Vitamin D Signaling through Induction of Paneth Cell Defensins Maintains Gut Microbiota and Improves Metabolic Disorders and Hepatic Steatosis in Animal Models.

Metabolic syndrome (MetS), characterized as obesity, insulin resistance, and non-alcoholic fatty liver diseases (NAFLD), is associated with vitamin D insufficiency/deficiency in epidemiological studies, while the underlying mechanism is poorly addressed. On the other hand, disorder of gut microbiota, namely dysbiosis, is known to cause MetS and NAFLD. It is also known that systemic inflammation blocks insulin signaling pathways, leading to insulin resistance and glucose intolerance, which are the driving force for hepatic steatosis. Vitamin D receptor (VDR) is highly expressed in the ileum of the small intestine, which prompted us to test a hypothesis that vitamin D signaling may determine the enterotype of gut microbiota through regulating the intestinal interface. Here, we demonstrate that high-fat-diet feeding (HFD) is necessary but not sufficient, while additional vitamin D deficiency (VDD) as a second hit is needed, to induce robust insulin resistance and fatty liver. Under the two hits (HFD+VDD), the Paneth cell-specific alpha-defensins including α-defensin 5 (DEFA5), MMP7 which activates the pro-defensins, as well as tight junction genes, and MUC2 are all suppressed in the ileum, resulting in mucosal collapse, increased gut permeability, dysbiosis, endotoxemia, systemic inflammation which underlie insulin resistance and hepatic steatosis. Moreover, under the vitamin D deficient high fat feeding (HFD+VDD), Helicobacter hepaticus, a known murine hepatic-pathogen, is substantially amplified in the ileum, while Akkermansia muciniphila, a beneficial symbiotic, is diminished. Likewise, the VD receptor (VDR) knockout mice exhibit similar phenotypes, showing down regulation of alpha-defensins and MMP7 in the ileum, increased Helicobacter hepaticus and suppressed Akkermansia muciniphila. Remarkably, oral administration of DEFA5 restored eubiosys, showing suppression of Helicobacter hepaticus and increase of Akkermansia muciniphila in association with resolving metabolic disorders and fatty liver in the HFD+VDD mice. An in vitro analysis showed that DEFA5 peptide could directly suppress Helicobacter hepaticus. Thus, the results of this study reveal critical roles of a vitamin D/VDR axis in optimal expression of defensins and tight junction genes in support of intestinal integrity and eubiosis to suppress NAFLD and metabolic disorders

PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations

Programmed death-1 (PD-1) is a cell surface receptor that functions as a T cell checkpoint and plays a central role in regulating T cell exhaustion. Binding of PD-1 to its ligand, programmed death-ligand 1 (PD-L1), activates downstream signaling pathways and inhibits T cell activation. Moreover abnormally high PD-L1 expression on tumor cells and antigen-presenting cells in the tumor microenvironment mediates tumor immune escape, and the development of anti-PD-1/PD-L1 antibodies has recently become a hot topic in cancer immunotherapy. Here, we review the structure of PD-1 and PD-L1, the function of the PD-1/PD-L1 signaling pathway, the application of PD-1 or PD-L1 monoclonal antibodies and future directions for anti-PD-1/PD-L1 antibodies with combination therapies. Cancer immunotherapy using PD-1/PD-L1 immune checkpoint blockade may require more studies, and this approach may be curative for patients with many types of cancer in the future

Salubrinal Alleviates Collagen-Induced Arthritis through Promoting P65 Degradation in Osteoclastogenesis

Rheumatoid arthritis (RA) is a complex systemic autoimmune disorder that primarily involves joints, further affects the life quality of patients, and has increased mortality. The pathogenesis of RA involves multiple pathways, resulting in some patients showing resistance to the existing drugs. Salubrinal is a small molecule compound that has recently been shown to exert multiple beneficial effects on bone tissue. However, the effect of Salubrinal in RA has not been clearly confirmed. Hence, we induced collagen-induced arthritis (CIA) in DBA/1J mice and found that Salubrinal treatment decreased the clinical score of CIA mice, inhibiting joint damage and bone destruction. Furthermore, Salubrinal treatment downregulated osteoclast number in knee joint of CIA in mice, and suppressed bone marrow-derived osteoclast formation and function, downregulated osteoclast-related gene expression. Moreover, Salubrinal treatment inhibited RANKL-induced NF-κB signaling pathway, and promoted P65 degradation through the ubiquitin-proteasome system, further restrained RANKL-induced osteoclastogenesis. This study explains the mechanism by which Salubrinal ameliorates arthritis of CIA in mice, indicating that Salubrinal may be a potential drug for RA, and expands the potential uses of Salubrinal in the treatment of bone destruction-related diseases

