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The gastrointestinal tract consists of an enormous surface area that is optimized to efficiently absorb nutrients, water, and electrolytes from food. At the same time, it needs to provide a tight barrier against the ingress of harmful substances, and protect against a reaction to omnipresent harmless compounds. A dysfunctional intestinal barrier is associated with various diseases and disorders. In this review, the role of intestinal permeability in common disorders such as infections with intestinal pathogens, inflammatory bowel disease, irritable bowel syndrome, obesity, celiac disease, non-celiac gluten sensitivity, and food allergies will be discussed. In addition, the effect of the frequently prescribed drugs proton pump inhibitors and non-steroidal anti-inflammatory drugs on intestinal permeability, as well as commonly used methods to assess barrier function will be reviewed.

Intestinal failure, following extensive anatomical or functional loss of small intestine, has debilitating long-term consequences for children 1 . The priority of patient care is to increase the length of functional intestine, particularly the jejunum, to promote nutritional independence 2 . Here we construct autologous jejunal mucosal grafts using biomaterials from pediatric patients and show that patient-derived organoids can be expanded efficiently in vitro. In parallel, we generate decellularized human intestinal matrix with intact nanotopography, which forms biological scaffolds. Proteomic and Raman spectroscopy analyses reveal highly analogous biochemical profiles of human small intestine and colon scaffolds, indicating that they can be used interchangeably as platforms for intestinal engineering. Indeed, seeding of jejunal organoids onto either type of scaffold reliably reconstructs grafts that exhibit several aspects of physiological jejunal function and that survive to form luminal structures after transplantation into the kidney capsule or subcutaneous pockets of mice for up to 2 weeks. Our findings provide proof-of-concept data for engineering patient-specific jejunal grafts for children with intestinal failure, ultimately aiding in the restoration of nutritional autonomy. In a first step toward developing autologous tissue grafts for the treatment of children with intestinal failure, patient-derived jejunal organoids seeded on scaffolds of decellularized human intestinal matrix formed grafts that had jejunal properties and formed luminal structures when transplanted into mice.

An increased intestinal permeability is a common feature in patients with diarrhoea-predominant irritable bowel syndrome (IBS-D). Probiotics have shown to improve IBS symptoms and might also affect intestinal barrier function. The aim of this study was to investigate the effects of a 6-week intervention with Limosilactobacillus reuteri ATCC PTA 6475 alone (single strain) or in combination with Limosilactobacillus reuteri DSM 17938 (dual strain) on gut barrier function, immune markers, and symptoms in IBS-D patients (ClinicalTrials.gov registration number: NCT03986476). 65 IBS-D patients were randomised into three groups (placebo, single strain, dual strain). Small and large intestinal permeability were assessed using a multi-sugar urinary recovery test. Blood, saliva, faecal samples, and several symptom scales were collected before, and after three and six weeks of intervention. Small and large intestinal permeability as well as other markers of gut barrier function were not significantly affected by the probiotic interventions. Serum IL-6 levels showed a tendency to be reduced in the single strain group (descriptive p = 0.052). In addition, high-sensitivity C-reactive protein was significantly reduced in the dual strain group (p = 0.041). The participants in both treatment groups reported less gastrointestinal symptoms after three weeks, but this reached significance only in the dual strain group (total score: p = 0.032, pain subscore: p = 0.028). After six weeks, none of the assessed symptoms were significantly different from the placebo. The probiotic compounds investigated in this study did not seem to affect IBS-D patients' gut barrier function, but showed potential anti-inflammatory and symptom-improving properties, which need to be confirmed in larger study cohorts.

The intestinal barrier plays a crucial role in maintaining gut health, and an increased permeability has been linked to several intestinal and extra-intestinal disorders. There is an increasing demand for interventions aimed at strengthening this barrier and for in vivo challenge models to assess their efficiency. This study investigated the effect of sauna-induced dehydration on intestinal barrier function (clinicaltrials.gov: NCT03620825). Twenty healthy subjects underwent three conditions in random order: (1) Sauna dehydration (loss of 3% body weight), (2) non-steroidal anti-inflammatory drug (NSAID) intake, (3) negative control. Intestinal permeability was assessed by a multi-sugar urinary recovery test, while intestinal damage, bacterial translocation and cytokines were assessed by plasma markers. The sauna dehydration protocol resulted in an increase in gastroduodenal and small intestinal permeability. Presumably, this increase occurred without substantial damage to the enterocytes as plasma intestinal fatty acid-binding protein (I-FABP) and liver fatty acid-binding protein (L-FABP) were not affected. In addition, we observed significant increases in levels of lipopolysaccharide-binding protein (LBP), IL-6 and IL-8, while sCD14, IL-10, IFN-ɣ and TNF-α were not affected. These results suggest that sauna dehydration increased intestinal permeability and could be applied as a new physiological in vivo challenge model for intestinal barrier function.

