The transcription factor hepatocyte nuclear factor 4A acts in the intestine to promote white adipose tissue energy storage.

The transcription factor hepatocyte nuclear factor 4 A (HNF4A) controls the metabolic features of several endodermal epithelia. Both HNF4A and HNF4G are redundant in the intestine and it remains unclear whether HNF4A alone controls intestinal lipid metabolism. Here we show that intestinal HNF4A is not required for intestinal lipid metabolism per se, but unexpectedly influences whole-body energy expenditure in diet-induced obesity (DIO). Deletion of intestinal HNF4A caused mice to become DIO-resistant with a preference for fat as an energy substrate and energetic changes in association with white adipose tissue (WAT) beiging. Intestinal HNF4A is crucial for the fat-induced release of glucose-dependent insulinotropic polypeptide (GIP), while the reintroduction of a stabilized GIP analog rescues the DIO resistance phenotype of the mutant mice. Our study provides evidence that intestinal HNF4A plays a non-redundant role in whole-body lipid homeostasis and points to a non-cell-autonomous regulatory circuit for body-fat management.

The effect of culturally-adapted health education interventions among culturally and linguistically diverse (CALD) patients with a chronic illness: A meta-analysis and descriptive systematic review.

OBJECTIVE: To review the effectiveness of health education interventions adapted for culturally and linguistically diverse (CALD) populations with a chronic illness. METHODS: A systematic review and meta-analysis were conducted. Eligible studies were identified across six databases. Data were extracted and intervention effect was summarized using standardized mean difference. If there were insufficient data for meta-analysis, a descriptive summary was included. Modifying effects of intervention format, length, intensity, provider, self-management skills taught, and behavioral change techniques (BCTs) utilized were examined. RESULTS: 58 studies were reviewed and data were extracted for 36 outcomes. Most interventions used multiple modes of delivery and were facilitated by bilingual health care professionals (HCPs). On average, interventions included 5.19 self-management skills and 4.82 BCTs. Interventions were effective in reducing BMI, cholesterol, triglycerides, blood glucose, HbA1C, and depression, and in increasing knowledge. Effectiveness was influenced partly by provider, with HCPs favored over lay providers or paraprofessionals in increasing knowledge; however, the opposite was noted for HbA1c. CONCLUSIONS: Health education interventions are effective among CALD populations, particularly at improving objective, distal outcomes (e.g., anthropometric measures). These interventions may be equally effective in improving proximal patient-reported outcomes (PROs); however, diversity in PROs limited analyses. PRACTICE IMPLICATIONS: Core outcome sets (COS) are needed to further investigate and compare health education intervention effectiveness on PROs.

Developing education materials for caregivers of culturally and linguistically diverse patients: Insights from a qualitative analysis of caregivers' needs, access and understanding of information.

OBJECTIVES: To explore the information needs of caregivers of culturally and linguistically diverse (CALD) patients, and how they access and understand health information related to the management of their care person's chronic illness(es). BACKGROUND: Caregivers of CALD patients experience greater unmet needs compared to the general caregiver population. They experience many challenges in identifying resources and accessing formal supports to aid in self-management behaviours. METHODS: Eleven caregivers were recruited from outpatient clinics in Québec, Canada. Consenting caregivers participated in one face-to-face or phone interview. A qualitative descriptive design and inductive content analysis were used to identify themes. RESULTS: Caregivers described a "village" approach to caregiving in which more than one individual was involved in patient care. The specific roles ascribed to caregivers defined their information needs. Caregivers described two categories of information needs: perceived and unperceived. Perceived information needs were explicit, and centred on the medical management of illnesses. Unperceived needs were unrecognized knowledge gaps that emerged during interviews and focused on self-care. CONCLUSION: Although caregivers' perceived needs are often met, their unperceived needs remain unmet. Health-care providers should perform need assessments to identify caregivers' unperceived needs, with the aims of providing culturally competent care and ongoing support.

The tyrosine phosphatase Shp-2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration.

The Src homology-2 domain-containing tyrosine phosphatase 2 (SHP-2) regulates many cellular processes, including proliferation, differentiation and survival. Polymorphisms in the gene encoding SHP-2 are associated with an increased susceptibility to develop ulcerative colitis. We recently reported that intestinal epithelial cell (IEC)-specific deletion of Shp-2 in mice (Shp-2IEC-KO ) leads to chronic colitis and colitis-associated cancer. This suggests that SHP-2-dependent signaling protects the colonic epithelium against inflammation and colitis-associated cancer development. To verify this hypothesis, we generated mice expressing the Shp-2 E76K activated form specifically in IEC. Our results showed that sustained Shp-2 activation in IEC increased intestine and crypt length, correlating with increased cell proliferation and migration. Crypt regeneration capacity was also markedly enhanced, as revealed by ex vivo organoid culture. Shp-2 activation alters the secretory cell lineage, as evidenced by increased goblet cell numbers and mucus secretion. Notably, these mice also demonstrated elevated ERK signaling in IEC and exhibited resistance against both chemical- and Citrobacter rodentium-induced colitis. In contrast, mice with IEC-specific Shp-2 deletion displayed reduced ERK signaling and rapidly developed chronic colitis. Remarkably, expression of an activated form of Braf in Shp-2-deficient mice restored ERK activation, goblet cell production and prevented colitis. Altogether, our results indicate that chronic activation of Shp-2/ERK signaling in the colonic epithelium confers resistance to mucosal erosion and colitis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The Muc2 mucin coats murine Paneth cell granules and facilitates their content release and dispersion.

