A small intestinal bile acid modulates the gut microbiome to improve host metabolic phenotypes following bariatric surgery.

Bariatric surgical procedures such as sleeve gastrectomy (SG) provide effective type 2 diabetes (T2D) remission in human patients. Previous work demonstrated that gastrointestinal levels of the bacterial metabolite lithocholic acid (LCA) are decreased after SG in mice and humans. Here, we show that LCA worsens glucose tolerance and impairs whole-body metabolism. We also show that taurodeoxycholic acid (TDCA), which is the only bile acid whose concentration increases in the murine small intestine post-SG, suppresses the bacterial bile acid-inducible (bai) operon and production of LCA both in vitro and in vivo. Treatment of diet-induced obese mice with TDCA reduces LCA levels and leads to microbiome-dependent improvements in glucose handling. Moreover, TDCA abundance is decreased in small intestinal tissue from T2D patients. This work reveals that TDCA is an endogenous inhibitor of LCA production and suggests that TDCA may contribute to the glucoregulatory effects of bariatric surgery.

Ang1 and Ang4 differentially affect colitis and carcinogenesis in an AOM-DSS mouse model.

INTRODUCTION: Angiogenin-1 (Ang1) and angiogenin-4 (Ang4) are 14-kDa ribonucleases with potent angiogenic and antimicrobial properties. The role of Ang1 and Ang4 in chronic colitis and colitis-associated cancer has not been previously studied. METHODS: Wild-type (WT) and angiogenin-1 knock-out (Ang1-KO) C57BL/6 mice were given azoxymethane, a colon carcinogen, 2 days in advance of three cycles of 3.5% dextran sodium sulfate (DSS). Disease activity index (DAI) was recorded, a colonoscopy was performed after each DSS treatment, and mice were euthanized (colitis, recovery, cancer) with tissue evaluated by histopathology. Ang1, Ang4, TNF-α, Il-1F062, IL-6, IL-10, IL-23, IL-33 mRNA levels were analyzed by RT-PCR. RESULTS: Ang1-KO mice exhibited more severe colitis compared to WT mice during both the acute (P<0.05) and recovery (P<0.05) phases of each DSS cycle. Consistent with these results, colonic TNF-α, IL1-ß, IL-6, IL-10, and IL-33 mRNA levels were significantly upregulated in Ang1-KO mice (P<0.05). While Ang4 increased to similar levels in both WT and Ang1-KO mice during colitis and recovery phases, WT mice were distinguished by a significant upregulation of Ang1. Interestingly, despite the reduced colitis, WT mice developed significantly more tumors compared to Ang1-KO mice (P<0.05). 134 tumors formed in WT mice (4.6 tumors/mouse) while only 46 tumors formed (1.5 tumors/mice) in Ang1-KO mice, which were also characterized by a 34-fold decrease in Ang4 compared to WT mice and the complete absence of Ang1. CONCLUSIONS: In a mouse model of colitis-associated cancer, Ang1-KO mice develop more severe colitis, but fewer tumors compared to WT mice. Ang1 levels correlate with the severity of colitis and the development of colitis-associated cancer, while Ang4 was upregulated during both colitis and cancer. Ang1 and Ang4 play important regulatory roles in the response to chronic colitis and the development of colitis-associated cancer and may serve as novel therapeutic targets.

Race, Income, and the Timeliness of Cleft Palate Repair in the United States.

Objective To determine if differences exist in the timing of cleft palate repair with respect to sex, race, income, and geographical location within the United States. Design Retrospective cross-sectional study using the Kids' Inpatient Database (KID) from 1997 to 2009. Setting Inpatient. Patients Children with cleft palate with or without cleft lip undergoing inpatient cleft palate repair. Main outcome measures Age at the time of palatoplasty (in months) by sex, race, income quartile, and geographic location. Results A total of 7,218 children with cleft palate underwent repair at a mean age of 12.1 months (95% CI 12.0-12.3). Females underwent palatoplasty at an older age (13.6 months) than males (13.2 months), a difference of 0.47 months (SE: 0.19, p=0.015). White children underwent surgery at an earlier age (12.1 months) than Black (12.9 months) (difference: 0.73 months, SE: 0.37, p=0.045), Hispanic (12.7 months) (difference: 0.57 months, SE 0.25, p=0.025), and Asian children (15.7 months) (difference: 3.60 months, SE 0.49, p<0.0001). Asian children were also found to undergo repair later than Hispanic (difference 3.03 months, SE 0.51, p<0.0001) and Black (difference: 2.87 months, SE 0.59, p<0.0001) children. Patients born into the highest income brackets were repaired 0.75 months earlier than those in the lowest bracket (SE: 0.26, p=0.005). Patients in the Midwest underwent palatoplasty later (14.3 months) than in the Northeast (12.9 months) (difference: 1.36 months, SE: 0.31, p<0.0001), South (13.2 months) (difference: 1.05 months, SE: 0.36, p=0.004), and West (13.2 months) (difference: 1.09 months, SE: 0.32, p=0.0007). Conclusions After controlling for confounding factors, our results suggest that in recent history, Black, Hispanic, and Asian children with cleft palate were repaired later than their White counterparts. In addition, children of affluent families were repaired earliest, and economically disadvantaged children were repaired later than their peers.

Progressive Primary Appendiceal Crohn's Disease in a 21-Year-old Female.

Crohn's disease is an inflammatory bowel disorder that can affect any portion of the gastrointestinal tract, most commonly the terminal ileum near the ileocecal valve. Crohn's disease can be characterized by transmural inflammation and deep fissuring ulcers that predispose to fistula formation and "skip" lesions separated by normal segments of bowel. While often affecting the terminal ileum near the ileocecal valve, Crohn's disease presenting primarily in the appendix is a rare entity. In part due to its low prevalence, cases of appendiceal Crohn's disease can be confused for acute, non-Crohn's-related appendicitis on initial presentation. Although there are published cases of primary appendiceal Crohn's disease in the medical literature, in most cases the diagnosis is made retrospectively following appendectomy for presumed appendicitis. We report on a case of Crohn's disease that was diagnosed pre-operatively, primarily involved the appendix, and which progressed radiographically despite medical therapy and resolution of clinical symptoms. Unique management issues related to this case include the appropriateness of systemic therapy for disease isolated to the appendix, an inability to endoscopically obtain tissue for a definitive diagnosis, and the decision to proceed with surgery in an asymptomatic patient with progressive disease on imaging. Intraoperatively, the appendix was severely inflamed and densely adherent to the left pelvic side wall and adjacent to the left ovary and fallopian tube. A laparoscopic appendectomy was performed. Pathology demonstrated acute appendicitis as well as marked mural chronic inflammation and epithelioid granulomas, consistent with Crohn's disease. Surgical resection may be the most appropriate treatment for Crohn's disease primarily involving the appendix, obviating the need for systemic therapy and minimizing the risk for appendiceal perforation and fistula formation.