Magnus Sundbom

Context: Obesity-associated adipose tissue dysfunction is characterized by extracellular matrix (ECM) remodeling and fibrosis, where collagen VI and its bioactive cleavage peptide endotrophin have been implicated as key mediators. Objective: Characterize collagen VI alpha-3 (COL6A3) depot-specific expression in obesity and determine whether endotrophin impairs adipocyte metabolism and insulin responsiveness. Design, Setting, and Participants: COL6A3 expression was examined in paired subcutaneous (SAT) and omental adipose tissue (OAT) from 60 individuals spanning a broad Body-Mass-Index (BMI) range. Plasma endotrophin was measured in a subset of the cohort (n=42). Endotrophin effects were assessed in adipose explants, primary human and SGBS adipocytes. Main outcome me: asures. Depot-specific COL6A3 expression relative to BMI and endotrophin's effects on adipose tissue gene expression, GLUT4 levels, and adipocyte glucose uptake rate. Results: COL6A3 expression was associated with adiposity only in SAT. BMI remained an independent predictor after adjustment for age, sex, and metabolic covariates. COL6A3 co-expression patterns were positively associated with ECM remodeling and inflammation genes in both depots, while inverse associations with lipid metabolism and insulin signaling genes were specific to SAT. Circulating endotrophin levels were associated with fat mass percentage and triglyceride-to-HDL-cholesterol ratio, but not with adipose tissue COL6A3 expression. Endotrophin treatment reduced expression of PPARγ, SLC2A4 (GLUT4), and NR3C1, decreased GLUT4 protein, and impaired adipocyte insulin-stimulated glucose uptake rate without affecting AKT phosphorylation. Endotrophin reduced PPARγ, DGAT2, and SLC2A4 expression in differentiating SGBS adipocytes. Glucocorticoids upregulated COL6A3 in both depots. Conclusions: These findings implicate COL6A3-associated ECM remodelling and endotrophin in adipose dysfunction and impaired adipocyte insulin responsiveness in obesity.

Background: Obesity and Type 2 diabetes (T2D) impair health‐related quality of life (HRQoL) across metabolic, mechanical and mental domains. Gastric bypass surgery improves HRQoL in the short term, but long‐term trajectories remain insufficiently understood. This study evaluated HRQoL 8 years after gastric bypass in a cohort with T2D, integrating quantitative assessments with qualitative exploration of lived experiences. Methods: Eleven individuals with obesity and T2D who underwent gastric bypass participated in an 8‐year follow‐up. Anthropometric and clinical data were collected. HRQoL was assessed using the RAND SF‐36, and changes over time were analyzed using repeated‐measures ANOVA. Correlations between changes in BMI, HbA1c and HRQoL domains were assessed with Spearman correlations. Semi‐structured qualitative interviews were conducted, transcribed verbatim and analyzed using reflexive thematic analysis. Results: Participants experienced modest weight regain but significant deterioration in glucose control from the 2‐year to the 8‐year follow‐up. RAND SF‐36 scores returned to preoperative levels, and the mental health score was significantly reduced compared to the 2‐year follow‐up ( q < 0.01). Weight regain correlated with reduced physical functioning, role‐physical and vitality scores (all r < −0.7, p < 0.05), while HbA1c increase correlated with poorer mental health and role‐emotional scores (all r < −0.6, p < 0.05). Qualitative interviews revealed that long‐term HRQoL was dynamic and shaped by an interplay of physical functioning, psychological wellbeing, body adaptations, social support and life events. An overarching theme emerged: Quality of life after gastric bypass is a multidimensional, evolving process influenced by changing health, life circumstances and psychosocial factors over time . Conclusions: Initial postoperative improvements in HRQoL were not sustained at 8 years and might have been influenced by weight regain, T2D relapse and intercurrent illness. However, lived experiences highlighted meaningful and durable benefits in physical functioning and self‐perception for several participants. The findings underscore the need for long‐term, holistic follow‐up that integrates metabolic monitoring with psychological and social support. Trial Registration: ClinicalTrials.gov registration: NCT02729246

Studying the pathogenesis of human-adapted microorganisms is challenging, since small animal models often fail to recapitulate human physiology. Hence, the comprehensive genetic and regulatory circuits driving the infection process of principal human pathogens such as Shigella flexneri remain to be defined. We combined large-scale Shigella infections of enteroids and colonoids with transposon-directed insertion sequencing and Bayesian statistical modeling to address infection bottlenecks, thereby establishing the comprehensive genome-wide map of Shigella genes required to infect human intestinal epithelium. This revealed the Shigella virulence effectors essential for epithelial cell colonization across geometries and intestinal segments, identified over 100 chromosomal genes involved in the process and uncovered a post-transcriptional mechanism whereby tRNA-modification enzymes and differential codon usage exert global control of a bacterial virulence program. Our findings provide a broadly applicable framework for combining advanced organotypic tissue culture with functional genomics and computational tools to map human–microorganism interactions at scale.