Effect of Oat β-Glucan on the Rheological Characteristics and Microstructure of Set-Type Yogurt

The oat β-glucan (OG) was added into set-type yogurt as a functional ingredient, in order to evaluate effects on the rheological characteristics and microstructure of set-type yogurt. When the OG concentration increased from 0 to 0.3%, the WHC gradually increased. At 0.3% OG, the set-type yogurt had the highest WHC of 94.67%. Additionally, the WHC continuously decreased, reaching the lowest WHC (about 80%) at 0.5% OG. When 0.3% OG was added, the highest score of sensory evaluation was about 85. The rheological result showed that the fermentation process went through the changes as follows: solid → liquid → solid → liquid. The addition of 0.3% OG decreased the fermentation time of set-type yogurt by about 16 min, making yogurt more inclined to be liquid. The acidity of set-type yogurt with OG was slightly higher. The result of microstructure showed that the addition of OG destroyed the three-dimensional network structure of yogurt, and some spherical aggregate particles could be clearly observed at 0.3% OG. Overall, this study provided a theoretical basis for the application of OG in set-type yogurt

Effects of Pleurotus eryngii (mushroom) powder and soluble polysaccharide addition on the rheological and microstructural properties of dough

Adding a certain proportion of Pleurotus eryngii can improve the nutritional value of wheat‐flour foods and enhance the utilization of this mushroom. In this research, partial wheat flour was substituted with P. eryngii powder (PEP) or soluble polysaccharide (SPPE) at different addition levels, and the effects of PEP and SPPE on the rheological and microstructural properties of dough were investigated. Farinographic assay results suggested that PEP significantly (p < 0.05) increased the water absorption of wheat flour but decreased the development time and stability of dough significantly (p < 0.05). Furthermore, it was capable of providing weaker extensographic characteristics and harder dough with the increasing of PEP addition levels. The dynamic oscillatory tests indicated that the PEP addition approximately increased the storage (G′) and loss (G″) moduli in the entire frequency range, while the tan δ roughly decreased with the increasing of PEP addition levels, which could be attributed to the low solubility and strong water‐trapping capacity of the dietary fiber in PEP. Due to the good water solubility and easy formation of hydrogen bonds, the addition of SPPE had inconsistent results with the PEP addition. The inner microstructure of dough showed that the continuity of gluten networks had been disrupted by PEP and SPPE addition and then resulted in a weaker extension and harder dough. This research could provide a foundation for the application of PEP in wheat‐flour foods, and PEP addition levels of 2.5%–5.0% are recommended

Dynamic changes of yak () gut microbiota during growth revealed by polymerase chain reaction-denaturing gradient gel electrophoresis and metagenomics

Objective To understand the dynamic structure, function, and influence on nutrient metabolism in hosts, it was crucial to assess the genetic potential of gut microbial community in yaks of different ages. Methods The denaturing gradient gel electrophoresis (DGGE) profiles and Illumina-based metagenomic sequencing on colon contents of 15 semi-domestic yaks were investigated. Unweighted pairwise grouping method with mathematical averages (UPGMA) clustering and principal component analysis (PCA) were used to analyze the DGGE fingerprint. The Illumina sequences were assembled, predicted to genes and functionally annotated, and then classified by querying protein sequences of the genes against the Kyoto encyclopedia of genes and genomes (KEGG) database. Results Metagenomic sequencing showed that more than 85% of ribosomal RNA (rRNA) gene sequences belonged to the phylum Firmicutes and Bacteroidetes, indicating that the family Ruminococcaceae (46.5%), Rikenellaceae (11.3%), Lachnospiraceae (10.0%), and Bacteroidaceae (6.3%) were dominant gut microbes. Over 50% of non-rRNA gene sequences represented the metabolic pathways of amino acids (14.4%), proteins (12.3%), sugars (11.9%), nucleotides (6.8%), lipids (1.7%), xenobiotics (1.4%), coenzymes, and vitamins (3.6%). Gene functional classification showed that most of enzyme-coding genes were related to cellulose digestion and amino acids metabolic pathways. Conclusion Yaks’ age had a substantial effect on gut microbial composition. Comparative metagenomics of gut microbiota in 0.5-, 1.5-, and 2.5-year-old yaks revealed that the abundance of the class Clostridia, Bacteroidia, and Lentisphaeria, as well as the phylum Firmicutes, Bacteroidetes, Lentisphaerae, Tenericutes, and Cyanobacteria, varied more greatly during yaks’ growth, especially in young animals (0.5 and 1.5 years old). Gut microbes, including Bacteroides, Clostridium, and Lentisphaeria, make a contribution to the energy metabolism and synthesis of amino acid, which are essential to the normal growth of yaks

Diversified gut microbiota in newborns of mothers with gestational diabetes mellitus.

