Microbiota Manipulation as an Emerging Concept in Cancer Therapy.

Background: The human body is colonized by billions of bacteria that provide nutrients to the host, train our immune system, and importantly affect our heath. It has long been suggested that microbes might play a role in tumor pathogenesis; however, compelling evidence was only provided in the past decades when novel detection methods that do not depend on culturing techniques had been developed. Summary: The microbiome impacts tumor development and anti-tumor therapies on various levels. Bacteria can promote or suppress tumor growth via direct interactions with cancer cells, production of metabolites that promote or inhibit tumor growth, and via stimulation or suppression of the local and systemic immune response. Cancer patients harbor a distinct microbiome when compared to healthy controls, which could potentially be employed to detect, identify, and treat cancer. Manipulation of the microbiome either via supplementation of single strains, bacterial consortia, fecal microbiota transfer or the use of pre- and probiotics has been suggested as therapeutic approach to directly target tumor growth or to enhance the efficacy of current state-of-the-art treatment options. Key Messages: (1) Bacteria have a tremendous impact on anti-cancer immune responses. (2) Cancer patients harbor a distinct microbiome when compared to healthy controls. (3) The microbiome seems to be cancer-type specific. (4) Exploitation of bacteria to promote anti-tumor therapy is a novel, very promising venue in cancer treatment.

[Microbiome: from pathophysiology to clinical application?] / Mikrobiom: von der Pathophysiologie in die Klinik?

The "microbiome" or the intestinal microbiota is currently in the focus of scientific interest. The number of publications on the topic of the microbiome is increasing every year. In particular, the role of the microbiome in the pathophysiology of various diseases has been studied. Currently it is impossible to have an overview on all new developments with over 25.000 publication in the field per year. However, some key news stand out from this large number of publications. The first microbiota compounds for the therapy of Clostridioides difficile colitis were approved by the FDA last year or are about to be approved. This means that, for the first time, standardized microbiome products are available in addition to fecal microbiota transplantation (FMT) and are finding their way into everyday clinical practice.

Crosstalk within peripheral blood mononuclear cells mediates anti-inflammatory effects of n-3 PUFA-rich lipid emulsions in parenteral nutrition.

BACKGROUND AND AIMS: Parenteral nutrition (PN) rich in n-6 and n-3 long-chain fatty acids is used in clinical practice for nourishing patients who are unable to receive adequate nutrition through their digestive systems. In this study, we compare the effect on inflammation of the commonly used lipid emulsions Omegaven (n-3-rich) and Intralipid (n-6-rich) in human peripheral blood mononuclear cells (PBMCs). METHODS: PBMCs were treated with different doses of n-3-rich Omegaven and n-6-rich Intralipid and the immune cells were characterized by flow cytometry. RESULTS: We show that incubation of PBMCs with n-3-rich Omegaven leads to an increase in expression of CD1d and CD86 in CD14+monocytes. At the same time, an increased number of NKT cells expressing cytotoxic T cell antigen 4 is observed, suggesting immunological synapse formation. Both CD14+monocytes and NKT cells showed an increase in IL-10 production and a reduction in the pro-inflammatory cytokines IFN-γ, TNF-α, and IL-4, which led to an increase in the number of FOXP3+T regulatory cells. In addition, we show that n-3-rich Omegaven reduces the expression of TNFα, IFNγ and IL-4 in CD4+T and CD8+T cells independent of the presented interaction between CD14+monocytes and NKT cells. The described mechanism of n-3 rich lipid emulsions was confirmed in PBMCs from patients with inflammatory bowel disease but not in colorectal cancer patients which seem to lack the interaction between CD14+monocytes and NKT cells. CONCLUSIONS: These results show a mechanism for the beneficial effect of the n-3-rich Omegaven in patients with inflammatory conditions but questions its use in patients with cancer. Hence, our results may assist in choosing the best lipid emulsion for patients who require PN.

[Eating disorders - what the gastroenterologist needs to know]. / Essstörungen für den/die Gastroenterologen:in ­ was sich zu wissen lohnt.