Paneth cells are a key subset of secretory epithelial cells found at the base of small intestinal crypts. Unlike intestinal goblet cells, which secrete the mucin Muc2, Paneth cells are best known for producing an array of antimicrobial factors. We unexpectedly identified Muc2 staining localized around Paneth cell granules. Electron microscopy (EM) confirmed an electron lucent halo around these granules, which was lost in Paneth cells from Muc2-deficient (-/-) mice. EM and immunostaining for lysozyme revealed that Muc2-/- Paneth cells contained larger, more densely packed granules within their cytoplasm, and we detected defects in the transcription of key antimicrobial genes in the ileal tissues of Muc2-/- mice. Enteroids derived from the small intestine of wild-type and Muc2-/- mice revealed phenotypic differences in Paneth cells similar to those seen in vivo. Moreover, lysozyme-containing granule release from Muc2-/- enteroid Paneth cells was shown to be impaired. Surprisingly, Paneth cells within human ileal and duodenal tissues were found to be Muc2 negative. Thus Muc2 plays an important role in murine Paneth cells, suggesting links in function with goblet cells; however human Paneth cells lack Muc2, highlighting that caution should be applied when linking murine to human Paneth cell functions. NEW & NOTEWORTHY We demonstrate for the first time that murine Paneth cell granules possess a halo comprised of the mucin Muc2. The presence of Muc2 exerts an impact on Paneth cell granule size and number and facilitates the release and dispersal of antimicrobials into the mucus layer. Interestingly, despite the importance of Muc2 in murine Paneth cell function, our analysis of Muc2 in human intestinal tissues revealed no trace of Muc2 expression by human Paneth cells.

Exosomes Induce Fibroblast Differentiation into Cancer-Associated Fibroblasts through TGFß Signaling.

A particularly important tumor microenvironment relationship exists between cancer cells and surrounding stromal cells. Fibroblasts, in response to cancer cells, become activated and exhibit myofibroblastic characteristics that favor invasive growth and metastasis. However, the mechanism by which cancer cells promote activation of healthy fibroblasts into cancer-associated fibroblasts (CAF) is still not well understood. Exosomes are nanometer-sized vesicles that shuttle proteins and nucleic acids between cells to establish intercellular communication. Here, bladder cancer-derived exosomes were investigated to determine their role in the activation of healthy primary vesical fibroblasts. Exosomes released by bladder cancer cells are internalized by fibroblasts and promoted the proliferation and expression of CAF markers. In addition, cancer cell-derived exosomes contain TGFß and in exosome-induced CAFs SMAD-dependent signaling is activated. Furthermore, TGFß inhibitors attenuated CAF marker expression in healthy fibroblasts. Therefore, these data demonstrate that bladder cancer cells trigger the differentiation of fibroblasts to CAFs by exosomes-mediated TGFß transfer and SMAD pathway activation. Finally, exosomal TGFß localized inside the vesicle and contributes 53.4% to 86.3% of the total TGFß present in the cancer cell supernatant. This study highlights a new function for bladder cancer exosomes as novel modulators of stromal cell differentiation.Implication: This study identifies exosomal TGFß as new molecular mechanism involved in cancer-associated fibroblast activation. Mol Cancer Res; 16(7); 1196-204. ©2018 AACR.

The Effectiveness of Self-Management Interventions for Individuals with Low Health Literacy and/or Low Income: A Descriptive Systematic Review.

