Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is ...an important risk factor for mortality. Our recent work demonstrated that tumor-derived PTHrP drives adipose tissue browning and cachexia. Here, we show that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia. Fat-specific knockout of PTHR blocked adipose browning and wasting. Surprisingly, loss of PTHR in fat tissue also preserved muscle mass and improved muscle strength. Similarly, PTHR knockout mice were resistant to cachexia driven by tumors. Our results demonstrate that PTHrP and PTH mediate wasting through a common mechanism involving PTHR, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle. Targeting the PTH/PTHrP pathway may have therapeutic uses in humans with cachexia.
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•5/6 nephrectomy and LLC tumors trigger cachexia and adipose tissue browning•Elevated circulating PTH and PTHrP stimulate browning through their receptor PTHR•PTHR function in fat is required for adipose tissue browning and wasting•Loss of PTHR in fat tissue also attenuates skeletal muscle atrophy
Kir et al. reveal a role for the PTH/PTHrP pathway in cachexia driven by kidney failure or cancer and show how PTH and PTHrP stimulate adipose tissue browning through their receptor PTHR. Loss of PTHR in adipocytes blocks atrophy of not only fat tissue, but also skeletal muscle in mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Metabolic syndrome comprises a cluster of related disorders that includes obesity, glucose intolerance, insulin resistance, dyslipidemia, and fatty liver. Recently, gut-derived chronic endotoxemia ...has been identified as a primary mediator for triggering the low-grade inflammation responsible for the development of metabolic syndrome. In the present study we examined the role of the small intestinal brush-border enzyme, intestinal alkaline phosphatase (IAP), in preventing a high-fat-diet–induced metabolic syndrome in mice. We found that both endogenous and orally supplemented IAP inhibits absorption of endotoxin (lipopolysaccharides) that occurs with dietary fat, and oral IAP supplementation prevents as well as reverses metabolic syndrome. Furthermore, IAP supplementation improves the lipid profile in mice fed a standard, low-fat chow diet. These results point to a potentially unique therapy against metabolic syndrome in at-risk humans.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Background Intestinal alkaline phosphatase (IAP) plays a pivotal role in maintaining gut health and well-being. Oral supplementation with IAP in mice improves gut barrier function and prevents ...luminal proinflammatory factors from gaining access to the circulation. In this study, we sought to explore the relationship between IAP and tight junction protein (TJP) expression and function. Study Design The effect of IAP deletion on TJP levels was studied in mouse embryonic fibroblasts (MEFs) generated from IAP-knockout and wild type mice. Regulation of TJPs by IAP was assayed in the human colon cancer Caco-2 and T84 cells by overexpressing the human IAP gene. Tight junction protein levels and localization were measured by using RT q-PCR and antibodies targeting the specific TJPs. Finally, the effect of IAP on inflammation-induced intestinal permeability was measured by in vitro trans-well epithelial electrical resistance (TEER). Results Intestinal alkaline phosphatase gene deletion in MEFs resulted in significantly lower levels of ZO-1, ZO-2, and Occludin compared with levels in wild-type control cells; IAP overexpression in Caco-2 and T84 cells resulted in approximate 2-fold increases in the mRNA levels of ZO-1 and ZO-2. The IAP treatment ameliorated lipopolysaccharide-induced increased permeability in the Caco-2 trans-well system. Furthermore, IAP treatment preserved the localization of the ZO-1 and Occludin proteins during inflammation and was also associated with improved epithelial barrier function. Conclusions Intestinal alkaline phosphatase is a major regulator of gut mucosal permeability and appears to work at least partly through improving TJP levels and localization. These data provide a strong foundation to develop IAP as a novel therapy to maintain gut barrier function.
