Tanja Elger

Background/Objectives: Non-invasive markers of primary sclerosing cholangitis (PSC) in patients with inflammatory bowel disease (IBD) are lacking, and serum ceramide species are altered in both diseases. This study investigated whether total and species-specific serum sphingomyelin-to-ceramide (SM/Cer) ratios identify concomitant PSC in IBD and reflect inflammatory activity. Methods: Serum SM and ceramide species were quantified by direct flow injection analysis–mass spectrometry in 16 healthy controls, 57 patients with IBD, 7 patients with PSC, and 13 patients with PSC-IBD. The total SM/Cer ratio and six species-specific ratios were analyzed in relation to IBD, PSC-IBD, inflammation markers, stool consistency, and medication. Results: The total SM/Cer and SM 42:1;O2/Cer 18:1;O2/24:0 ratios discriminated PSC-IBD from those with IBD alone, with areas under the receiver operating characteristic curve of 0.76 and 0.82, specificities of 95% and 91%, and sensitivities of 62% and 69%, respectively. Their diagnostic performance was comparable to that of the corresponding ceramide species. Combining the SM/Cer ratios with alkaline phosphatase and bilirubin levels improved diagnostic performance compared with standard laboratory measures alone. Moreover, multiple linear regression revealed that the SM/Cer ratios were less confounded by age and fecal calprotectin than the individual ceramide species levels. The SM 36:1;O2/Cer 18:1;O2/18:0 and SM 38:1;O2/Cer 18:1;O2/20:0 ratios were lower in patients with IBD, PSC, and PSC-IBD than in controls. Of these, only the latter ratio correlated negatively with inflammatory markers. Associations of SM/Cer ratios with current medication and stool consistency were modest and require further validation. Conclusions: Serum total SM/Cer and SM 42:1;O2/Cer 18:1;O2/24:0 ratios identify concomitant PSC in patients with IBD with high specificity, while fecal calprotectin has little or no effect on these ratios. Because they need only a small serum sample, these ratios are promising non-invasive markers for selecting patients with IBD for cholangiographic evaluation. Validation in larger, prospective cohorts is needed.

Background/Objectives: Liver diseases and chronic inflammatory bowel diseases (IBD) are closely associated, particularly primary sclerosing cholangitis (PSC) and ulcerative colitis (UC). In severe cases of PSC, liver transplantation (LT) may be required, just as severe IBD may necessitate biologic therapy. Evidence on combining biologics with post-transplant immunosuppression is limited, particularly regarding hepatotoxicity, infections, and drug–drug interactions. We therefore assessed the safety of biologic therapy for IBD in LT recipients. Methods: In this retrospective, single-center analysis, all patients treated at the inflammatory bowel disease and post–liver transplantation outpatient clinics of the University Hospital Regensburg were screened. Patients with both LT and IBD were included in the analysis. Medical records, laboratory parameters, and imaging studies were reviewed. Conclusions: A total of 17 liver transplant recipients with IBD were identified. Eleven patients had PSC as the underlying liver disease, while the remaining patients had autoimmune hepatitis (AIH), PSC–AIH overlap syndrome, or cryptogenic liver cirrhosis. Three patients had Crohn’s disease, and 14 had ulcerative colitis. Five patients required biologic therapy because of active IBD. Two patients received two sequential biologic agents, whereas one patient received four different biologics during follow-up. No significant safety signals were observed regarding hepatotoxicity, susceptibility to infections, or interactions with concomitant immunosuppressive therapy, including tacrolimus, mycophenolate mofetil, ciclosporin, and prednisolone. No evidence of clinically relevant safety concerns associated with biologic therapy was identified in liver transplant recipients with IBD. Therefore, biologic therapy combined with conventional post-transplant immunosuppression appears feasible and well tolerated in LT recipients with active IBD; larger prospective studies are needed. However, larger prospective studies are needed to confirm these findings.

