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Background: Faecal biomarkers can be used to assess inflammatory bowel disease (IBD). Aim: To explore the performance of some promising biomarkers in diagnosing and predicting disease course in IBD. Methods: We included 65 patients with treatment-na & iuml;ve, new-onset Crohn's disease (CD), 90 with ulcerative colitis (UC), 67 symptomatic controls (SC) and 41 healthy controls (HC) in this prospective observational study. We analysed faecal samples for calprotectin (FC), myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein ECP and eosinophil-derived neurotoxin (EDN) and compared markers among groups. We assessed the diagnostic capability of biomarkers with receiver operating characteristic curves. Clinical disease course was determined for each patient with IBD and analysed the association with biomarkers by logistic regression. Results: All markers were elevated at inclusion in patients with IBD compared with HC (p < 0.001) and SC (p < 0.001). FC (AUC 0.85, 95% CI: 0.79-0.89) and MPO (AUC 0.85, 95% CI: 0.80-0.89) showed the highest diagnostic accuracy in distinguishing IBD from SC. The diagnostic ability of biomarkers differed between IBD subtypes with the highest performance for FC and MPO in CD. The diagnostic accuracy was further improved by combining FC and MPO (p = 0.02). Levels of FC, MPO and HNL at inclusion were predictive of an aggressive disease course with MPO showing the strongest association (p = 0.006). Conclusions: This study provides new insight into the diagnostic and prognostic capability of neutrophil and eosinophil biomarkers in IBD and suggests that MPO, alone or in combination with FC, may add to the diagnostic power of faecal biomarkers., This work was supported by the Swedish Foundation for Strategic Research (grant number RB13-016) (J.H.), Swedish Research Council (grant number 2020-02021) (J.H.), the Örebro University Hospital Research Foundation (grant numbers OLL-890291) (J.H.) and Medical Faculty, Uppsala University, Uppsala, Sweden M.C.

Background: Better prognostic measures for ulcerative colitis (UC) could significantly advance patient care. While the prognostic capacity of circulating proteins in UC has been explored, the role of mucosal proteins remains largely unknown. We examined mucosal protein markers in patients with incident ulcerative colitis and evaluated their prognostic value. Methods: Biopsies from macroscopically inflamed colonic/rectal mucosa of adult patients in the Swedish inception cohort of IBD (SIC IBD) were obtained at diagnosis of UC. Patients were followed prospectively, and clinical data were recorded after 3 and 12 months. Disease course was categorised as indolent or aggressive at 12 months, based on a composite outcome of colectomy, hospital admission for active disease, treatment refractoriness towards ≥2 biological agents; the use of >2 courses of corticosteroids, or a cumulative dose of >2.5 g. Relative estimates of 162 protein markers were assessed in homogenised tissue supernatants, using proximity extension assay technology (Olink Proteomics, Uppsala, Inflammation and Oncology II panel). Mann-Whitney U test, with Benjamini-Hochberg correction was used to identify differentially regulated mucosal proteins in aggressive vs indolent disease course, with a 5% false discovery rate (FDR). Smoothly clipped absolute deviation regularised logistic regression models were used to identify prognostic signatures distinguishing aggressive from indolent disease course. Performance was estimated in a leave-one-out cross-validation and reported as the area under the receiver operating characteristic (ROC) curve (AUC). Results: 117 patients provided a macroscopically inflamed colonic/rectal biopsy at diagnosis of UC. Basic demographics and clinical characteristics are presented in Table 1. Relative protein levels of WFdc2 and CCL20 were significantly lower in lysates from patients developing an aggressive course vs patients developing an indolent course, while estimates of MM

