Novel dietary strategies to manage sarcopenia.

PURPOSE OF REVIEW: Sarcopenia is a wasting disease, mostly age-related in which muscle strength and mass decline, such as physical performance. With aging, both lower dietary protein intake and anabolic resistance lead to sarcopenia. Moreover, aging and sarcopenia display low-grade inflammation, which also worsen muscle condition. In this review, we focused on these two main targets to study dietary strategies. RECENT FINDINGS: The better understanding in mechanisms involved in sarcopenia helps building combined dietary approaches including physical activity that would slow the disease progression. New approaches include better understanding in the choice of quality proteins, their amount and schedule and the association with antioxidative nutrients. SUMMARY: First, anabolic resistance can be countered by increasing significantly protein intake. If increasing amount remains insufficient, the evenly delivery protein schedule provides interesting results on muscle strength. Quality of protein is also to consider for decreasing risk for sarcopenia, because varying sources of proteins appears relevant with increasing plant-based proteins ratio. Although new techniques have been developed, as plant-based proteins display a lower availability, we need to ensure an adapted overall amount of proteins. Finally, specific enrichment with leucine from whey protein remains the dietary combined approach most studied and studies on citrulline provide interesting results. As cofactor at the edge between anabolic and antioxidative properties, vitamin D supplementation is to recommend. Antioxidative dietary strategies include both fibers, vitamins, micronutrients and polyphenols from various sources for positive effects on physical performance. The ω 3 -polyunsaturated fatty acids also display positive modifications on body composition. Gut microbiota modifiers, such as prebiotics, are promising pathways to improve muscle mass and function and body composition in sarcopenic patients. Nutritional interventions could be enhanced by combination with physical activity on sarcopenia. In healthy older adults, promoting change in lifestyle to get near a Mediterranean diet could be one of the best options. In sarcopenia adults in which lifestyle changes appears unprobable, specific enrichement potentialized with physical activity will help in the struggle against sarcopenia. Longitudinal data are lacking, which makes it hard to draw strong conclusions. However, the effects of a physical activity combined with a set of nutrition interventions on sarcopenia seems promising.

Does so-called "healthy" content on instagram display balanced recipes? A pilot study in relation to the risk of unhealthy eating patterns in social network users.

OBJECTIVE: social networks (SN) including Instagram have increased in popularity. However, SN-mediated content may influence eating behaviors in a negative way. This study analyzed whether Instagram content claimed as "healthy" complies with nutritional guidelines. METHODS: recipes posted in French on Instagram with the caption #healthy or similar ones were analyzed, once from February to May 2023 and again in April 2024. Health authorities' guidelines and food pyramid inclusion criteria were used for the quantitative and qualitative analysis, respectively. Recipes were then classified as balanced, partially unbalanced or unbalanced, with the two subgroups "restrictive" and "excessive", and according to the main protein source. RESULTS: we coded a total of 114 courses (2 datasets of 57 courses each). Among these, 3 were classified as balanced main courses, 45 as partially unbalanced main courses and 66 as unbalanced main courses (21 were deemed as restrictive, 21 as excessive and 24 were otherwise inadequate), with a majority of hypocaloric courses. Approximately half of the recipes were vegetarian or vegan. DISCUSSION: these results suggest that food recipes published on Instagram as #healthy may, at times, be far from nutritional guidelines and could rather promote unbalanced eating patterns. This suggest that food-related content on SN might be insufficiently moderated and that recipes referenced as #healthy should perhaps be accompanied by warnings and preventive measures. This observation, in addition to other detrimental behaviors displayed on SN (e.g. extreme physical activity or body image pressure) may contribute to the increased incidence of eating disorders (ED) associated with problematic SN use. Alerts on this risk and accessible tools for the prevention and early detection of ED risk in SN users are urgently needed.

Analysis of feeding and eating disorders in 191 children according to psychiatric or gastroenterological recruitment: The PEDIAFED cohort study.