Background: Phosphatidylcholine (PC) is a major phospholipid that contributes to intestinal barrier protection and is essential for hepatic secretion of lipids and bile acids. Because inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) are closely linked, we hypothesized that individual serum PC species would reflect disease activity. We therefore investigated whether serum PC profiling could identify clinically useful biomarkers across the gut–liver axis. Methods: Serum concentrations of 21 PC species were quantified by direct flow injection high-resolution mass spectrometry in 16 healthy controls, 57 patients with IBD, and 20 patients with PSC. Results: In IBD, multiple serum PC species were inversely associated with inflammatory activity, showing negative correlations with serum C-reactive protein and fecal calprotectin. Patients with fecal calprotectin concentrations above the diagnostic cut-off of 120 µg/g had lower levels of PC 34:3, 36:1, 36:2, 36:3, 36:4, 36:5, 38:3, 38:4, 38:5, 38:7, 40:5, and 40:6, as well as lower total PC. In contrast, in PSC, PC 30:0, 32:0, 32:1, and 34:1 were increased compared with IBD and correlated positively with gamma-glutamyltransferase and alkaline phosphatase. Furthermore, these shorter-chain PC species as well as PC 36:1 were markedly elevated in PSC with advanced liver fibrosis compared with PSC without fibrosis. Conclusions: Serum PC species show a reciprocal disease-associated pattern in IBD and PSC. In IBD, lower concentrations of predominantly unsaturated PC species are associated with active intestinal inflammation, whereas in PSC, higher concentrations of shorter-chain PC species are associated with cholestatic injury and advanced liver fibrosis. IBD and PSC exhibit opposing serum PC signatures, suggesting that dysregulated PC metabolism is a pathophysiological feature of intestinal inflammation and PSC-associated liver fibrosis.

Background: Soluble CD137 (sCD137) has immunoregulatory properties and is increased in chronic inflammatory and autoimmune diseases, as well as in liver cirrhosis. Its relevance in inflammatory bowel disease (IBD) and primary sclerosing cholangitis associated with IBD (PSC-IBD) remains unclear. We measured serum sCD137 levels in IBD, PSC-IBD, PSC without IBD, and metabolic dysfunction-associated steatotic liver disease (MASLD, as a liver disease control) and assessed whether sCD137 is associated with intestinal inflammatory activity or liver disease severity. Methods: Serum sCD137 levels were measured in 77 patients with IBD, 33 with PSC-IBD, 11 with PSC without IBD, 26 with MASLD, and 78 healthy controls. In IBD, associations with serum C-reactive protein, fecal calprotectin, and symptom burden were examined. In PSC and PSC-IBD, associations with liver dysfunction and fibrosis stage, assessed by measurement of liver stiffness, were analyzed. Results: Serum sCD137 levels were higher in IBD than in controls, with similar levels in Crohn’s disease and ulcerative colitis. In IBD, sCD137 was not associated with C-reactive protein, fecal calprotectin, stool consistency, symptom extent, disease duration, or disease localization. Serum sCD137 levels were higher in PSC/PSC-IBD than in controls, patients with MASLD, and patients with isolated IBD. Patients with PSC without IBD showed similar levels to those with PSC-IBD. In PSC/PSC-IBD, serum sCD137 levels did not increase with a higher fibrosis stage. Conclusions: Serum sCD137 is a disease-associated systemic immune marker in IBD and PSC, with a stronger signal in PSC-associated disease than in isolated IBD. However, sCD137 does not reflect intestinal inflammatory activity or liver fibrosis severity in this cohort, suggesting that it captures disease-associated immune dysregulation rather than current inflammatory or fibrotic burden.

Background/Objectives: Systemic levels of the adipokine adiponectin are elevated in chronic liver disease including primary sclerosing cholangitis (PSC). Inflammatory bowel disease (IBD) and PSC are closely associated diseases, but in IBD serum adiponectin levels are near normal. Urinary and fecal biomarkers have been suggested to be superior to the corresponding serum protein for disease diagnosis, but urinary and fecal adiponectin have not been analyzed in PSC. The aim of this study was to evaluate the adiponectin in human serum, urine, and feces as a potential diagnostic tool for PSC. Methods: Serum and urine samples were collected from 74 IBD patients, 40 PSC patients (35 patients with PSC and IBD (16 patients for urine) and 5 patients with PSC without underlying IBD), and 17 controls. Feces samples from 53 IBD patients and 11 PSC patients (8 of them with PSC-IBD) were available for this study. Adiponectin levels were analyzed by enzyme-linked immunosorbent assay. Results: Urinary and serum adiponectin levels in IBD patients and controls were comparable. Urinary, fecal and serum adiponectin in patients with ulcerative colitis and Crohn’s disease were similar and did not change, even with higher fecal calprotectin, a marker of intestinal inflammation in IBD. The three IBD patients with a high Gastrointestinal Symptom Rating Scale score as a marker for clinical activity had highly elevated urinary adiponectin. Systemic adiponectin levels were significantly elevated in the PSC-IBD cohort relative to the IBD-only group, suggesting its potential utility in clinical screening. Urinary and fecal adiponectin levels were similar between the cohorts. In PSC/PSC-IBD, serum adiponectin did not increase with higher fibrosis scores. Serum, urine, and fecal adiponectin were not correlated in both patient cohorts, except for a negative association of fecal and urine adiponectin in PSC. Conclusions: This exploratory study revealed preliminary findings suggesting an association between urinary adiponectin and severe gastrointestinal symptoms in IBD. In PSC-IBD, serum adiponectin is higher compared to IBD patients and continuous measurement may be used for PSC-IBD screening.