Eating disorders are potentially life-threatening disorders that go along with severe psychiatric and somatic comorbidities. It is expected that the number of patients will dramatically increase in the post COVID-19 pandemic era.Four main eating disorders are mentioned in the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) and the International Classification of Diseases 11 (ICD-11): anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED) und avoidant restrictive food intake disorder (ARFID). Many traditional assumptions in eating disorders are currently challenged due to recent research results. The gastroenterologist is usually not the first point of contact for patients with eating disorders. However, he is crucial, especially in the management of gastroenterologic complications of eating disorders.Focus of the overview will be on relevant gastroenterologic aspects and less on the psychiatric treatment. Basics of the most common eating disorders will be repeated, opportunities in diagnosing an eating disorder and the most relevant gastroenterologic complications will be described. Obesity and its management, an entity that often goes along with an eating disorder, is not in the spotlight of the review.

Spermidine Ameliorates Colitis via Induction of Anti-Inflammatory Macrophages and Prevention of Intestinal Dysbiosis.

BACKGROUND AND AIMS: Exacerbated immune activation, intestinal dysbiosis and a disrupted intestinal barrier are common features among inflammatory bowel disease [IBD] patients. The polyamine spermidine, which is naturally present in all living organisms, is an integral component of the human diet, and exerts beneficial effects in human diseases. Here, we investigated whether spermidine treatment ameliorates intestinal inflammation and offers therapeutic potential for IBD treatment. METHODS: We assessed the effect of oral spermidine administration on colitis severity in the T cell transfer colitis model in Rag2-/- mice by endoscopy, histology and analysis of markers of molecular inflammation. The effects on the intestinal microbiome were determined by 16S rDNA sequencing of mouse faeces. The impact on intestinal barrier integrity was evaluated in co-cultures of patient-derived macrophages with intestinal epithelial cells. RESULTS: Spermidine administration protected mice from intestinal inflammation in a dose-dependent manner. While T helper cell subsets remained unaffected, spermidine promoted anti-inflammatory macrophages and prevented the microbiome shift from Firmicutes and Bacteroides to Proteobacteria, maintaining a healthy gut microbiome. Consistent with spermidine as a potent activator of the anti-inflammatory molecule protein tyrosine phosphatase non-receptor type 2 [PTPN2], its colitis-protective effect was dependent on PTPN2 in intestinal epithelial cells and in myeloid cells. The loss of PTPN2 in epithelial and myeloid cells, but not in T cells, abrogated the barrier-protective, anti-inflammatory effect of spermidine and prevented the anti-inflammatory polarization of macrophages. CONCLUSION: Spermidine reduces intestinal inflammation by promoting anti-inflammatory macrophages, maintaining a healthy microbiome and preserving epithelial barrier integrity in a PTPN2-dependent manner.

Evaluation of the effect of tramadol, paracetamol and metamizole on the severity of experimental colitis.

Application of dextran sodium sulfate (DSS) is often used to induce experimental colitis. Current state of the art is to refrain from the use of analgesics due to their possible interaction with the model. However, the use of analgesics would be beneficial to reduce the overall constraint imposed on the animals. Here, we analyzed the effect of the analgesics Dafalgan (paracetamol), Tramal (tramadol) and Novalgin (metamizole) on DSS-induced colitis. To study the effect of those analgesics in colitis mouse models, acute and chronic colitis was induced in female C57BL6 mice by DSS administration in the drinking water. Analgesics were added to the drinking water on days four to seven (acute colitis) or on days six to nine of each DSS cycle (chronic colitis). Tramadol and paracetamol had minor effects on colitis severity. Tramadol reduced water uptake and activity levels slightly, while mice receiving paracetamol presented with a better overall appearance. Metamizole, however, significantly reduced water uptake, resulting in pronounced weight loss. In conclusion, our experiments show that tramadol and paracetamol are viable options for the use in DSS-induced colitis models. However, paracetamol seems to be slightly more favorable since it promoted the overall wellbeing of the animals upon DSS administration without interfering with typical readouts of colitis severity.

Performance of two-dimensional shear wave elastography and transient elastography compared to liver biopsy for staging of liver fibrosis.