Gestational diabetes mellitus (GDM), a high-risk pregnancy complication of great effect on the perinatal health of women and newborns, may cause changes of gut microbiota in mothers and further affect gut microbiota in newborns. This study aimed to investigate the potential effect of mother GDM on newborns' gut microbiota. Meconium DNA was extracted from a total of 34 full-term and C-sectioned newborns, in which 20 newborns had mothers diagnosed with GDM, while 14 had unaffected mothers. Sequencing and bioinformatics analysis of 16S rRNA indicated that the gut microbiota of GDM newborns showed differences compared to control newborns. The taxonomy analyses suggested that the overall bacterial content significantly differed by maternal diabetes status, with the microbiome of the GDM group showing lower alpha-diversity than that of control group. The phyla of Proteobacteria and Actinobacteria in GDM newborns increased, while that of Bacteroidetes significantly reduced (P<0.05). Moreover, several unique gut microbiota in phylum of Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, Chloroflexi, Acidobacteria, and Planctomycetes found in control newborns were absent in GDM ones. At genus level, the relative abundance of Prevotella and Lactobacillus significantly decreased (P<0.05) in GDM newborns. Correlation analysis indicated that maternal fasting glucose levels were positively correlated with the relative abundance of phylum Actinobacteria and genus Acinetobacter, while negatively correlated with that of phylum Bacteroidetes and genus Prevotella. However, bacteria in GDM grade A2 (GDM_A2) newborns did not show any statistical variation compared to those from control newborns, which might be attributed to the additional intervention by insulin. The results of this study have important implications for understanding the potential effects of GDM on the gut microbiota of newborns and thus possibly their metabolism at later stages in their lives

Vitamin D Signaling through Induction of Paneth Cell Defensins Maintains Gut Microbiota and Improves Metabolic Disorders and Hepatic Steatosis in Animal Models.

Metabolic syndrome (MetS), characterized as obesity, insulin resistance, and non-alcoholic fatty liver diseases (NAFLD), is associated with vitamin D insufficiency/deficiency in epidemiological studies, while the underlying mechanism is poorly addressed. On the other hand, disorder of gut microbiota, namely dysbiosis, is known to cause MetS and NAFLD. It is also known that systemic inflammation blocks insulin signaling pathways, leading to insulin resistance and glucose intolerance, which are the driving force for hepatic steatosis. Vitamin D receptor (VDR) is highly expressed in the ileum of the small intestine, which prompted us to test a hypothesis that vitamin D signaling may determine the enterotype of gut microbiota through regulating the intestinal interface. Here, we demonstrate that high-fat-diet feeding (HFD) is necessary but not sufficient, while additional vitamin D deficiency (VDD) as a second hit is needed, to induce robust insulin resistance and fatty liver. Under the two hits (HFD+VDD), the Paneth cell-specific alpha-defensins including α-defensin 5 (DEFA5), MMP7 which activates the pro-defensins, as well as tight junction genes, and MUC2 are all suppressed in the ileum, resulting in mucosal collapse, increased gut permeability, dysbiosis, endotoxemia, systemic inflammation which underlie insulin resistance and hepatic steatosis. Moreover, under the vitamin D deficient high fat feeding (HFD+VDD), Helicobacter hepaticus, a known murine hepatic-pathogen, is substantially amplified in the ileum, while Akkermansia muciniphila, a beneficial symbiotic, is diminished. Likewise, the VD receptor (VDR) knockout mice exhibit similar phenotypes, showing down regulation of alpha-defensins and MMP7 in the ileum, increased Helicobacter hepaticus and suppressed Akkermansia muciniphila. Remarkably, oral administration of DEFA5 restored eubiosys, showing suppression of Helicobacter hepaticus and increase of Akkermansia muciniphila in association with resolving metabolic disorders and fatty liver in the HFD+VDD mice. An in vitro analysis showed that DEFA5 peptide could directly suppress Helicobacter hepaticus. Thus, the results of this study reveal critical roles of a vitamin D/VDR axis in optimal expression of defensins and tight junction genes in support of intestinal integrity and eubiosis to suppress NAFLD and metabolic disorders