BACKGROUND: With the burden of chronic illness increasing globally, self-management is a crucial strategy in reducing healthcare costs and increasing patient quality of life. Low income and low health literacy are both associated with poorer health outcomes and higher rates of chronic disease. Thus, self-management represents an important healthcare strategy for these populations. The purpose of this study is to review self-management interventions in populations with low income or low health literacy and synthesize the efficacy of these interventions. METHODS: A systematic review of trials evaluating the efficacy of self-management interventions in populations with low income or low health literacy diagnosed with a chronic illness was conducted. Electronic databases were primarily searched to identify eligible studies. Data were extracted and efficacy summarized by self-management skills, outcomes, and content tailoring. RESULTS: 23 studies were reviewed, with ten reporting an overall positive effect on at least one primary outcome. Effective interventions most often included problem-solving as well as taking action and/or resource utilization. A wide range of health-related outcomes were considered, were efficacious empowerment and disease-specific quality of life were found to be significant. The efficacy of interventions did not seem to vary by duration, format, or mode of delivery or whether these included individuals with low health literacy and/or low income. Tailoring did not seem to impact on efficacy. DISCUSSION: Findings suggest that self-management interventions in populations with low income or low health literacy are most effective when three to four self-management skills are utilized, particularly when problem-solving is targeted. Healthcare providers and researchers can use these findings to develop education strategies and tools for populations with low income or low health literacy to improve chronic illness self-management.

Ileal antimicrobial peptide expression is dysregulated in old age.

In an effort to understand the mechanisms underlying the high prevalence of gastrointestinal tract disorders in old age, we investigated the expression of intestinal antimicrobial peptides in the terminal small intestine of aged mice. Our results show that old mice have reduced transcript levels of ileal α-defensins and lysozyme, two important types of intestinal antimicrobial peptides produced by Paneth cells. In contrast, expression of the C-type lectins Reg3b and Reg3g, as well as ß-defensin 1, angiogenin 4 and Relmb, which are made by several epithelial cell types, was significantly upregulated in aged animals suggesting an ongoing response to epithelial distress. Those changes in antimicrobial peptide gene expression associated with histological damage of the ileal epithelium and subtle modifications in the composition of the commensal microbiota. Our findings suggest that dysregulation of antimicrobial peptides expression is a feature of homeostasis disruption in the aged intestine and may contribute to geriatric gastrointestinal dysfunction.

Bile Acid Administration Elicits an Intestinal Antimicrobial Program and Reduces the Bacterial Burden in Two Mouse Models of Enteric Infection.

In addition to their chemical antimicrobial nature, bile acids are thought to have other functions in the homeostatic control of gastrointestinal immunity. However, those functions have remained largely undefined. In this work, we used ileal explants and mouse models of bile acid administration to investigate the role of bile acids in the regulation of the intestinal antimicrobial response. Mice fed on a diet supplemented with 0.1% chenodeoxycholic acid (CDCA) showed an upregulated expression of Paneth cell α-defensins as well as an increased synthesis of the type-C lectins Reg3b and Reg3g by the ileal epithelium. CDCA acted on several epithelial cell types, by a mechanism independent from farnesoid X receptor (FXR) and not involving STAT3 or ß-catenin activation. CDCA feeding did not change the relative abundance of major commensal bacterial groups of the ileum, as shown by 16S analyses. However, administration of CDCA increased the expression of ileal Muc2 and induced a change in the composition of the mucosal immune cell repertoire, decreasing the proportion of Ly6G+ and CD68+ cells, while increasing the relative amount of IgGκ+ B cells. Oral administration of CDCA to mice attenuated infections with the bile-resistant pathogens Salmonella enterica serovar Typhimurium and Citrobacter rodentium, promoting lower systemic colonization and faster bacteria clearance, respectively. Our results demonstrate that bile acid signaling in the ileum triggers an antimicrobial program that can be potentially used as a therapeutic option against intestinal bacterial infections.

Gata4 is critical to maintain gut barrier function and mucosal integrity following epithelial injury.

The intestinal epithelial barrier is critical to limit potential harmful consequences from exposure to deleterious luminal contents on the organism. Although this barrier is functionally important along the entire gut, specific regional regulatory mechanisms involved in the maintenance of this barrier are poorly defined. Herein, we identified Gata4 as a crucial regulator of barrier integrity in the mouse proximal intestinal epithelium. Conditional deletion of Gata4 in the intestine led to a drastic increase in claudin-2 expression that was associated with an important increase of gut barrier permeability without causing overt spontaneous inflammation. Administration of indomethacin, a non-steroidal anti-inflammatory drug (NSAID) that causes enteritis, led to rapid and restricted proximal small intestinal injuries in Gata4 mutant mice as opposed to control mice. Comparative analysis of gene transcript profiles from indomethacin-challenged control and Gata4 mutant mice identified defects in epithelial cell survival, inflammatory cell recruitment and tissue repair mechanisms. Altogether, these observations identify Gata4 as a novel crucial regulator of the intestinal epithelial barrier and as a critical epithelial transcription factor implicated in the maintenance of proximal intestinal mucosal integrity after injury.

Operation airway: the first sustainable, multidisciplinary, pediatric airway surgical mission.