BACKGROUND: Staging of liver fibrosis traditionally relied on liver histology; however, transient elastography (TE) and more recently two-dimensional shear wave elastography (2D-SWE) evolved to noninvasive alternatives. Hence, we evaluated the diagnostic accuracy of 2D-SWE assessed by the Canon Aplio i800 ultrasound system using liver biopsy as reference and compared the performance to TE. METHODS: In total, 108 adult patients with chronic liver disease undergoing liver biopsy, 2D-SWE and TE were enrolled prospectively at the University Hospital Zurich. Diagnostic accuracies were evaluated using the area under the receiver operating characteristic (AUROC) analysis, and optimal cut-off values by Youden's index. RESULTS: Diagnostic accuracy of 2D-SWE was good for significant (≥F2; AUROC 85.2%, 95% confidence interval (95%CI):76.2-91.2%) as well as severe fibrosis (≥F3; AUROC 86.8%, 95%CI: 78.1-92.4%) and excellent for cirrhosis (AUROC 95.6%, 95%CI: 89.9-98.1%), compared to histology. TE performed equally well (significant fibrosis: 87.5%, 95%CI: 77.7-93.3%; severe fibrosis: 89.7%, 95%CI: 82.0-94.3%; cirrhosis: 96%, 95%CI: 90.4-98.4%), and accuracy was not statistically different to 2D-SWE. 2D-SWE optimal cut-off values were 6.5, 9.8 and 13.1 kPa for significant fibrosis, severe fibrosis and cirrhosis, respectively. CONCLUSIONS: Performance of 2D-SWE was good to excellent and well comparable with TE, supporting the application of this 2D-SWE system in the diagnostic workup of chronic liver disease.

[Which microbiota-based therapies have proven to be effective today?] / Welche mikrobiotaorientierten Therapien sind heute gesichert effektiv?

BACKGROUND: There is increasing interest in the microbiota (this includes bacteria, fungi and viruses) and microbiota-based therapies. The relationship between changes in the composition of the intestinal microbiota and the pathogenesis of various diseases is of specific interest. In particular, the possibilities offered by targeted manipulation of the microbiota composition as specific treatment approaches look promising. OBJECTIVES: This review article summarizes the current data on microbiota-based therapies as well as the evidence-based treatment options applicable for certain diseases. RESULTS: Current data on the clinical effectiveness of microbiota-based therapies varies greatly between different diseases. While certain therapies proved successful in the treatment of some diseases, the data is still insufficient on their effectiveness in other diseases. So far, the most successful treatment in this context is fecal microbiota transplantation with a success rate of 80-90% for the treatment of Clostridioides difficile colitis. CONCLUSIONS: The correction of dysbioses of the intestinal microbiota could provide new possibilities for the treatment of diseases. However, due to the lack of a causal-functional understanding and the mainly descriptive knowledge to date, applications are still limited. The current clinical studies addressing the changes and the importance of intestinal microbiota could lead to new therapeutic options in the treatment of diverse diseases in the future.

Glycoprotein (GP)96 Is Essential for Maintaining Intestinal Epithelial Architecture by Supporting Its Self-Renewal Capacity.

BACKGROUND & AIMS: Glycoprotein (GP)96 is an endoplasmic reticulum-resident master chaperone for cell surface receptors including the Wnt co-receptors low-density lipoprotein-receptor-related protein 5/6. Intestinal epithelial cell (IEC)-specific deletion of Gp96 is embryonically lethal. However, the role of GP96 in adult intestinal tissue and especially within the intestinal stem cell (ISC) niche is unknown. Here, we investigated how GP96 loss interferes with intestinal homeostasis by compromising viability, proliferation, and differentiation of IECs. METHODS: Tamoxifen was used to induce Cre-mediated deletion of Gp96 in GP96-VillincreERT2 (Cre recombinase-Estrogen-Receptor Transgene 2) mice and intestinal organoids. With H&E and immunofluorescence staining we assessed alterations in intestinal morphology and the presence and localization of IEC types. Real-time polymerase chain reaction and Western blot analysis were performed to explore the molecular mechanisms underlying the severe phenotype of Gp96 KO mice and organoids. RESULTS: IEC-specific deletion of Gp96 in adult mice resulted in a rapid degeneration of the stem cell niche, followed by complete eradication of the epithelial layer and death within a few days. These effects were owing to severe defects in ISC renewal and premature ISC differentiation, which resulted from defective Wnt and Notch signaling. Furthermore, depletion of GP96 led to massive induction of endoplasmic reticulum stress. Although effects on ISC renewal and adequate differentiation were partly reversed upon activation of Wnt/Notch signaling, viability could not be restored, indicating that reduced viability was mediated by other mechanisms. CONCLUSIONS: Our work shows that GP96 plays a fundamental role in regulating ISC fate and epithelial regeneration and therefore is indispensable for maintaining intestinal epithelial homeostasis.