Under conditions of starvation and disease, the gut barrier becomes impaired, and trophic feeding to prevent gut mucosal atrophy has become a standard treatment of critically ill patients. However, ...the mechanisms responsible for the beneficial effects of enteral nutrition have remained a mystery. Using in vitro and in vivo models, we demonstrate that the brush-border enzyme, intestinal alkaline phosphatase (IAP), has the ability to detoxify lipopolysaccharide and prevent bacterial invasion across the gut mucosal barrier. IAP expression and function are lost with starvation and maintained by enteral feeding. It is likely that the IAP silencing that occurs during starvation is a key component of the gut mucosal barrier dysfunction seen in critically ill patients.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Background: The primary treatment of ulcerative colitis (UC) is conservative, and substantial therapeutic progress has been made in the past few decades. Meanwhile, biologicals have become a mainstay ...in the treatment for steroid-refractory UC. Despite further development of drug therapy and an increased time span to operation, a significant proportion of patients with UC require surgical intervention. Surgical intervention needs to be carried out in medically refractory cases, imminent or malignant transformation, or complications. This article discusses the impact of modern drug therapy on surgery for UC. Methods: A selective literature search of PubMed was conducted, taking into account current studies, reviews, meta-analyses, and guidelines. Selected articles were then reviewed in detail and recommendations were drafted based on data and conclusions of the articles. Results: In recent years, modern drug therapy has changed the timing, approach, and outcomes of surgery for UC. Most of the studies showed a decrease in surgery rates over time while the rate of emergency colectomies remains unchanged. So far, no convincing surgery-sparing effect of newer medications has been established, and it remains debatable if surgery rates have decreased because of improved management for UC in general or due to the introduction of biologicals. The intensified conservative therapy with increasing use of biologics has been accompanied by a trend towards performing a three-step procedure in the last decade. There is a subset of patients with complex refractory disease who most likely benefit from elective surgery as an alternative to prolonged conservative therapies after failure of first-line treatment. The majority of patients after ileal pouch-anal anastomosis can avoid hospitalizations and colitis-related medications with their associated potential adverse effects. In addition, the procedure substantially reduces UC-related symptoms and the risk for dysplasia or cancer. There is a long-term pouch success rate of >90% after 10 and 20 years of follow-up. Conclusion: Conservative medical therapy in the treatment of UC will continue to develop and the number of approved therapeutics will grow. Surgery should not be considered as the negative endpoint of treatment modalities but as a good alternative to a prolonged conservative therapy for some patients. In conclusion, a close cooperation between the various disciplines in the pre- and postoperative management is essential in order to optimize the timing and outcome of patients with UC.
Abstract Background Mentoring of junior faculty by senior faculty is an important part of promotion and/or tenure and enhanced job satisfaction. This study reports the development and results to date ...of a faculty mentorship program in surgery. Methods We implemented a departmental faculty mentoring program in July 2014 that consisted of both structured and informal meetings between junior faculty mentees and assigned senior faculty mentors. All senior faculty mentors attended a brief mentor training session. We then developed an evidence-based mentorship instrument that featured standardized metrics of academic success. This instrument was completed by each mentee, and then reviewed at the junior faculty's annual career conference with their division chief. A survey was distributed in July 2015 to assess junior faculty satisfaction with the new mentorship program. Results Junior or senior faculty consisted of six of three women and 16 of 11 men, respectively. Junior faculty members were aged 40 ± 3 y and had been an attending for 4 ± 2 y. Mentorship meetings occurred approximately three times during the year (range = 0-10). Total meeting time with senior mentors per meeting was a mean of 40 min (range = 0-300 min). Over 75% of junior faculty members were very or somewhat satisfied with the mentorship program and would like to continue in the program. The best aspect of the program was the opportunity to meet with an accomplished surgeon outside their division. Opportunities to improve the program included better matching of mentor to mentee by disease or research focus. Interestingly, almost the entire junior faculty members tended to have at least two other mentors besides the mentor assigned to them in this program. In terms of program outcomes, junior faculty members agreed that the mentorship program improved their overall career plans and enhanced their involvement in professional organizations but has not yet helped with academic productivity, home and/or work balance, and overall job satisfaction. Conclusions A mandatory, structured mentorship program with senior surgeons benefits most junior faculty members in terms of academic career planning and becoming more involved with surgical organizations. More research is required to understand the best method to pair mentors and mentees and more objective measurements of academic surgery success.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The intestinal microbiota plays a pivotal role in maintaining human health and well-being. Previously, we have shown that mice deficient in the brush-border enzyme intestinal alkaline phosphatase ...(IAP) suffer from dysbiosis and that oral IAP supplementation normalizes the gut flora. Here we aimed to decipher the molecular mechanism by which IAP promotes bacterial growth. We used an isolated mouse intestinal loop model to directly examine the effect of exogenous IAP on the growth of specific intestinal bacterial species. We studied the effects of various IAP targets on the growth of stool aerobic and anaerobic bacteria as well as on a few specific gut organisms. We determined the effects of ATP and other nucleotides on bacterial growth. Furthermore, we examined the effects of IAP on reversing the inhibitory effects of nucleotides on bacterial growth. We have confirmed that local IAP bioactivity creates a luminal environment that promotes the growth of a wide range of commensal organisms. IAP promotes the growth of stool aerobic and anaerobic bacteria and appears to exert its growth promoting effects by inactivating (dephosphorylating) luminal ATP and other luminal nucleotide triphosphates. We observed that compared with wild-type mice, IAP-knockout mice have more ATP in their luminal contents, and exogenous IAP can reverse the ATP-mediated inhibition of bacterial growth in the isolated intestinal loop. In conclusion, IAP appears to promote the growth of intestinal commensal bacteria by inhibiting the concentration of luminal nucleotide triphosphates.