OBJECTIVE: The DSM-5 classification introduced new Feeding and Eating Disorders (FED) diagnostic categories, notably Avoidant and Restrictive Food Intake Disorder (ARFID), which, like other FED, can present psychiatric and gastrointestinal symptoms. However, paediatric clinical research that focuses on children below the age of 12 years remains scarce. The aim of this study was first to investigate the clinical features of FED in a cohort of children, second to compare them according to their recruitment (gastroenterology or psychiatry unit). METHOD: This non-interventional retrospective cohort study analysed 191 patients in a French paediatric tertiary care centre (gastroenterology n = 100, psychiatry n = 91). The main outcome variables were clinical data (type of FED, BMI, nutritional support, chronic diseases, psychiatric comorbidities, sensory, sleep, language disorders, gastrointestinal complaints, adverse life events, family history). The outcome was defined by a Clinical Global Impression of Change-score. RESULTS: FED diagnoses were ARFID (n = 100), Unspecified FED (UFED, n = 57), anorexia nervosa (AN, n = 33) and one pica/rumination. Mean follow-up was 3.28 years (SD 1.91). ARFID was associated with selective and sensory disorders (p < 0.001); they had more anxiety disorders than patients with UFED (p < 0.001). Patients with UFED had more chewing difficulties, language disorder (p < 0.001), and more FED related to chronic disease (p < 0.05) than patients with ARFID and AN. Patients with AN were female, underweight, referred exclusively to the psychiatrist, and had more depression than patients with ARFID and UFED (p < 0.001). The gastroenterology cohort included more UFED, while the psychiatry cohort included more psychiatric comorbidities (p < 0.001). A worse clinical outcome was associated with ARFID, a younger age at onset (p < 0.001), selective/sensory disorders and nutritional support (p < 0.05). CONCLUSION: ARFID and UFED children were diagnosed either by gastroenterologists or psychiatrists. Due to frequently associated somatic and psychiatric comorbidities, children with FED should benefit from a multidisciplinary assessment and care.

Effects of Glutamine, Curcumin and Fish Bioactive Peptides Alone or in Combination on Intestinal Permeability in a Chronic-Restraint Stress Model.

Irritable bowel syndrome (IBS), a multifactorial intestinal disorder, is often associated with a disruption in intestinal permeability as well as an increased expression of pro-inflammatory markers. The aim of this study was to first test the impact of treatment with glutamine (Gln), a food supplement containing natural curcumin extracts and polyunsaturated n-3 fatty acids (Cur); bioactive peptides from a fish protein hydrolysate (Ga); and a probiotic mixture containing Bacillus coagulans, Lactobacillus acidophilus, Lactobacillus gasseri and Lactobacillus helveticus. These compounds were tested alone on a stress-based IBS model, the chronic-restraint stress model (CRS). The combination of Gln, Cur and Ga (GCG) was also tested. Eight-week-old C57Bl/6 male mice were exposed to restraint stress for two hours every day for four days and received different compounds every day one week before and during the CRS procedure. Plasma corticosterone levels were measured as a marker of stress, and colonic permeability was evaluated ex vivo in Ussing chambers. Changes in the gene expression of tight junction proteins (occludin, claudin-1 and ZO 1) and inflammatory cytokines (IL1ß, TNFα, CXCL1 and IL10) were assessed using RT-qPCR. The CRS model led to an increase in plasma corticosterone and an increase in colonic permeability compared with unstressed animals. No change in plasma corticosterone concentrations was observed in response to CRS with the different treatments (Gln, Cur, Ga or GCG). Stressed animals treated with Gln, Cur and Ga alone and in combination showed a decrease in colonic permeability when compared to the CRS group, while the probiotic mixture resulted in an opposite response. The Ga treatment induced an increase in the expression of the anti-inflammatory cytokine IL-10, and the GCG treatment was able to decrease the expression of CXCL1, suggesting the synergistic effect of the combined mixture. In conclusion, this study demonstrated that a combined administration of glutamine, a food supplement containing curcumin and polyunsaturated n-3 fatty acids, and bioactive peptides from a fish hydrolysate was able to reduce colonic hyperpermeability and reduce the inflammatory marker CXCL1 in a stress-based model of IBS and could be of interest to patients suffering from IBS.

