01/01/17

Sunday, January 1, 2017

Walking group: Banish boredom, boost motivation

From: http://www.mayoclinic.org/healthy-lifestyle/fitness/in-depth/walking/art-20045837

Regulation and function of bone morphogenetic protein signaling in colonic injury and inflammation

The bone morphogenetic proteins (BMPs) regulate gastrointestinal homeostasis. We investigated the expression of BMP-4 and the localization and function of BMP signaling during colonic injury and inflammation. Mice expressing the β-galactosidase (β-gal) gene under the control of a BMP-responsive element (BRE), BMP-4-β-gal/ mice, and animals generated by crossing villin-Cre mice to mice with floxed alleles of BMP receptor 1A (villin-Cre;Bmpr1a^flox/flox) were treated with dextran sodium sulfate (DSS) to induce colonic injury and inflammation. Expression of BMP-4, β-gal, BMPR1A, IL-8, α-smooth muscle actin, and phosphorylated Smad1, -5, and -8 was assessed by X-Gal staining, quantitative RT-PCR, and immunohistochemistry. Morphology of the colonic mucosa was examined by staining with hematoxylin and eosin. The effect of IFN-, TNF-α, IL-1β, and IL-6 on BMP-4 mRNA expression was investigated in human intestinal fibroblasts, whereas that of BMP-4 on IL-8 was assessed in human colonic organoids. BMP-4 was localized in α-smooth muscle actin-positive mesenchymal cells while the majority of BMP-generated signals targeted the epithelium. DSS caused injury and inflammation leading to reduced expression of BMP-4 and of BMPR1A mRNAs, and to decreased BMP signaling. Deletion of BMPR1A enhanced colonic inflammation and damage. Administration of anti-TNF-α antibodies to DSS-treated mice ameliorated colonic inflammation and increased the expression of BMP-4 and BMPR1A mRNAs. TNF-α and IL-1β inhibited both basal and IFN--stimulated BMP-4 expression, whereas IL-6 had no effect. BMP-4 reduced TNF-α-stimulated IL-8 mRNA expressor IL-8 mRNA expression in the organoids. Inflammation and injury inhibit BMP-4 expression and signaling, leading to enhanced colonic damage and inflammation. These observations underscore the importance of BMP signaling in the regulation of intestinal inflammation and homeostasis.

NEW & NOTEWORTHY In this study we report a series of novel observations that underscore the importance of bone morphogenetic protein (BMP) signaling in the regulation of colonic homeostasis during the development of injury and inflammation. In particular, we present evidence that BMP signaling mitigates the response of the colonic epithelium to injury and inflammation and that cytokines, such as TNF-α and IL-1β, inhibit the expression of BMP-4.

From: Ji, T., Takabayashi, H., Mao, M., Han, X., Xue, X., Brazil, J. C., Eaton, K. A., Shah, Y. M., Todisco, A. http://ajpgi.physiology.org/cgi/content/abstract/312/1/G24?rss=1

Probiotic mixture VSL#3 reduces colonic inflammation and improves intestinal barrier function in Muc2 mucin-deficient mice

MUC2 mucin is the major glycoprotein in colonic mucus that separates intestinal microbiota from underlying host cells and serves as a food source for some eubacteria. MUC2 deficiency results in impaired epithelial barrier function, imbalance in gut microbiota, and spontaneous colitis. Probiotics have been shown to have a protective effect against colitis. In this study we used Muc2 mucin-deficient (Muc2^–/–) and Muc2^+/+ littermates to test whether the probiotic mixture VSL#3 requires an intact mucin barrier to exert its beneficial effect. VSL#3 alone reduced basal colonic proinflammatory cytokine levels and improved epithelial barrier function in Muc2^–/– animals. Similarly, in dextran sulfate sodium-induced colitis, VSL#3 dampened the proinflammatory chemokines KC, monocyte chemoattractant protein-1, and macrophage inflammatory protein-2 and upregulated the tissue regeneration growth factors transforming growth factor-β, fibroblast growth factor-1, and vascular endothelial growth factor-A, which accelerated resolution of colitis symptoms in Muc2^–/– animals. Importantly, improved colonic health in VSL#3-treated animals was associated with attenuated reactive oxygen species production by peritoneal macrophages, restoration of antimicrobial peptide gene expression in the small intestine, and increased abundance of bacterial commensals in the gut. The beneficial effects of VSL#3 in Muc2^–/– animals were mediated by acetate, an important short-chain fatty acid produced by gut bacteria. These studies provide evidence for the first time that VSL#3 can enhance epithelial barrier function by dampening the proinflammatory cytokine and chemokine response, accelerating restitution, and altering commensal microbiota in the absence of a functional mucus barrier.

NEW & NOTEWORTHY It is unclear whether probiotics require an intact mucin barrier to first colonize and/or exert their protective functions. In this study we used mucin-deficient (Muc2^–/–) mice to interrogate if the multispecies probiotic mixture VSL#3 could enhance epithelial barrier function. In the absence of a mucus bilayer, VSL#3 dampened proinflammatory and chemokine production, accelerated restitution, and markedly improved gut permeability mediated by the short-chain fatty acid acetate in the colon.