Background: Mental health (MH) has been reported to be poorer among patients with inflammatory bowel disease (IBD) than general population. However, it is not known whether MH is more driven by inflammation itself or related to gastrointestinal (GI) symptoms. Also, the dynamics of MH following IBD diagnosis is not well understood. Methods: In the Swedish Inception Cohort of IBD (SIC-IBD), patients with Crohn’s disease (CD), ulcerative colitis (UC) and unclassified IBD (IBD-U) as well as symptomatic controls (SC) and healthy controls (HC) filled in Patient Health Questionnaire-9 (PHQ-9), a validated screening tool for depression. Patients completed PHQ-9 at diagnosis and at one year follow-up while the controls completed it once. Disease outcome was defined at one year based on requirement of advanced treatments/ surgery. Results: In total, 286 individuals (16 HC, 89 SC, 62 CD, 104 UC, 15 IBD-U) completed the questionnaire at baseline. HC had significantly lower PHQ-9 score, (fewer depressive symptoms), at baseline compared to all the other groups (p<0.01). The baseline PHQ-9 score was not significantly different between SC and CD, UC and IBD-U patients (p=0.06). At one year follow-up, 38 CD and 53 UC patients completed the PHQ-9. Between baseline and follow-up, UC patients had a significant drop in their PHQ-9 score (p<0.0000001), whereas CD patients did not have any significant change in their PHQ-9 score (p=0.06). Furthermore, UC patients had significantly lower PHQ-9 score compared with CD patients at follow-up (p=0.04, Figure 1). Baseline PHQ-9 score was not correlated with calprotectin at baseline neither in UC nor CD patients (p=0.7 and 0.5 respectively). Also, there was no positive correlation between PHQ-9 score change and calprotectin change in either UC or CD patients, and neither baseline nor follow-up PHQ-9 scores were significantly different in patients with poor or good outcome (p>0.05). When analysed separately by sex, there was still no corr

Background: We aimed to identify protein signatures predictive of a future diagnosis of inflammatory bowel disease (IBD). Methods: We conducted a case-control study, nested within large population-based cohorts with biorepositories. Samples were obtained from individuals who later in life were diagnosed with IBD (preclinical cases) and compared with age and sex-matched individuals who remained free from IBD during follow-up (controls). Using proximity extension assays (Olink, Uppsala), we measured 176 proteins. We applied regularized logistic regression to identify protein signatures of preclinical disease in serum from the discovery cohort (n=312). Their performance was validated in an external preclinical cohort (n=222). The biological relevance of identified proteins was further assessed in an inception cohort (n=144). Finally, we used an IBD twin cohort (n=327) to examine the impact of genetic and shared environmental factors on identified proteins. Results: We identified 34 proteins associated with preclinical Crohn’s disease (CD) in the discovery cohort (Pfalse discovery rate <0.10), with 9 confirmed in the validation cohort (Pfalse discovery rate <0.05). For preclinical ulcerative colitis (UC), 45 proteins were identified and 12 validated (Fig. 1A-B). In the discovery cohort, a signature of 29 proteins differentiated preclinical CD cases from controls with an AUC of 0.85 (Fig. 1G). Its performance was confirmed when applied to the preclinical validation cohort (AUC=0.84, Fig. 1H). Moreover, the signature had excellent capacity to differentiate newly diagnosed CD from healthy controls in the inception cohort (AUC = 0.99, Fig. 1I). The preclinical UC signature had a significant, but albeit lower, predictive capacity in the discovery (AUC=0.77), validation (AUC=0.67) and inception cohort (AUC=0.90, Fig. 1G-I).15 of 17 proteins associated with preclinical IBD demonstrated significantly higher intra-pair correlation coefficients in healthy monozygotic- compa

INTRODUCTION: Fecal calprotectin (FC) is a noninvasive tool for examining response to biologics in inflammatory bowel disease (IBD), but its performance in relation to other novel fecal markers of various cellular origins is unknown. METHODS: We performed a prospective multicenter cohort study and included patients with active IBD who provided a fecal sample at initiation of biological therapy. Levels of FC, myeloperoxidase (MPO), human neutrophil lipocalin (HNL), and eosinophil-derived neurotoxin (EDN) were analyzed and related to clinical remission status at 3 months. Changes in levels of markers at 3 months were calculated, and the impact of concomitant use of corticosteroids at baseline was estimated. RESULTS: In patients achieving clinical remission (n = 27), a decrease in levels of FC (P = 0.005), MPO (P < 0.001), HNL (P < 0.001), and EDN (P < 0.001) was observed, whereas no significant decrease was seen in patients not achieving remission (n = 39). There was a significant difference in the change in the level of MPO (P = 0.01) and HNL (P = 0.02) between patients achieving clinical remission and those who did not, but changes in FC and EDN could not differentiate between these groups. Patients with concomitant systemic corticosteroids at inclusion had lower levels of HNL (P = 0.01) and EDN (P < 0.001) at baseline, compared with patients without corticosteroids. DISCUSSION: Fecal MPO, HNL, and EDN are all promising biomarkers for assessing the treatment outcome of biologics in patients with IBD. Fecal levels of EDN and HNL are significantly affected by corticosteroids indicating a greater sensitivity to the effects of corticosteroids compared with levels of FC and MPO.