Eater profile and associated factors in pediatric patients of the PEDIANUT cohort.

Appetite traits have multifactorial origins. In association with environmental and genetic factors, they could become problematic and lead to Feeding or Eating Disorders (FED). As the DSM-5 classification is not suitable for pediatric FED, another way to describe eating behavior is to distinguish the clinical profiles of "small eater" and "big eater". The aim of this study was to identify socio-demographic and medical factors associated with these profiles, and to compare problematic and non-problematic profiles. From the Pedianut study, we analyzed socio-demographic, medical and family history data among 401 children according to 4 age groups (<1 year n = 101, 1-6 years n = 99, 6-12 years n = 100, 12-18 years n = 101). The information collected on eating behavior made it possible to define small eater profile (SEP) and big eater profile (BEP) using predefined grids. BEP was more frequent in adolescents (35.6%), and SEP was more frequent in children aged 1-6 years (34.3%). BEP was associated with having separated parents, being male and the oldest sibling (p < 0.05). Problematic BEP was associated with eating while watching television, being a girl, and having sensory disorders (p < 0.05). SEP was associated, whatever age, with non-breastfeeding, chronic illness, psychological history, sensory disorders, language delays (in the 1-6 year age group), and family history of FED (in the adolescent group) (p < 0.05). This analysis of factors associated with eater profile opens new perspectives for research on risk factors associated with eating traits, which warrants further study in larger populations to delineate transition from healthy to problematic eating.

Delayed avoidant restrictive food intake disorder diagnosis leading to Ogilvie's syndrome in an adolescent.

PURPOSE: Avoidant restrictive food intake disorder (ARFID) was recently characterized, according to the DSM-5 classification, as a feeding and eating disorder (FED). However, ARFID remains poorly known by most pediatricians, but also by psychiatrists and primary care professionals. Despite the fact that patients with ARFID generally have a higher BMI than patients with anorexia nervosa, our purpose was to highlight the fact that they may present severe nutritional deficiencies and major somatic complications when the diagnosis is delayed. METHOD: We describe here a case of a 16-year-old boy who presented with severe undernutrition (BMI = 11.5) leading to Ogilvie's syndrome, which resolved with enteral refeeding. Because of undernutrition, very bad dental condition, and encopresis, some physicians wrongly suspected child neglect, but retrospective analysis of his personal history revealed a long-term FED and sensory specificities that led to the final diagnosis of an ARFID-autism spectrum disorder (ASD) association. A literature review was conducted on the ARFID somatic complications. CONCLUSION: The training of health professionals in the clinical forms of pediatric FED, including ARFID, is necessary, to promote early diagnosis and prevent poor nutritional outcomes. In this case the association of ARFID-ASD and the delay in access to specialized care favored by the disadvantaged social environment led to severe gastrointestinal complications. LEVEL OF EVIDENCE: V, descriptive study.

Autoantibodies reactive to adrenocorticotropic hormone can alter cortisol secretion in both aggressive and nonaggressive humans.