Objective: To determine the 10-year outcomes regarding weight loss and remission of obesity-related diseases after primary Roux-en-Y gastric bypass (RYGB), when performed in routine clinical care. Summary of Background Data: Long-term results of metabolic bariatric surgery (MBS) are important, as the number of patients needing help with this chronic condition is increasing globally. However, results from larger nation-wide studies are lacking. Methods: Cohort study of RYGB-patients from the Scandinavian Obesity Surgery Registry (SOReg), a national Swedish quality registry of MBS. Supplementary data was obtained from the Prescribed Drug Register (pharmacological therapy) and the National Diabetes Register (clinical data). Weight loss, complete remission of comorbidities (defined as no pharmacological therapy and normal laboratory values), and associations for new-onset disease were studied. Results: 29,578 individuals (mean age 41.0±11.0 y, 75.6% females) had a RYGB in Sweden 2007-2012. At ten years, mean body weight was reduced from 112.7 kg to 91.4 kg, corresponding to a total body weight loss of 24.6%. A significant complete remission rate persisted in type 2 diabetes (29.7%), hypertension (15.1%) and dyslipidemia (8.8%), while the use of antidepressants increased by 38.6%, P<0.001 for all. The use of continuous positive airway pressure for sleep apnea decreased from 9.8% to 4.1%. New-onset disease was in general associated to age, low weight loss and presence of other comorbidities. Conclusions: At ten years, patients undergoing primary RYGB in Sweden demonstrate lasting weight loss and substantial remission of obesity-related diseases. RYGB is a valuable treatment option in the long-term for patients with severe obesity.

Background: Esophagectomy is associated with pulmonary complications. This study evaluated if thoracoscopic minimally invasive esophagectomy (MIE) mitigates these risks by comparing pulmonary findings on postoperative computed tomography (CT) between open esophagectomy and MIE. Method: Postoperative (day 5) thoracic CT from 40 patients (20 open and 20 MIE) who had undergone esophagectomy with epidural analgesia and right-sided thoracic drainage were reviewed. On an axial view, the areas of atelectasis and pleural effusion were measured at 1 and 5 cm above the right diaphragmatic dome and at the level of the carina. In addition, the total distribution of atelectasis and pleural effusion was estimated on an ordinal scale (0–5), with ≥3 considered clinically important. Results: The groups were well-matched in terms of age, sex, and smoking status. There were no differences in the areas of atelectasis or pleural effusion for open surgery compared with MIE. The groups did not differ in the proportion of patients with clinically important atelectasis (right: 30% vs. 25%, left: 65% vs. 65%) or pleural effusion (right: 15% vs. 15%, left: 65% vs. 45%). More pleural effusion and atelectasis at the 1-cm level was present on the left side at day 5 in both open and MIE patients. Conclusion: Despite major differences in surgical trauma and ventilation strategies between open and MIE, CT evaluation at day 5 was surprisingly similar. Less right-sided pleural effusion demonstrates the effect of surgical drains. We believe that the defined levels of measurement used in this study, performed at clear anatomical landmarks, can be of value in future studies.

Potential metastatic mechanisms and clinical aspects in patients with non-gastrointestinal tumor metastasis to the upper gastrointestinal tract

Intestinal enteroids are stem cell-based “mini-guts” that mimic many aspects of the corresponding epithelial barrier in vivo . Here, we established and characterized differentiated apical-out (AO) and basal-out (BO) jejunal enteroids in suspension and followed their differentiation by quantitative global proteomics and different microscopic techniques. The barrier integrity and function and subcellular location of nutrient and clinically important drug transporters were investigated in the matured enteroids using live-cell microscopy. The presystemic metabolism of two drugs by CYP3A4 was determined and the results were used to predict the pharmacokinetics after oral administration by a PBPK population model. The differentiated AO enteroids displayed a protein profile that overlapped both qualitatively and quantitatively with that of freshly isolated jejunal enterocytes and tissue. They exhibited a morphology that recapitulates the mature villus enterocyte in vivo , formed an intact barrier with a well-developed glycocalyx and are impermeable to the hydrophilic low molecular weight compound lucifer yellow and transported a medium chain fatty acid derivative by FATP4 into lipid deposits. The clinically important ABC-transporters Pgp and BCRP were expressed at near in vivo levels, had the correct subcellular localization and effluxed their substrates. Terfenadine and midazolam were metabolized by CYP3A4 and the results were used to predict the clinical pharmacokinetics of the drugs after oral administration with good accuracy. We conclude that suspended 3D AO enteroids provide a physiologically relevant model for studies of intestinal function that offers convenient access to the apical surface and is easy to dispense in multi-wells formats for large scale experimentation.

Introduction: Understanding meal-induced changes in gut hormones, gastric motility, and appetite is crucial for developing next generation obesity therapies employing permutations of gut hormone analogues. The goal of this study was to investigate how GLP-1, GIP, ghrelin, and motilin interact to influence appetite and gastric motility at physiologic conditions and elucidate differences between healthy individuals and individuals with obesity. Methods Fasted study subjects (healthy n = 41; obese n = 32) consumed a 270-kcal meal and wireless motility capsule. GIP, active GLP-1, acyl-ghrelin, and motilin were measured by electrochemiluminescence. MotiliGI and GIMS software were used for motility analysis, while visual analog scoring measured appetite. Results Gastric emptying was more rapid in individuals with obesity than healthy controls (p < 0.01). Gastric emptying time was negatively associated with both motility index and hunger contraction frequency (p < 0.01, p < 0.05) in the healthy but not in the obese In controls, gastric motility index correlated positively with ghrelin (p < 0.01) and motilin (p < 0.0001) and negatively with GIP (p < 0.05), but not GLP-1. In the obesity group, no gut hormones correlated with motility index. GIP and GLP-1 correlated with decreased hunger in both groups (p < 0.0001, p = 0.001) and (p < 0.0001, p < 0.05), along with increased satiety in controls (p < 0.0001, p = 0.001) and the obesity group (p = 0.049, p = 0.01). Ghrelin correlated positively with hunger (p < 0.0001) and negatively with satiety (p = 0.049) in controls, but not individuals with obesity. Motilin was neither associated with hunger nor satiety in either group. Conclusion In the gastric phase, individuals with obesity show rapid gastric emptying with altered flatline hormone and motility meal-responses. In healthy controls, GIP promotes satiety, and ghrelin and motilin promote hunger through actions on motility. Like GIP, GLP-1 promotes satiety along with trending suppression of postprandial gastric motility.