OBJECTIVE: This study aimed to describe the development and implementation of the first sustainable, multidisciplinary, pediatric airway surgical mission in an underserved country. METHODS: This prospective, qualitative study was conducted for the first 4 Operation Airway missions in Quito, Ecuador. The major goals of the missions were to assist children with aerodigestive abnormalities, create a sustainable program where the local team could independently provide for their own patient population, develop an educational curriculum and training program for the local team, and cultivate a collaborative approach to provide successful multidisciplinary care. RESULTS: Twenty patients ages 4 months to 21 years were included. Twenty-three bronchoscopies, 5 salivary procedures, 2 tracheostomies, 1 T-tube placement, 1 tracheocutaneous fistula closure, 2 open granuloma excisions, and 6 laryngotracheal reconstructions (LTRs) were performed. All LTR patients were decannulated. A new type of LTR (1.5 stage) was developed to meet special mission circumstances. Two videofluoroscopic swallow studies and 40 bedside swallow evaluations were performed. One local pediatric otolaryngologist, 1 pediatric surgeon, 3 anesthesiologists, 7 intensivists, 16 nurses, and 2 speech-language pathologists have received training. More than 25 hours of lectures were given, and a website was created collaboratively for educational and informational dissemination (http://www.masseyeandear.org/specialties/pediatrics/pediatric-ent/airway/OperationAirway/). CONCLUSION: We demonstrated the successful creation of the first mission stemming from a teaching institution with the goal of developing a sustainable, autonomous surgical airway program.

Enterohepatic bacterial infections dysregulate the FGF15-FGFR4 endocrine axis.

BACKGROUND: Enterohepatic bacterial infections have the potential to affect multiple physiological processes of the body. Fibroblast growth factor 15/19 (FGF15 in mice, FGF19 in humans) is a hormone that functions as a central regulator of glucose, lipid and bile acid metabolism. FGF15/19 is produced in the intestine and exert its actions on the liver by signaling through the FGFR4-ßKlotho receptor complex. Here, we examined the in vivo effects of enterohepatic bacterial infection over the FGF15 endocrine axis. RESULTS: Infection triggered significant reductions in the intestinal expression of Fgf15 and its hepatic receptor components (Fgfr4 and Klb (ßKlotho)). Infection also resulted in alterations of the expression pattern of genes involved in hepatobiliary function, marked reduction in gallbladder bile volumes and accumulation of hepatic cholesterol and triglycerides. The decrease in ileal Fgf15 expression was associated with liver bacterial colonization and hepatobiliary pathophysiology rather than with direct intestinal bacterial pathogenesis. CONCLUSIONS: Bacterial pathogens of the enterohepatic system can disturb the homeostasis of the FGF15/19-FGFR4 endocrine axis. These results open up a possible link between FGF15/19-FGFR4 disruptions and the metabolic and nutritional disorders observed in infectious diseases.

15-Deoxy-Δ(12,14)-prostaglandin J2 inhibits IL-13 production in T cells via an NF-κB-dependent mechanism.

Interleukin (IL)-13 is a cytokine produced by activated CD4(+) T cells that plays a critical role in promoting allergic responses and tumor cell growth. The 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)) is a natural ligand for the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ), a known regulator of anti-inflammatory activities. We determined the effects of 15d-PGJ(2) on IL-13 expression in the Jurkat E6.1 T-cell line and in peripheral blood mononuclear cells. Semi-quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay revealed that treatment of activated T cells with 15d-PGJ(2) significantly decreased IL-13 mRNA transcription and secretion, respectively. This inhibition by 15d-PGJ(2) was independent of PPAR-γ since treatment with GW9662, an irreversible antagonist of the nuclear receptor, produced no effect. Our data also revealed the involvement of nuclear factor-κB in mediating 15d-PGJ(2)-dependent down regulation of IL-13 expression. Collectively, these results demonstrate the potential of 15d-PGJ(2) in attenuating expression and production of IL-13 in activated T cells.

High sodium butyrate levels induce MDR1 activation in colorectal cells: Impact of 15-deoxy-Δ(12,14)-prostaglandin J(2) on the resistance to saquinavir.

The bioavailability of HIV protease inhibitors is altered by P-glycoproteins (P-gp). The aim of this study was to elucidate the impact of sodium butyrate (NaBut), a unique product of the bacterial fermentation found in elevated concentrations in AIDS patients on P-gp expression. As prostaglandin production is upregulated under inflammatory conditions, we determined the role of 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)) in the NaBut-induced P-gp functionality in colonic epithelial cells. Treatment with NaBut significantly increased MDR1 transcription and P-gp expression on the surface of both types of cells. Nevertheless, the addition of 15d-PGJ(2) to NaBut-stimulated cells significantly upregulated MDR1 mRNA expression and P-gp expression and functionality, leading to an important diminution of saquinavir accumulation by these cells. Our data provide evidence that both NaBut and prostaglandins may profoundly affect the intracellular accumulation of saquinavir in AIDS patients with compromised colonic walls.