Violent aggression in humans may involve a modified response to stress, but the underlying mechanisms are not well understood. Here we show that naturally present autoantibodies reactive to adrenocorticotropic hormone (ACTH) exhibit distinct epitope-binding profiles to ACTH peptide in subjects with a history of violent aggression compared with controls. Namely, while nonaggressive male controls displayed a preferential IgG binding to the ACTH central part (amino acids 11-24), subjects who had committed violent acts of aggression had IgG with increased affinity to ACTH, preferentially binding to its N terminus (amino acids 1-13). Purified IgGs from approximately half of the examined sera were able to block ACTH-induced cortisol secretion of human adrenal cells in vitro, irrespective of the source of sample (from a control subject or a violent aggressor). Nevertheless, in the resident-intruder test in mice, i.p. injection of residents with ACTH and IgG from aggressive subjects, but not from control subjects, shortened latency for the first attack against intruders. Immunohistochemical screening of violent aggressors' sera on rat brain and pituitary sections did not show IgG binding to ACTH-producing cells, but 4 of 16 sera revealed selective binding to a nonidentified antigen in vasopressinergic neurons of the hypothalamic paraventricular and supraoptic nuclei. Thus, the data show that ACTH-reactive plasmatic IgGs exhibit differential epitope preference in control and violently aggressive subjects. These IgGs can modulate ACTH-induced cortisol secretion and, hence, are involved in the regulation of the stress response. However, the possible role of ACTH-reactive autoantibodies in aggressive behavior needs further investigation.

Commensal Hafnia alvei strain reduces food intake and fat mass in obese mice-a new potential probiotic for appetite and body weight management.

BACKGROUND/OBJECTIVES: Based on the recent identification of E.coli heat shock protein ClpB as a mimetic of the anorexigenic α-melanocyte stimulating hormone (α-MSH), the objective of this study was to preclinically validate Hafnia alvei, a ClpB-producing commensal bacterium as a potential probiotic for appetite and body weight management in overweight and obesity. METHODS: The involvement of enterobacterial ClpB in the putative anti-obesity effects was studied using ClpB-deficient E.coli. A food-grade H. alvei HA4597 strain synthetizing the ClpB protein with an α-MSH-like motif was selected as a candidate probiotic to be tested in ob/ob and high-fat diet (HFD)-fed obese and overweight mice. The relevance of the enterobacterial ClpB gene to human obesity was studied by in silico analysis of fecal metagenomes of 569 healthy individuals from the "MetaHIT" database. RESULTS: Chronic per os administration of native but not ClpB-deficient E.coli strain reduced body weight gain (p < 0.05) and daily meal frequency (p < 0.001) in ob/ob mice. Oral gavage of H.alvei for 18 and 46 days in ob/ob and HFD-fed obese mice, respectively, was well tolerated, reduced body weight gain and fat mass in both obesity models (p < 0.05) and decreased food intake in hyperphagic ob/ob mice (p < 0.001). Elevated fat tissue levels of phosphorylated hormone-sensitive lipase were detected in H.alvei -treated ob/ob mice (p < 0.01). Enterobacterial ClpB gene richness was lower in obese vs. non-obese humans (p < 0.0001) and correlated negatively with BMI in genera of Enterobacter, Klebsiella and Hafnia. CONCLUSIONS: H.alvei HA4597 strain reduces food intake, body weight and fat mass gain in hyperphagic and obese mice. These data combined with low enterobacterial ClpB gene abundance in the microbiota of obese humans provide the rationale for using H.alvei as a probiotic for appetite and body weight management in overweight and obesity.

Comparison of different modes of antibiotic delivery on gut microbiota depletion efficiency and body composition in mouse.