BACKGROUND: Diabetes is a chronic disease with several long-term complications. Several glucose-lowering drugs are used to treat type 2 diabetes mellitus (T2DM), e.g., glimepiride and liraglutide, in which both having different modes of action. Circulating microRNAs (miRNAs) are suggested as potential biomarkers that are associated with the disease development and the effects of the treatment. In the current study we evaluated the effect of glimepiride, liraglutide on the expression of the circulating miRNAs. METHODS: The present study is a post hoc trial from a previously randomized control trial comparing liraglutide versus glimepiride both in combination with metformin in subjects with T2DM, and subclinical heart failure. miRNAs were determined in the subjects' serum samples with next generation sequencing. Expression patterns of the circulating miRNAs were analyzed using bioinformatic univariate and multivariate analyses (clinical trial registration: NCT01425580). RESULTS: Univariate analyses show that treatment with glimepiride altered expression of three miRNAs in patient serum, miR-206, miR-182-5p, and miR-766-3p. Both miR-182-5p and miR-766-3p were also picked up among the top contributing miRNAs with penalized regularised logistic regressions (Lasso). The highest-ranked miRNAs with respect to Lasso coefficients were miR-3960, miR-31-5p, miR-3613-3p, and miR-378a-3p. Liraglutide treatment did not significantly influence levels of circulating miRNAs. CONCLUSION: Present study indicates that glucose-lowering drugs differently affect the expression of circulating miRNAs in serum in individuals with T2DM. More studies are required to investigate possible mechanisms by which glimepiride is affecting the expression of circulating miRNAs.

Introduction: Fecal calprotectin (FC) is anoninvasive tool for examining response to biologics in inflammatory boweldisease (IBD), but its performance in relation to other novel fecal markers of various cellular origins is unknown. Methods: We performed a prospective multicenter cohort study and included patients with active IBD who provided a fecal sample at initiation of biological therapy. Levels of FC, myeloperoxidase (MPO), human neutrophil lipocalin (HNL), and eosinophil-derived neurotoxin (EDN) were analyzed and related to clinical remission status at 3 months. Changes in levels of markers at 3 months were calculated, and the impact of concomitant use of corticosteroids at baseline was estimated. Results: In patients achieving clinical remission (n = 27), a decrease in levels of FC (P = 0.005), MPO (P < 0.001), HNL (P < 0.001), and EDN (P < 0.001) was observed, whereas no significant decrease was seen in patients not achieving remission (n = 39). There was a significant difference in the change in the level of MPO (P = 0.01) and HNL (P = 0.02) between patients achieving clinical remission and those who did not, but changes in FC and EDN could not differentiate between these groups. Patients with concomitant systemic corticosteroids at inclusion had lower levels of HNL (P = 0.01) and EDN (P < 0.001) at baseline, compared with patients without corticosteroids. Discussion: Fecal MPO, HNL, and EDN are all promising biomarkers for assessing the treatment outcome of biologics in patients with IBD. Fecal levels of EDN and HNL are significantly affected by corticosteroids indicating a greater sensitivity to the effects of corticosteroids compared with levels of FC and MPO., This work was supported by the Swedish Foundation for Strategic Research (grant number RB13-016), Medical Faculty, Uppsala University, Uppsala, Sweden (M.C.) and the Orebro University Hospital Research Foundation (grant numbers OLL-936004, OLL-890291, OLL-790011, OLL-723021, and OLL-333321 to J.H.).

