The gut microbiota benefits humans via short-chain fatty acid (SCFA) production from carbohydrate fermentation, and deficiency in SCFA production is associated with type 2 diabetes mellitus (T2DM). We conducted a randomized clinical study of specifically designed isoenergetic diets, together with fecal shotgun metagenomics, to show that a select group of SCFA-producing strains was promoted by dietary fibers and that most other potential producers were either diminished or unchanged in patients with T2DM. When the fiber-promoted SCFA producers were present in greater diversity and abundance, participants had better improvement in hemoglobin A1c levels, partly via increased glucagon-like peptide-1 production. Promotion of these positive responders diminished producers of metabolically detrimental compounds such as indole and hydrogen sulfide. Targeted restoration of these SCFA producers may present a novel ecological approach for managing T2DM.

Recent reports have suggested that the gut microbiota is involved in the progression of colorectal cancer (CRC). The composition of gut microbiota in CRC precursors has not been adequately described. To characterize the structure of adherent microbiota in this disease, we conducted pyrosequencing-based analysis of 16S rRNA genes to determine the bacterial profile of normal colons (healthy controls) and colorectal adenomas (CRC precursors). Adenoma mucosal biopsy samples and adjacent normal colonic mucosa from 31 patients with adenomas and 20 healthy volunteers were profiled using the Illumina MiSeq platform. Principal coordinate analysis (PCoA) showed structural segregation between colorectal adenomatous tissue and control tissue. Alpha diversity estimations revealed higher microbiota diversity in samples from patients with adenomas. Taxonomic analysis illustrated that abundance of eight phyla (Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, Chloroflexi, Cyanobacteria, Candidate-division TM7, and Tenericutes) was significantly different. In addition, Lactococcus and Pseudomonas were enriched in preneoplastic tissue, whereas Enterococcus, Bacillus, and Solibacillus were reduced. However, both PCoA and cluster tree analyses showed similar microbiota structure between adenomatous and adjacent non-adenoma tissues. These present findings provide preliminary experimental evidence supporting that colorectal preneoplastic lesion may be the most important factor leading to alterations in bacterial community composition.

No abstract

This study analyzed IL-23p19 expression in inflamed mucosa of IBD and the role in the induction of IEL and NK cell activation as well as Th17 cell differentiation. Expression of IL-23p19 was performed by immunohistochemistry and quantitative real-time PCR. Expression of IL-23R was assessed by flow cytometry. Cytolytic activities of IEL and NK cells by IL-23 were determined by a standard (51)Cr-release assay. Cytokine levels were analyzed by ELISA and quantitative real-time PCR. Expression of IL-23p19 was increased significantly in inflamed mucosa of CD compared with that in UC and healthy controls. Double-staining confirmed that IL-23p19(+) cells were mainly CD68(+) macrophages/DCs. IL-23R(+) cells were increased significantly in PB- and LP-CD4(+) and -CD8(+) T and NK cells. IL-23 markedly promoted IBD IEL and NK cell activation and cytotoxicity and triggered IBD PB- and LP-T cells to secrete significantly higher levels of IFN-γ, TNF, IL-2, and IL-17A compared with controls. Importantly, IL-23 promoted IBD PB- or LP-CD4(+) T cells to differentiate into Th17 cells, characterized by increased expression of IL-17A and RORC. Anti-TNF treatment could markedly reduce IL-23 expression and Th17 cell infiltration in inflamed mucosa of CD patients. These data indicate that IL-23 is highly expressed in inflamed mucosa of IBD and plays an important role in the induction of IEL, NK, and T cell activation, proinflammatory cytokine secretion, and Th17 cell differentiation. Targeted therapy directed against IL-23p19 may have a therapeutic role in treatment of IBD.

Hypertriglyceridemia (HTG) aggravates the course of acute pancreatitis (AP). Intestinal barrier dysfunction is implicated in the pathogenesis of AP during which dysbiosis of intestinal microbiota contributes to the dysfunction in intestinal barrier. However, few studies focus on the changes in intestine during HTG-related acute necrotizing pancreatitis (ANP). Here, we investigated the changes in intestinal microbiota and Paneth cell antimicrobial peptides (AMPs) in HTG-related ANP (HANP) in rats. Rats fed a high-fat diet to induce HTG and ANP was induced by retrograde injection of 3.5% sodium taurocholate into biliopancreatic duct. Rats were sacrificed at 24 and 48 h, respectively. Pancreatic and ileal injuries were evaluated by histological scores. Intestinal barrier function was assessed by plasma diamine oxidase activity and D-lactate level. Systemic and intestinal inflammation was evaluated by tumor necrosis factor alpha (TNFα), interleukin (IL)-1β, and IL-17A expression. 16S rRNA high throughput sequencing was used to investigate changes in intestinal microbiota diversity and structure. AMPs (α-defensin5 and lysozyme) expression was measured by real-time polymerase chain reaction (PCR) and immunofluorescence. The results showed that compared with those of normal-lipid ANP (NANP) groups, the HANP groups had more severe histopathological injuries in pancreas and distal ileum, aggravated intestinal barrier dysfunction and increased TNFα, IL-1β, and IL-17A expression in plasma and distal ileum. Principal component analysis showed structural segregation between the HANP and NANP group. α-Diversity estimators in the HANP group revealed decreased microbiota diversity compared with that in NANP group. Taxonomic analysis showed dysbiosis of intestinal microbiota structure. In the HANP group, at phyla level, Candidatus_Saccharibacteria and Tenericutes decreased significantly, whereas Actinobacteria increased. At genus level, Allobaculum, Bifidobacterium, and Parasutterella increased significantly, while Alloprevotella, Anaerotruncus, Candidatus_Saccharimonas, Christensenellaceae_R-7_group, Rikenellaceae_RC9_gut_group, Ruminiclostridium_5, Ruminococcaceae_UCG-005, and Ruminococcaceae_UCG-014 decreased. Compared with those in the NANP rats, mRNA expression of lysozyme and α-defensin5 and protein expression of lysozyme decreased significantly in the HANP rats. Moreover, in the NANP rats and the HANP rats, Allobaculum abundance was inversely correlated with lysozyme expression, while Anaerotruncus abundance was positively correlated with it by Spearman test. In conclusion, intestinal microbiota dysbiosis and decreased AMPs of Paneth cells might participate in the pathogenesis of intestinal barrier dysfunction in HANP.