TiO2 nanoparticles abrogate the protective effect of the Crohn's disease-associated variation within the PTPN22 gene locus.

OBJECTIVE: Inflammatory bowel disease (IBD) is a multifactorial condition driven by genetic and environmental risk factors. A genetic variation in the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene has been associated with autoimmune disorders while protecting from the IBD subtype Crohn's disease. Mice expressing the murine orthologous PTPN22-R619W variant are protected from intestinal inflammation in the model of acute dextran sodium sulfate (DSS)-induced colitis. We previously identified food-grade titanium dioxide (TiO2, E171) as a neglected IBD risk factor. Here, we investigate the interplay of the PTPN22 variant and TiO2-mediated effects during IBD pathogenesis. DESIGN: Acute DSS colitis was induced in wild-type and PTPN22 variant mice (PTPN22-R619W) and animals were treated with TiO2 nanoparticles during colitis induction. Disease-triggering mechanisms were investigated using bulk and single-cell RNA sequencing. RESULTS: In mice, administration of TiO2 nanoparticles abrogated the protective effect of the variant, rendering PTPN22-R619W mice susceptible to DSS colitis. In early disease, cytotoxic CD8+ T-cells were found to be reduced in the lamina propria of PTPN22-R619W mice, an effect reversed by TiO2 administration. Normalisation of T-cell populations correlated with increased Ifng expression and, at a later stage of disease, the promoted prevalence of proinflammatory macrophages that triggered severe intestinal inflammation. CONCLUSION: Our findings indicate that the consumption of TiO2 nanoparticles might have adverse effects on the gastrointestinal health of individuals carrying the PTPN22 variant. This demonstrates that environmental factors interact with genetic risk variants and can reverse a protective mechanism into a disease-promoting effect.

Effect of closed and permanent stoma on disease course, psychological well-being and working capacity in Swiss IBD cohort study patients.

BACKGROUND: Little is known about the impact of ostomy formation in inflammatory bowel disease patients on course of disease, psychological well-being, quality of life and working capacity. METHODS: We analyzed patients over a follow-up of up to 16 years in the Swiss inflammatory bowel disease cohort study (SIBDCS) with prospective data collection. We compared Ulcerative colitis and Crohn's disease patients with and without ostomy as well as permanent and closed stoma formation before and after surgery, investigating disease activity, psychological wellbeing and working capacity in a case-control design. RESULTS: Of 3825 SIBDCS patients, 176 with ostomy were included in the study and matched with 176 patients without ostomy using propensity score, equaling 352 patients for the analysis. As expected, we observed a lower mean and maximal disease activity in patients after stoma surgery compared with control patients without stoma. Overall, psychological wellbeing in patients with stomas vs. controls as well as patients with permanent vs. closed stoma was similar in terms of disease-specific quality of life (total score of the Inflammatory Bowel Disease Quality of Life questionnaire), psychological distress (total score of the Hospital Anxiety and Depression Scale), and stress at work (effort-reward-imbalance ratio), with the exception of a higher Posttraumatic Diagnostic Scale total score in patient with vs. without stoma. Compared to IBD patients without stoma, the adverse impact on working capacity in overall stoma IBD patients appeared to be modest. However we observe a significantly higher reduction in working capacity in permanent vs. closed stoma in CD but not UC patients. CONCLUSION: As to be expected, IBD patients may benefit from closed and permanent stoma application. Stoma surgery appears to only modestly impact working capacity. Importantly, stoma surgery was not associated with adverse psychological outcomes, with comparable psychological well-being regardless of presence and type of stoma.

Comparison of the Gut Microbiome between Atopic and Healthy Dogs-Preliminary Data.