Psychological stress has been shown to increase intestinal permeability and is associated with the development of gastrointestinal disorders. This study aimed to investigate skydiving as an alternative model to analyse the effect of acute psychological stress on intestinal barrier function. Twenty healthy subjects participated in a tandem skydive followed by a negative control visit, of which 19 (9 females and 10 males, 25.9 ± 3.7 years) were included in the study. Intestinal permeability was assessed by a multi-sugar urinary recovery test. Sucrose recovery and lactulose/rhamnose ratio in 0-5h urine indicated gastroduodenal and small intestinal permeability, respectively, and sucralose/erythritol ratio in 5-24h urine indicated colonic permeability. Blood samples were taken to assess markers associated with barrier function. This study has been registered at ClinicalTrials.gov (NCT03644979) on August 23, 2018. Skydiving resulted in a significant increase in salivary cortisol levels directly after skydiving compared to the control visit. Cortisol levels were still increased two hours after landing, while cortisol levels before skydiving were not significantly different from the baseline at the control visit. Skydiving did not induce a significant increase in gastroduodenal, small intestinal or colonic permeability. There was also no significant increase in plasma intestinal and liver fatty acid-binding proteins, suggesting no damage to the enterocytes. These results show that the acute intense psychological stress induced by skydiving does not affect intestinal permeability in healthy subjects. Future models aiming to investigate the effect of stress on human intestinal barrier function should consider a more sustained exposure to the psychological stressor.

Background Unaccompanied refugee minors (URMs) seeking asylum show high rates of posttraumatic stress disorder (PTSD), depression and anxiety. In addition, they experience post-migration stressors like an uncertain residence status. Therefore, psychotherapeutic interventions for URMs are urgently needed but have scarcely been investigated up to now. This study aimed to examine manualized individual trauma-focused cognitive behavioural therapy (TF-CBT) for URMs with PTSD involving their professional caregivers (i.e. social workers in child and adolescent welfare facilities). Methods We conducted an uncontrolled pilot study with three follow-up assessments (post-intervention, 6 weeks, and 6 months). Participants who met the PTSD diagnostic criteria were treated in a university psychotherapeutic outpatient clinic in Germany with a mean of 15 sessions of TF-CBT. All participants (n = 26) were male UM (M age  = 17.1, SD = 1.0), predominately from Afghanistan (n = 19, 73.1%) and did not have a residence permit. The sample was severely traumatized according to the number of traumatic event types reported (M = 11.3, SD = 2.8). The primary outcome was PTSD measured with the Child and Adolescent Trauma Screen (CATS) and the Diagnostic Interview for Mental Disorders in Childhood and Adolescence (Kinder-DIPS). Secondary outcomes were depression, behavioural and somatic symptoms. All but the somatic symptoms were assessed in both self-report and proxy report. Results At post-intervention the completer sample (n = 19) showed significantly decreased PTSD symptoms, F (1, 18) = 11.41, p  = .003, with a large effect size (d = 1.08). Improvements remained stable after 6 weeks and 6 months. In addition to PTSD symptoms, their caregivers reported significantly decreased depressive and behavioural symptoms in participants. According to the clinical interview, 84% of PTSD cases recovered after TF-CBT treatment. After 6 months, youths whose asylum request had been rejected showed increased PTSD symptoms according to individual trajectories in the Kinder-DIPS. The effect was, however, non-significant. Conclusions Intervention studies are feasible with URMs. This pilot study presents preliminary evidence for the efficacy of an evidence-based intervention like TF-CBT in reducing PTSD symptoms in URMs. Stressors related to asylum proceedings after the end of therapy have the potential to negatively influence psychotherapy outcomes.

The Arabidopsis ER-α-mannosidase I (MNS3) generates an oligomannosidic N-glycan structure that is characteristically found on ER-resident glycoproteins. The enzyme itself has so far not been detected in the ER. Here, we provide evidence that in plants MNS3 exclusively resides in the Golgi apparatus at steady-state. Notably, MNS3 remains on dispersed punctate structures when subjected to different approaches that commonly result in the relocation of Golgi enzymes to the ER. Responsible for this rare behavior is an amino acid signal motif (LPYS) within the cytoplasmic tail of MNS3 that acts as a specific Golgi retention signal. This retention is a means to spatially separate MNS3 from ER-localized mannose trimming steps that generate the glycan signal required for flagging terminally misfolded glycoproteins for ERAD. The physiological importance of the very specific MNS3 localization is demonstrated here by means of a structurally impaired variant of the brassinosteroid receptor BRASSINOSTEROID INSENSITIVE 1. The Arabidopsis ER-α-mannosidase I MNS3 generates N -glycan structures typical of ER-resident glycoproteins. Here Schoberer et al. identify a novel motif that anchors MNS3 to the cis -Golgi, spatially separating MNS3 from ER-localized mannose trimming associated with the ER-associated degradation pathway.

