured. Results of the analysis of variance indicated that the glucose concentration and temperature had significant impacts on the crystallization. The mode of action of the glucose concentration was suggested to be different from that of the incubation temperature. This study also examined the molecular mobility of components (i.e., glucose, propylene glycol, phenytoin) in the admixtures using diffusion NMR techniques. The findings will provide valuable information for the clinical use of injectable phenytoin.
To investigate the characteristics of dislocation evolution in ferritic and austenitic stainless steels under tensile deformation, neutron diffraction line-profile analysis was carried out. The ...austenitic steel exhibited higher work hardening than the ferritic steel. The difference in the work hardening ability between the two steels was explained with the dislocation density estimated by the line-profile analysis. The higher dislocation density of the austenitic steel would originate from its lower stacking fault energy. Dislocation arrangement parameters indicated that the strength of interaction between dislocations in the austenitic steel was stronger than that in the ferritic steel. This would mainly originate from the difference in dislocation substructures; while dislocation tangle, which can be prompted by the cross slip, was expected in the ferritic steels, highly dense dislocation walls induced by planar glide of dislocations as well as the tangle were expected in the austenitic steel. It was confirmed that the stronger interaction between dislocations in the austenitic steel resulted in the smaller strain field of dislocation. Consequently, the coefficient for the root square of dislocation density in the Bailey-Hirsh equation became smaller in the austenitic steel. X-ray diffraction line-profile analysis was also carried out for the tensile-deformed specimens. The dislocation arrangement parameter evaluated by X-ray diffraction was smaller than that evaluated by neutron diffraction. This would be caused by the difference in the relationship between the loading direction and the scattering vector. On the other hand, the dislocation density evaluated by both methods was almost identical.
The crystallization of phenytoin occurring after its dilution with infusion fluid is a major concern in the clinical use of injectable phenytoin. To gain further understanding of the crystallization, ...this study assessed details of the involvement of glucose in this action. For sample preparation, phenytoin crystals were created by diluting the injectable phenytoin with infusion fluids with different glucose concentrations at different temperature, and then the characteristics of the crystallization (e.g., crystal size in the long direction, accumulated amount over 24h, and crystallization rate constant) were measured. Results of the analysis of variance indicated that the glucose concentration and temperature had significant impacts on the crystallization. The mode of action of the glucose concentration was suggested to be different from that of the incubation temperature. This study also examined the molecular mobility of components (i.e., glucose, propylene glycol, phenytoin) in the admixtures using diffusion NMR techniques. The findings will provide valuable information for the clinical use of injectable phenytoin.
PDF