Sepsis is a time dependent condition. Screening tools based on clinical parameters have been shown to increase the identification of sepsis. The aim of current study was to evaluate the additional predictive value of immunological molecular markers to our previously developed prehospital screening tools. This is a prospective cohort study of 551 adult patients with suspected infection in the ambulance setting of Stockholm, Sweden between 2017 and 2018. Initially, 74 molecules and 15 genes related to inflammation were evaluated in a screening cohort of 46 patients with outcome sepsis and 50 patients with outcome infection no sepsis. Next, 12 selected molecules, as potentially synergistic predictors, were evaluated in combination with our previously developed screening tools based on clinical parameters in a prediction cohort (n = 455). Seven different algorithms with nested cross-validation were used in the machine learning of the prediction models. Model performances were compared using posterior distributions of average area under the receiver operating characteristic (ROC) curve (AUC) and difference in AUCs. Model variable importance was assessed by permutation of variable values, scoring loss of classification as metric and with model-specific weights when applicable. When comparing the screening tools with and without added molecular variables, and their interactions, the molecules per se did not increase the predictive values. Prediction models based on the molecular variables alone showed a performance in terms of AUCs between 0.65 and 0.70. Among the molecular variables, IL-1Ra, IL-17A, CCL19, CX3CL1 and TNF were significantly higher in septic patients compared to the infection non-sepsis group. Combing immunological molecular markers with clinical parameters did not increase the predictive values of the screening tools, most likely due to the high multicollinearity of temperature and some of the markers. A group of sepsis patients was consistently miss-class, This study was supported by grants from Nyckelfonden, Laerdal, Falck Foundation, Knowledge Foundation (20160044, 20200017), the Emergency Department of Södersjukhuset, Stockholm, and Örebro University.Author Correction: Predicting sepsis using a combination of clinical information and molecular immune markers sampled in the ambulance. Tuerxun, K., Eklund, D., Wallgren, U. et al. Sci Rep 14, 21306 (2024). https://doi.org/10.1038/s41598-024-72325-y

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the gastrointestinal tract, which generally manifests as Crohn's disease (CD) or ulcerative colitis (UC). These subtypes are heterogeneous in terms of disease location and histological features, while sharing common clinical presentation, genetic associations and thus, common immune regulatory pathways. METHODS: Using miRNA and mRNA coupled transcriptome profiling and systems biology approaches, we report a comprehensive analysis of blood transcriptomes from treatment-naïve (n=110) and treatment-exposed (n=177) IBD patients as well as symptomatic- (n=65) and healthy controls (n=95). RESULTS: Broadly, the peripheral blood transcriptomes of CD and UC patients were similar. However, there was an extensive gene deregulation in the blood of IBD patients, while only a slight deregulation in symptomatic controls, when compared with healthy controls. The deregulated mRNAs and miRNAs are mainly involved in the innate immunity and are especially enriched in neutrophil activation-related pathways. Oxidative phosphorylation and neutrophil activation-related modules were found to be differentially co-expressed among treatment-naïve IBD as compared to healthy controls. In the deregulated neutrophil activation-related co-expression module, the IL1B was identified as the central gene. The co-expression levels among IL1B and chemosensing receptor (CXCR1/2 and FPR1/2) genes were reduced in the blood of IBD patients when compared with healthy controls. CONCLUSIONS: Immune dysregulation seen in peripheral blood transcriptomes of treatment-naïve IBD patients is mainly driven by neutrophil activation., Funding agency:German Research Foundation (DFG) EXC 2167

Myeloid-derived suppressor cells (MDSCs) are functionally immunosuppressive cells that arise and expand during extensive inflammatory conditions by increased hematopoietic output or reprogramming of immune cells. In sepsis, an increase of circulating MDSCs is associated with adverse outcomes, but unique traits that can be used to identify increased activity of MDSCs are lacking. By using endotoxin tolerance as a model of sepsis-induced monocytic MDSCs (M-MDSC-like cells), this study aims to identify the mediator and transcriptional regulator profile associated with M-MDSC activity. After analyzing 180 inflammation-associated proteins, a profile of differentially expressed cytokines was found in M-MDSC-like cells versus normal monocytes stimulated with LPS. These cytokines were associated with 5 candidate transcription factors, where particularly PU.1 showed differential expression on both transcriptional and protein levels in M-MDSC-like cells. Furthermore, inhibition of PU.1 led to increased production of CXCL5 and CCL8 in M-MDSC-like cells indicating its role in regulating the ability of M-MDSC-like cells to recruit other immune cells. Taken together, the study identifies a unique profile in the pattern of immune mediators defining M-MDSC activity upon LPS stimulation, which offers a functional link to their contribution to immunosuppression., Funding agencies:General ElectricNorlin's Foundation for Medical Research