BACKGROUND: The use of animal models with depleted intestinal microbiota has recently increased thanks to the huge interest in the potential role of these micro-organisms in human health. In particular, depletion of gut bacteria using antibiotics has recently become popular as it represents a low cost and easy alternative to germ-free animals. Various regimens of antibiotics are used in the literature, which differ in composition, dose, length of treatment and mode of administration. In order to help investigators in choosing the most appropriate protocol for their studies, we compared here three modes of antibiotic delivery to deplete gut bacteria in C57Bl/6 mice. We delivered one of the most frequently used combination of antibiotics (a mix of ampicillin, neomycin, metronidazole and vancomycin) either ad libitum in drinking water or by oral gavage once or twice per day. RESULTS: We quantified the global bacterial density, as well as the abundance of specific bacterial and fungal taxa, in mouse feces in response to antibiotics exposure. We observed that oral gavage once a day with antibiotics is not a reliable method as it occasionally triggers hyperproliferation of bacteria belonging to the Escherichia/Shigella taxon and leads, as a consequence, to a moderate decrease in fecal bacterial density. Antibiotics delivery by oral gavage twice a day or in drinking water induces in contrast a robust and consistent depletion of mouse fecal bacteria, as soon as 4 days of treatment, and is associated with an increase in fecal moisture content. Extending exposure to antibiotics beyond 7 days does not improve total bacteria depletion efficiency and promotes fungal overgrowth. We show in addition that all tested protocols impact neither gut microbiota recolonization efficiency, 1 or 2 weeks after the stop of antibiotics, nor mice body composition after 1 week of treatment. CONCLUSIONS: Our study provides key experimental data and highlights important parameters to consider before selecting an appropriate protocol for antibiotic-mediated depletion of gut bacteria, in order to optimize the accuracy and the reproducibility of results and to facilitate comparison between studies.

Dispositional optimism is associated with weight status, eating behavior, and eating disorders in a general population-based study.

OBJECTIVE: The objective of this cross-sectional study was to assess whether optimism is associated with body mass index (BMI), eating behavior and eating disorders (EDs) in a population-based study. METHOD: In 2016, a total of 32,805 participants aged ≥18 years from the NutriNet-Santé cohort completed the Life Orientation Test-Revised, assessing dispositional optimism. Height and weight were self-reported. Eating behavior was assessed with the revised 21-item Three-Factor Eating Questionnaire. Risk of EDs was evaluated with the Sick-Control-One-Fat-Food Questionnaire. Linear and Logistic regression was used to analyze the association between optimism, BMI categories, eating behavior and ED risk, controlling for sociodemographic, lifestyle and depressive symptom characteristics. RESULTS: Our sample was composed of 73.5% women, and the mean age was 55.39 ± 13.70 years. More optimistic participants were less likely to be underweight (OR = 0.82; 95% CI: 0.75, 0.89), or obese, particularly class III obese (BMI ≥40 kg/m2 ) (OR = 0.69; 95% CI: 0.56, 0.84) compared with less optimistic individuals. Optimism was negatively associated with cognitive restraint (ß = -.07; 95%CI: -0.08; -0.06), emotional eating (ß = -.17; 95% CI: -0.19, -0.16) and uncontrolled eating (ß = -.10; 95% CI: -0.11, -0.09). In addition, more optimistic participants had a lower risk of EDs (OR = 0.60; 95% CI: 0.56, 0.64). DISCUSSION: Our findings showed that optimism was associated with weight status, eating behavior and risk of EDs in both women and men. The causal structure of the underlying observed association remains unclear and should be further investigated.

Colonic Proteome Signature in Immunoproteasome-Deficient Stressed Mice and Its Relevance for Irritable Bowel Syndrome.

A role for immunoproteasome in the regulation of intestinal permeability has been previously suggested both in mice during water avoidance stress (WAS) and in patients with irritable bowel syndrome (IBS). Here, we provide evidence that the ubiquitin-proteasome system (UPS) contributes to the pathophysiology of IBS. Indeed, we report that colonic proteome is altered in WAS mice and that ß2i subunit deficiency modifies the proteome response that is associated with a limitation of colonic hyperpermeability. Interestingly, we show specific alterations of proteins involved in UPS, mitochondrial, and energy metabolism. We also report changes in the pattern of colonic ubiquitome in diarrhea-predominant IBS (IBS-D) patients and particularly a reduced expression of ubiquitinated proteins involved in the nuclear factor-kappa B (NF-κB) inflammatory signaling pathway. All these data suggest that immunoproteasome targeting may represent a new therapeutic strategy for the treatment of IBS patients with increased intestinal permeability.

Neuropeptide 26RFa (QRFP) is a key regulator of glucose homeostasis and its activity is markedly altered in obese/hyperglycemic mice.