ObjectivesIntestinal barrier dysfunction plays an important role in acute necrotizing pancreatitis (ANP) and intestinal microbiota dysbiosis was involved in intestinal barrier failure. Paneth cells protect intestinal barrier and are associated with intestinal microbiota. Here, we investigated changes in intestinal microbiota and antimicrobial peptides of Paneth cells in ileum during ANP.MethodsRats with ANP were established by retrograde injection of 3.5% sodium taurocholate into biliopancreatic duct and sacrificed at 24h and 48h, respectively. Injuries of pancreas and distal ileum were evaluated by histopathological score. Intestinal barrier function was assessed by plasma diamine oxidase activity (DAO) and D-lactate. Systemic and intestinal inflammation was evaluated by TNFα, IL-1β and IL-17A concentration by ELISA, respectively. 16S rRNA high throughput sequencing on fecal samples was used to investigate the changes in intestinal microbiota in the ANP group at 48h. Lysozyme and α-defensin5 were measured by real-time PCR, western blot and immunofluoresence.ResultsANP rats had more severe histopathological injuries in pancreas and distal ileum, injured intestinal barrier and increased expression of TNFα, IL-1β and IL-17A in plasma and distal ileum compared with those of the sham-operated (SO) group. Principal component analysis (PCA) showed structural segregation between the SO and ANP groups. Operational taxonomic unit (OTU) number and ACE index revealed decreased microbiota diversity in the ANP group. Taxonomic analysis showed dysbiosis of intestinal microbiota structure. At phyla level, Saccharibacteria and Tenericutes decreased significantly. At genus level, Escherichia-Shigella and Phascolarctobacterium increased significantly, while Candidatus_Saccharimonas, Prevotellaceae_UCG-001, Lachnospiraceae_UCG-001, Ruminiclostridium_5 and Ruminococcaceae_UCG-008 decreased significantly. Lysozyme and α-defensin5 mRNA expression levels decreased significantly in ANP group at 48h. Protein expression of lysozyme decreased in ANP groups at 24h and 48h. Meanwhile, the relative abundance of Escherichia-Shigella correlated inversely with the decrease in lysozyme.ConclusionThe disorder in intestinal microbiota and decreases of Paneth cell antimicrobial peptides might participate in the pathogenesis of intestinal barrier dysfunction during ANP.

D receptors control pancreatic inflammation in AP by inhibiting NF-κB activation via a PP2A-dependent Akt signalling pathway.

Previous studies revealed that there existed great individual variations of gut microbiota in mice, and the gut bacteria of mice were changed with the occurrence and development of diseases. To identify the core gut bacteria in healthy mice and explore their relationships with the host phenotypes would help to understand the underlying mechanisms. In this study, we identified 37 genus-level core bacteria from feces of 101 healthy mice with different ages, sexes, and mouse strains in three previous studies. They collectively represented nearly half of the total sequences, and predominantly included carbohydrate- and amino acids-metabolizing bacteria and immunomodulatory bacteria. Among them, Anaerostipes indwelt the gut of all healthy mice. Co-abundance analysis showed that these core genera were clustered into five groups (Group C1–C5), which were ecologically related. For example, the abundances of Group C2 including probiotics Bifidobacterium and Lactobacillus slightly positively correlated with those of Group C1. Principal component analysis (PCA) and multivariate analysis of variance test revealed that these core gut genera were distinguished with age and sex, and also associated with their health/disease state. Linear discriminant analysis effect size (LEfSe) method showed that bacteria in Group C1 and C2/C3 increased with the age in infancy and early adulthood, and were more abundant in female mice than in male ones. The metabolic syndrome (MS) induced by high fat diet (HFD) and accelerated postnatal growth would decrease Group C2 genera, whereas probiotics intervention would reverse HFD-induced reduction of Group C2. Spearman correlation analysis indicated that the principal components based on the abundance of the 37 core genera were significantly correlated with host characteristic parameters of MS. These results demonstrated that the 37 core genera in five co-abundance groups from healthy mice were related to host phenotypes. It was indicated that these prevalent gut bacterial genera could be representative of the healthy gut microbiome in gnotobiotic animal models, and might also be candidates of probiotics and fecal microbiota transplantation.