Human studies show that in addition to skin barrier and immune cell dysfunction, both the cutaneous and the gut microbiota can influence the pathogenesis of atopic diseases. There is currently no data on the gut-skin axis in allergic canines. Therefore, the aim of this study was to assess the bacterial diversity and composition of the gut microbiome in dogs with atopic dermatitis (AD). Stool samples from adult beagle dogs (n = 3) with spontaneous AD and a healthy control group (n = 4) were collected at Days 0 and 30. After the first sampling, allergic dogs were orally dosed on a daily basis with oclacitinib for 30 days, and then re-sampled. Sequencing of the V3-V4 region of the 16S rRNA gene was performed on the Illumina MiSeq platform and the data were analyzed using QIIME2. The atopic dogs had a significantly lower gut microbiota alpha-diversity than healthy dogs (p = 0.033). In healthy dogs, a higher abundance of the families Lachnospiraceae (p = 0.0006), Anaerovoracaceae (p = 0.006) and Oscillospiraceae (p = 0.021) and genera Lachnospira (p = 0.022), Ruminococcustorques group (p = 0.0001), Fusobacterium (p = 0.022) and Fecalibacterium (p = 0.045) was seen, when compared to allergic dogs. The abundance of Conchiformibius (p = 0.01), Catenibacterium spp. (p = 0.007), Ruminococcus gnavus group (p = 0.0574) and Megamonas (p = 0.0102) were higher in allergic dogs. The differences in alpha-diversity and on the compositional level remained the same after 1 month, adding to the robustness of the data. Additionally, we could also show that a 4-week treatment course with oclacitinib was not associated with changes in the gut microbiota diversity and composition in atopic dogs. This study suggests that alterations in the gut microbiota diversity and composition may be associated with canine AD. Large-scale studies preferably associated to a multi-omics approach and interventions targeting the gut microbiota are needed to confirm these results.

Endothelial Barrier Disruption by Lipid Emulsions Containing a High Amount of N3 Fatty Acids (Omegaven) but Not N6 Fatty Acids (Intralipid).

Lipid emulsions are crucial for life-saving total parenteral nutrition (TPN). Their composition provides a high amount of essential fatty acids and calories for millions of patients with serious diseases. Nevertheless, several TPN-mediated side-effects have been reported in over 90% of patients. This project aimed to investigate the effect of a high amount of ω3 fatty acids (Omegaven®) emulsion vs. a high amount of ω6 fatty acids (Intralipid®) emulsions on the endothelial barrier function. EA.hy926 cell line was cultured and incubated with 0.01, 0.1, and 1 mM lipid emulsions. The influence of these lipid emulsions on the barrier function was assessed using ECIS technology, immunofluorescent microscopy, viability measurements by flow cytometry, multiplex cytokines analysis, and qRT-PCR. BODIPY staining confirmed the uptake of fatty acids by endothelial cells. ECIS measurements demonstrated that a high concentration of Omegaven® prevents barrier formation and impairs the barrier function by inducing cell detachment. Moreover, the expression of VE-cadherin and F-actin formation showed a reorganization of the cell structure within 2 h of 1 mM Omegaven® addition. Interestingly, the study's findings contradict previous studies and revealed that Omegaven® at high concentration, but not Intralipid, induces cell detachments, impairing endothelial cells' barrier function. In summary, our studies shed new light on the effect of lipid emulsions on the endothelium.

Ingested nano- and microsized polystyrene particles surpass the intestinal barrier and accumulate in the body.

Plastic pollution is a major global challenge of our times, baring a potential threat for the environment and the human health. The increasing abundance of nanoplastic (NP) and microplastic (MP) particles in the human diet might negatively affect human health since they - particularly in patients suffering from inflammatory bowel disease (IBD) - might surpass the intestinal barrier. To investigate whether ingested plastic particles cross the intestinal epithelium and promote bowel inflammation, mice were supplemented with NP or MP polystyrene (PS) particles for 24 or 12 weeks before inducing acute or chronic dextran sodium sulfate (DSS) colitis with continuous plastic administration. Although ingested PS particles accumulated in the small intestine and organs distant from the gastrointestinal tract, PS ingestion did not affect intestinal health nor did it promote colitis severity. Although the lack of colitis-promoting effects of small PS particles might be a relief for IBD patients, potential accumulative effects of ingested plastic particles on the gastrointestinal health cannot be excluded.