Recent studies have shown that the hypothalamic neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and increasing insulin sensitivity. In this study, we further characterized the role of the 26RFa/GPR103 peptidergic system in the global regulation of glucose homeostasis using a 26RFa receptor antagonist and also assessed whether a dysfunction of the 26RFa/GPR103 system occurs in obese hyperglycemic mice. First, we demonstrate that administration of the GPR103 antagonist reduces the global glucose-induced incretin effect and insulin sensitivity whereas, conversely, administration of exogenous 26RFa attenuates glucose-induced hyperglycemia. Using a mouse model of high-fat diet-induced obesity and hyperglycemia, we found a loss of the antihyperglcemic effect and insulinotropic activity of 26RFa, accompanied with a marked reduction of its insulin-sensitive effect. Interestingly, this resistance to 26RFa is associated with a downregulation of the 26RFa receptor in the pancreatic islets, and insulin target tissues. Finally, we observed that the production and release kinetics of 26RFa after an oral glucose challenge is profoundly altered in the high-fat mice. Altogether, the present findings support the view that 26RFa is a key regulator of glucose homeostasis whose activity is markedly altered under obese/hyperglycemic conditions.

Screening four broad categories of eating disorders: suitability of a clinical algorithm adapted from the SCOFF questionnaire.

BACKGROUND: We evaluated the performance of a clinical algorithm (Expali™), combining two or more positive answers to SCOFF questionnaire with Body Mass Index (BMI), to identify four Broad Categories of eating disorders (ED) derived from DSM-5. METHODS: The clinical algorithm (Expali™) was developed from 104 combinations of BMI levels and answers to five SCOFF questions with at least two positive answers. Two senior ED physicians allocated each combination to one of the four Broad Categories of ED derived from DSM-5: restrictive disorder, bulimic disorder, hyperphagic disorder and other unspecified ED diagnosed by ED clinicians. The performance of Expali™ was evaluated on data from 206 patients with ED. Sensitivity, specificity values and Youden index were calculated for each category. RESULTS: The 206 patients were diagnosed as follows: 31.5% restrictive disorder, 18.9% bulimic disorder, 40.8% hyperphagic disorder and 8.8% other ED. The sensitivity of Expali™ for restrictive, bulimic, hyperphagic and other unspecified ED were respectively: 76.9, 69.2, 79.7 and 16.7%. The Youden index was respectively 0.73, 0.57, 0.67 and 0.07. CONCLUSIONS: In a SCOFF-positive ED population (at least two positive answers), the clinical algorithm Expali™ demonstrated good suitability by correctly classifying three of the four Broad Categories of eating disorders (restrictive, bulimic and hyperphagic disorder). It could be useful both to healthcare professionals and the general population to enable earlier detection and treatment of ED and to improve patient outcomes.

Development of a Remote-Controlled Implantable Rat Sacral Nerve Stimulation System.

OBJECTIVES: Sacral nerve stimulation (SNS) is a surgical treatment of urinary and fecal incontinence. Despite its clinical efficacy, the mechanisms of action of SNS are still poorly known. This may be related to the use of acute stimulation models. Up to date, no rodent model of chronic SNS implants has been developed. Therefore, the aim of this study was to create a fully implantable and remotely controllable stimulating device to establish an animal model of chronic SNS. MATERIALS AND METHODS: The stimulating device consisted of an implantable pulse generator linked to a platinum electrode. The communication with the device was made through an inductive link which allowed to adjust the stimulation parameters; that is, to turn the device on and off or check the battery status remotely. Rats underwent two surgical procedures. In the first procedure, we achieved chronic sacral stimulation but the implanted electrode was not fixated. In the second procedure, the electrode was fixated in the sacral foramen using dental resin. In both cases, the correct positioning of the electrode was evaluated by computed tomography (CT) imaging and the presence of tail tremor in response to high intensity stimulation. We only tested the function of implanted electrode with fixation using micturition frequency assessment following bipolar or unipolar SNS for three days after recovery. RESULTS: CT imaging showed that implantation of the electrode required fixation as we found that the second surgical procedure yielded a more precise placement of the implanted electrode. The correct placement of implanted electrode observed with imaging was always correlated with a successful tail tremor response in rats, therefore we pursued our next experiments with the second surgical procedure and only assessed the tail tremor response. We found that both bipolar and unipolar SNS reduced micturition frequency. CONCLUSION: This stimulating device provides an efficient method to perform chronic SNS studies in rats.