From: Kumar, M., Kissoon-Singh, V., Coria, A. L., Moreau, F., Chadee, K. http://ajpgi.physiology.org/cgi/content/abstract/312/1/G34?rss=1

Novel insights into fecal incontinence in men

Fecal incontinence (FI) in men is common, yet data on sex differences in clinical features, physiology, and treatment are scarce. Our aim was to provide insights into FI in males compared with females. Prospectively collected data from 73 men and 596 women with FI in a tertiary referral center were analyzed. Anorectal physiology, clinical characteristics, and outcome of instrumented biofeedback (BF) were recorded. Thirty-one men with FI proceeded to BF and were matched with 62 age-matched women with FI who underwent BF. Men with FI had higher resting, squeeze, and cough anal sphincter pressures (P < 0.001) and were more able to hold a sustained squeeze compared with women (P = 0.04). Men with FI had higher rectal pressure and less inadequate rectal pressure on strain and higher sensory thresholds (P < 0.05). Men, but not women, with isolated soiling had higher anal resting and squeeze pressures compared with those with overt FI (P < 0.05). Men were less likely to undergo BF when offered compared with women. Baseline symptom severity did not differ between the groups. In men, the absence of an organic cause for the FI and the presence of overt FI, but not isolated soiling, were correlated with improvement in patient satisfaction following BF. The outcomes of 50% reduction in FI episodes, physician assessment, symptoms, and quality of life scores after BF all significantly improved in men similarly to women. We conclude that men, compared with women, with FI have unique clinical features and physiology and are less likely to have investigations and treatment despite successful outcome with BF. Future studies to customize treatment in males and determine barriers to therapy are warranted.

NEW & NOTEWORTHY Fecal incontinence in men is common, yet data on sex differences in clinical features, physiology, and treatment are scarce. We provide evidence that men, compared with women, with fecal incontinence have unique clinical features and physiology and are less likely to have investigations and treatment despite successful outcome with anorectal biofeedback therapy.

From: Mazor, Y., Jones, M., Andrews, A., Kellow, J. E., Malcolm, A. http://ajpgi.physiology.org/cgi/content/abstract/312/1/G46?rss=1

A model of the enteric neural circuitry underlying the generation of rhythmic motor patterns in the colon: the role of serotonin

We discuss the role of multiple cell types involved in rhythmic motor patterns in the large intestine that include tonic inhibition of the muscle layers interrupted by rhythmic colonic migrating motor complexes (CMMCs) and secretomotor activity. We propose a model that assumes these motor patterns are dependent on myenteric descending 5-hydroxytryptamine (5-HT, serotonin) interneurons. Asynchronous firing in 5-HT neurons excite inhibitory motor neurons (IMNs) to generate tonic inhibition occurring between CMMCs. IMNs release mainly nitric oxide (NO) to inhibit the muscle, intrinsic primary afferent neurons (IPANs), glial cells, and pacemaker myenteric pacemaker interstitial cells of Cajal (ICC-MY). Mucosal release of 5-HT from enterochromaffin (EC) cells excites the mucosal endings of IPANs that synapse with 5-HT descending interneurons and perhaps ascending interneurons, thereby coupling EC cell 5-HT to myenteric 5-HT neurons, synchronizing their activity. Synchronized 5-HT neurons generate a slow excitatory postsynaptic potential in IPANs via 5-HT₇ receptors and excite glial cells and ascending excitatory nerve pathways that are normally inhibited by NO. Excited glial cells release prostaglandins to inhibit IMNs (disinhibition) to allow full excitation of ICC-MY and muscle by excitatory motor neurons (EMNs). EMNs release ACh and tachykinins to excite pacemaker ICC-MY and muscle, leading to the simultaneous contraction of both the longitudinal and circular muscle layers. Myenteric 5-HT neurons also project to the submucous plexus to couple motility with secretion, especially during a CMMC. Glial cells are necessary for switching between different colonic motor behaviors. This model emphasizes the importance of myenteric 5-HT neurons and the likely consequence of their coupling and uncoupling to mucosal 5-HT by IPANs during colonic motor behaviors.

From: Smith, T. K., Koh, S. D. http://ajpgi.physiology.org/cgi/content/abstract/312/1/G1?rss=1

Weight gain in mice on a high caloric diet and chronically treated with omeprazole depends on sex and genetic background

The impact of omeprazole (OM), a widely used over-the-counter proton pump inhibitor, on weight gain has not been extensively explored. We examined what factors, e.g., diet composition, microbiota, genetic strain, and sex, might affect weight gain in mice fed a high caloric diet while on OM. Inbred C57BL/6J strain, a 50:50 hybrid (B6SJLF1/J) strain, and mice on a highly mixed genetic background were fed four diets: standard chow (STD, 6% fat), STD with 200 ppm OM (STD + O), a high-energy chow (HiE, 11% fat), and HiE chow with OM (HiE + O) for 17 wk. Metabolic analysis, body composition, and fecal microbiota composition were analyzed in C57BL/6J mice. Oral glucose tolerance tests were performed using mice on the mixed background. After 8 wk, female and male C57BL/6J mice on the HiE diets ate less, whereas males on the HiE diets compared with the STD diets gained weight. All diet treatments reduced energy expenditure in females but in males only those on the HiE + O diet. Gut microbiota composition differed in the C57BL/6J females but not the males. Hybrid B6SJLF1/J mice showed similar weight gain on all test diets. In contrast, mixed strain male mice fed a HiE + O diet gained ~40% more weight than females on the same diet. In addition to increased weight gain, mixed genetic mice on the HiE + O diet cleared glucose normally but secreted more insulin. We concluded that sex and genetic background define weight gain and metabolic responses of mice on high caloric diets and OM.

From: Saqui-Salces, M., Tsao, A. C., Gillilland, M. G., Merchant, J. L. http://ajpgi.physiology.org/cgi/content/abstract/312/1/G15?rss=1

Remarkable recovery: Retired NYPD sergeant beats rare cancer

Hector Camacho was diagnosed with a rare cancer last year, and told his chances of survival were less than five percent -- now he is cancer free

From: http://www.cbsnews.com/news/hector-camacho-remarkable-recovery-retired-nypd-sergeant-beats-rare-cancer/