Background and Aims
Bacterially derived factors from the gut play a major role in the activation of inflammatory pathways in the liver and in the pathogenesis of alcoholic liver disease. The ...intestinal brush-border enzyme intestinal alkaline phosphatase (IAP) detoxifies a variety of bacterial pro-inflammatory factors and also functions to preserve gut barrier function. The aim of this study was to investigate whether oral IAP supplementation could protect against alcohol-induced liver disease.
Methods
Mice underwent acute binge or chronic ethanol exposure to induce alcoholic liver injury and steatosis ± IAP supplementation. Liver tissue was assessed for biochemical, inflammatory, and histopathological changes. An ex vivo co-culture system was used to examine the effects of alcohol and IAP treatment in regard to the activation of hepatic stellate cells and their role in the development of alcoholic liver disease.
Results
Pretreatment with IAP resulted in significantly lower serum alanine aminotransferase compared to the ethanol alone group in the acute binge model. IAP treatment attenuated the development of alcohol-induced fatty liver, lowered hepatic pro-inflammatory cytokine and serum LPS levels, and prevented alcohol-induced gut barrier dysfunction. Finally, IAP ameliorated
the
activation of hepatic stellate cells and prevented their lipogenic effect on hepatocytes.
Conclusions
IAP treatment protected mice from alcohol-induced hepatotoxicity and steatosis. Oral IAP supplementation could represent a novel therapy to prevent alcoholic-related liver disease in humans.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Background Proctectomy for ulcerative colitis (UC) can be performed via intramesorectal (IME) or total mesorectal excision (TME). Methods We compared patient-reported bowel and sexual ...function among IME versus TME UC patients (September 2000 to March 2011) using the Memorial Sloan-Kettering Cancer Center Bowel Function scale, Fecal Incontinence Quality of Life, Fecal Incontinence Severity Index, Female Sexual Function Instrument, and International Index of Erectile Dysfunction surveys. Results Eighty-nine IME versus TME patients (35 ± 2 years, 57% male, 62% IME) had similar baseline characteristics, although IME patients had more open procedures ( P ≤ .03). IME patients reported better fecal continence ( P = .009) but similar fecal incontinence-related quality of life ( P ≥ .44). For sexual function, there were no differences for either women (Female Sexual Function Instrument; P ≥ .20) or men (International Index of Erectile Dysfunction; P ≥ .22). Conclusions IME appears to be associated with better fecal continence but no difference in overall bowel or sexual function compared with TME in patients with UC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
OBJECTIVE:To determine the role of intestinal alkaline phosphatase (IAP) in enteral starvation-induced gut barrier dysfunction and to study its therapeutic effect as a supplement to prevent ...gut-derived sepsis.
BACKGROUND:Critically ill patients are at increased risk for systemic sepsis and, in some cases, multiorgan failure leading to death. Years ago, the gut was identified as a major source for this systemic sepsis syndrome. Previously, we have shown that IAP detoxifies bacterial toxins, prevents endotoxemia, and preserves intestinal microbiotal homeostasis.
METHODS:WT and IAP-KO mice were used to examine gut barrier function and tight junction protein levels during 48-hour starvation and fed states. Human ileal fluid samples were collected from 20 patients postileostomy and IAP levels were compared between fasted and fed states. To study the effect of IAP supplementation on starvation-induced gut barrier dysfunction, WT mice were fasted for 48 hours +/− IAP supplementation in the drinking water.
RESULTS:The loss of IAP expression is associated with decreased expression of intestinal junctional proteins and impaired barrier function. For the first time, we demonstrate that IAP expression is also decreased in humans who are deprived of enteral feeding. Finally, our data demonstrate that IAP supplementation reverses the gut barrier dysfunction and tight junction protein losses due to a lack of enteral feeding.
CONCLUSIONS:IAP is a major regulator of gut mucosal permeability and is able to ameliorate starvation-induced gut barrier dysfunction. Enteral IAP supplementation may represent a novel approach to maintain bowel integrity in critically ill patients.
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