Colonic Mucosal Proteome Signature Reveals Reduced Energy Metabolism and Protein Synthesis but Activated Autophagy during Anorexia-Induced Malnutrition in Mice.

Anorexia nervosa is an eating disorder often associated with intestinal disorders. To explore the underlying mechanisms of these disorders, the colonic proteome was evaluated during activity-based anorexia. Female C57Bl/6 mice were randomized into three groups: Control, Limited Food Access (LFA) and Activity-Based Anorexia (ABA). LFA and ABA mice had a progressive limited access to food but only ABA mice had access to an activity wheel. On colonic mucosal protein extracts, a 2D PAGE-based comparative proteomic analysis was then performed and differentially expressed proteins were identified by LC-ESI-MS/MS. Twenty-seven nonredundant proteins that were differentially expressed between Control, LFA, and ABA groups were identified. ABA mice exhibited alteration of several mitochondrial proteins involved in energy metabolism such as dihydrolipoyl dehydrogenase and 3-mercaptopyruvate sulfurtransferase. In addition, a downregulation of mammalian target of rapamycin (mTOR) pathway was observed leading, on the one hand, to the inhibition of protein synthesis, evaluated by puromycin incorporation and mediated by the increased phosphorylation of eukaryotic elongation factor 2, and on the other hand, to the activation of autophagy, assessed by the increase of the marker of autophagy, form LC3-phosphatidylethanolamine conjugate/Cytosolic form of Microtubule-associated protein 1A/1B light chain 3 (LC3II/LC3I) ratio. Colonic mucosal proteome is altered during ABA suggesting a downregulation of energy metabolism. A decrease of protein synthesis and an activation of autophagy were also observed mediated by mTOR pathway.

Glutamine and the regulation of intestinal permeability: from bench to bedside.

PURPOSE OF REVIEW: Glutamine is the most abundant amino acid in plasma and plays a key role in maintaining the integrity of intestinal barrier. RECENT FINDINGS: Experimental studies showed that glutamine is able to modulate intestinal permeability and tight junction protein expression in several conditions. Recent articles underlined its putative beneficial role in gastrointestinal disorders such as irritable bowel syndrome. SUMMARY: Glutamine is a major nutrient to maintain intestinal barrier function in animals and humans. Depletion of glutamine results in villus atrophy, decreased expression of tight junction proteins and increased intestinal permeability. Moreover, glutamine supplementation can improve gut barrier function in several experimental conditions of injury and in some clinical situations. Furthermore, preventive effects of glutamine in experimental models of intestinal injuries have been recently reported. Despite promising data in experimental models, further studies are needed to evaluate glutamine supplementation in clinical practice.

Interactions between microsatellite instability and human gut colonization by Escherichia coli in colorectal cancer.

Recent studies suggest that colonization of colonic mucosa by pathogenic Escherichia coli could be involved in the development of colorectal cancer (CRC), especially through the production of genotoxins such as colibactin and/or by interfering with the DNA mismatch repair (MMR) pathway that leads to microsatellite instability (MSI). The present study, performed on 88 CRC patients, revealed a significant increase in E. coli colonization in the MSI CRC phenotype. In the same way, E. coli persistence and internalization were increased in vitro in MMR-deficient cells. Moreover, we demonstrated that colibactin-producing E. coli induce inhibition of the mutL homologue 1 (MLH1) MMR proteins, which could lead to genomic instability. However, colibactin-producing E. coli were more frequently identified in microsatellite stable (MSS) CRC. The present study suggests differences in the involvement of colibactin-producing E. coli in colorectal carcinogenesis according to the CRC phenotype. Further host-pathogen interactions studies should take into account CRC phenotypes.