IntroductionThe question of how financial considerations influence medical decision-making is coming to a head in cancer medicine, as cancer medicine is getting more expensive and extensive. As the debate continues, empirical data on specific decision-making situations that are influenced by financial consideration and on the characterisation of financial influence in cancer medicine remain scarce.MethodsWe conducted a qualitative semistructured interview study with physicians who had experience in controlling and budgeting in different settings of cancer care in Germany. Qualitative content analysis was performed to identify specific decision-making situations in cancer medicine influenced by financial considerations and to characterise the financial influence.Resultsn=16 interviews were conducted. We identified 21 medical decision-making situations influenced by financial considerations specific to cancer medicine, which were characterised into four subcategories of financial influence derived from the data: (1) no reimbursement, (2) reimbursement that does not completely cover costs, (3) reimbursement that exceeds the costs and (4) costs covered for treatments with questionable cost-effectiveness. These results imply that medical decisions in cancer medicine could be influenced by financial considerations.ConclusionsThe findings support the hypothesis that medical decision-making in cancer medicine can be influenced by financial considerations. They provide specific examples and a characterisation of the influence as starting points for further quantitative studies on the extent of the financial influence and on the possible effect on high-risk patient groups. Further, they underline the need for ethical analysis regarding the implications for quality of care.

Background While adverse impacts of climate change on physical health are well-known, research on its effects on mental health is still scarce. Thus, it is unclear whether potential impacts have already reached treatment practice. Our study aimed to quantify psychotherapists’ experiences with patients reporting climate change-related concerns and their views on dealing with this topic in psychotherapy. Methods In a nationwide online survey, responses were collected from 573 psychotherapists from Germany. Therapists reported on the presence of such patients, their socio-demographic characteristics, and climate change-related reactions. Psychotherapists’ views on dealing with this topic in psychotherapy were also assessed. Descriptive statistics were used to analyse the responses. Results About 72% (410/573) of psychotherapists indicated having had patients expressing concerns about climate change during treatment. Out of these therapists, 41% (166/410) stated that at least one patient sought treatment deliberately because of such concerns. Patients were mainly young adults with higher education. Most frequent primary diagnoses were depression, adjustment disorder, and generalized anxiety disorder. Psychotherapists having encountered such patients differed from those without such encounters in their views on potential functional impairment and the necessity to target the concerns in treatment. Although 79% (326/415) of all respondents felt adequately prepared by their current therapeutic skills, 50% (209/414) reported a lack of information on how to deal with such concerns in therapy. Conclusions Results indicate that psychotherapists are frequently confronted with climate change-related concerns and regard the mental health impact of climate change on their patients as meaningful to psychotherapeutic care. Regular care could be improved by a continuous refinement of the conceptualization and knowledge of the mental health influences of climate change. This would allow providing tailored methods of assessing and addressing climate change-related concerns in practice.

-glycosylation is an essential protein modification that plays roles in many diverse biological processes including protein folding, quality control and protein interactions. Despite recent advances in characterization of the -glycosylation and -glycan processing machinery our understanding of -glycosylation related processes in plant development is limited. In , failure of mannose trimming from oligomannosidic -glycans in the endoplasmic reticulum (ER) and /medial-Golgi leads to a defect in root development in the triple mutant. Here, we show that the severe root phenotype of is restored in asparagine-linked glycosylation (ALG)-deficient plants with distinct defects in the biosynthesis of the lipid-linked oligosaccharide precursor. The root growth of these ALG-deficient plants is not affected by the α-mannosidase inhibitor kifunensine. Genetic evidence shows that the defect is uncoupled from the glycan-dependent ER-associated degradation (ERAD) pathway that removes misfolded glycoproteins with oligomannosidic -glycans from the ER. Restoration of mannose trimming using a -Golgi targeted α-mannosidase suppresses the defect of roots. These data suggest that processing of terminal mannose residues from oligomannosidic -glycans is important for an unknown late-Golgi or post-Golgi process that is implicated in proper root formation.