Targeting immunoproteasome and glutamine supplementation prevent intestinal hyperpermeability.

BACKGROUND: Intestinal hyperpermeability has been reported in several intestinal and non-intestinal disorders. We aimed to investigate the role of the ubiquitin proteasome system in gut barrier regulation in two mice models: the water avoidance stress model (WAS) and a post-inflammatory model (post-TNBS). METHODS: Both models were applied in C57BL/6 male mice (n=7-8/group); Proteasome was targeted by injection of a selective proteasome inhibitor or by using knock-out mice for ß2i proteasome subunit. Finally, glutamine supplementation was evaluated. RESULTS: In both models (WAS at day 10, post-TNBS at day 28), we observed an increase in proteasome trypsin-like activity and in inducible ß2/constitutive ß2 subunit protein expression ratio, associated with an increase in intestinal permeability. Moreover, intestinal hyperpermeability was blunted by intraperitoneal injection of selective proteasome inhibitor in WAS and post-TNBS mice. Of note, knock-out mice for the ß2i subunit exhibited a significant decrease in intestinal permeability and fecal pellet output during WAS. Glutamine supplementation also improved colonic permeability in both models. CONCLUSIONS: In conclusion, the proteasome system is altered in the colonic mucosa of WAS and post-TNBS mice with increased trypsin-like activity. Associated intestinal hyperpermeability was blunted by immunoproteasome inhibition.

Bone marrow hematons: An access point to the human hematopoietic niche.

To understand the complex interactions between hematopoietic stem cells and the bone marrow niche, a human experimental model is needed. Our hypothesis is that hematons are an appropriate ex vivo model of human bone marrow. We analyzed the hierarchical hematopoietic cell content and the tissue organization of single hematons from healthy donors. Most (>90%) hematons contained precursors of all cell lineages, myeloid progenitors, and LTC-ICs without preferential commitment. Approximately, half of the hematons could generate significant levels of lympho-myeloid hematopoiesis after transplantation in an NSG mouse model, despite the low absolute numbers of transplanted CD34+ cells. Mesenchymal STRO-1+ and/or CD271+ cells formed a critical network that preserved hematon cohesion, and STRO-1+ cells colocalized with most hematopoietic CD34+ cells (68%). We observed an influence of age and gender. These structures represent a particularly attractive model for studying the homeostasis of the bone marrow niche and pathological changes that occur during diseases.

Effects of tracheal occlusion with retinoic acid administration on normal lung development.

INTRODUCTION: Tracheal occlusion (TO) is an investigational therapy for severe congenital diaphragmatic hernia that decreases pulmonary hypoplasia, but sustained TO also induces deficient surfactant synthesis. Intramuscular maternal administration of retinoic acid (RA) in a surgical rabbit model of congenital diaphragmatic hernia showed a beneficial effect on lung maturation. We evaluated the potential of RA delivery into the trachea and studied the combined effects of TO and RA on normal lung development. METHODS: Experiments were performed on normal rabbit fetuses. Liposomes and capric triglyceride (Miglyol® ), alone and with RA, were administered in the trachea just before TO (d26). Lung morphology and surfactant production were studied at term (d30). RESULTS: Tracheal occlusion increased lung weight and enhanced alveolar development but increased apoptotic activity and decreased surfactant expression. Tracheal injection of RA improved surfactant production to levels of normal controls. CONCLUSION: We established the potential of liposome and Miglyol as RA vehicle for delivering this bioactive molecule in the fetal airways. Tracheal RA injection seems to oppose the effects of TO in fetuses with normal lungs. © 2017 John Wiley & Sons, Ltd.