Background/Objectives: Lysophosphatidylcholine (LPC) is composed of various lipid species, some of which exert pro-inflammatory and others anti-inflammatory activities. However, most of the LPC species analyzed to date are reduced in the serum of patients with inflammatory bowel disease (IBD) compared to healthy controls. To our knowledge, the correlation between serum LPC species levels and measures of inflammation, as well as their potential as markers for monitoring IBD activity, has not yet been investigated. Methods: Thirteen LPC species, varying in acyl chain length and number of double bonds, were measured in the serum of 16 controls and the serum of 57 patients with IBD. Associations with C-reactive protein (CRP) and fecal calprotectin levels as markers of IBD severity were assessed. Results: Serum levels of LPC species did not differ between the healthy controls and the entire patient cohort. In patients with IBD, serum levels of LPC 16:1, 18:0, 18:3, 20:3, and 20:5, as well as total LPC concentrations, showed inverse correlations with both CRP and fecal calprotectin levels, indicating an association with inflammatory activity. Nine LPC species were significantly reduced in patients with high fecal calprotectin compared to those with low values. LPC species with 22 carbon atoms and 4 to 6 double bonds were not related to disease activity. Stool consistency and gastrointestinal symptoms did not influence serum LPC profiles. Corticosteroid treatment was associated with lower serum LPC 20:3 and 22:5 levels, while mesalazine, anti-TNF, and anti-IL-12/23 therapies had no significant impact on LPC concentrations. There was a strong positive correlation between LPC species containing 15 to 18 carbon atoms and serum cholesterol, triglycerides, and phosphatidylcholine levels. However, there was no correlation with markers of liver disease. Conclusions: Shorter-chain LPC species are reduced in patients with active IBD and reflect underlying hypolipidemia. While these lipid alterations provide insight into IBD-associated metabolic changes, they appear unsuitable as diagnostic or disease monitoring biomarkers.

Background/Objectives: Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum cholesterol levels and inflammation, both of which are dysregulated in inflammatory bowel disease (IBD). Free cholesterol (FC) and the various types of cholesteryl ester (CE) have different functions in the body. However, it is not yet known whether these lipids undergo parallel changes in male and female patients with active IBD, nor whether PCSK9 correlates with these lipids and disease severity in either sex. The present study measured the serum levels of PCSK9, FC, and 15 CE species in IBD patients, focusing on the associations of these molecules with sex, each other, and with disease severity. Methods: The serum PCSK9 levels of 80 IBD patients (42 males and 38 females) and 24 controls (12 males and 12 females) were measured by enzyme-linked immunosorbent assay. In addition, FC and 15 CE species levels of 53 randomly selected IBD patients and 16 controls were determined by direct flow injection analysis (FIA) using a high-resolution hybrid quadrupole-orbitrap mass spectrometer (FIA-FTMS). Results: Serum PCSK9 levels in controls and IBD patients were comparable and did not correlate with disease severity in IBD patients. There was no discernible difference in serum PCSK9, FC, and CE levels between patients with Crohn’s disease (CD) and those with ulcerative colitis (UC). FC and almost all CE species decreased in male patients with active IBD but were not related to disease severity in the female patients. The decrease in different CE species in male IBD patients with diarrhea compared to those with normal stool consistency appears to be related to IBD severity. Bile acids regulate serum cholesterol levels, and FC and CE levels were positively correlated with fecal levels of secondary bile acids in the patients with UC but not CD. This association also existed in male UC patients and could not be evaluated in women due to the small sample size. Conclusions: In active IBD, a reduction in FC and almost all CE species was observed only in males, while serum PCSK9 levels remained within normal ranges in both sexes. It can be hypothesized that blocking PCSK9 may further reduce serum cholesterol levels, which may have adverse effects in male patients with active IBD.

Background/Objectives: Inflammatory bowel disease (IBD) is a chronic immune-mediated pathology associated with the dysregulation of lipid metabolism. The administration of nervonic acid, a very long-chain fatty acid, has been shown to improve colonic inflammation in a mouse model of colitis. Our study aimed to quantify fecal levels of nervonic acid, as well as the very long-chain fatty acids, lignoceric acid, and pentacosanoic acid, to identify associations with IBD activity. Methods: Stool samples were collected from 62 patients with IBD and 17 healthy controls. Nervonic acid, lignoceric acid, and pentacosanoic acid were quantified by gas chromatography coupled with mass spectrometry (GC-MS). Lipid levels, normalized to the dry weight of fecal homogenates, were used for calculations. Results: Patients with IBD exhibited elevated fecal nervonic acid levels compared to healthy controls, with no significant differences observed between ulcerative colitis and Crohn’s disease. A fecal nervonic acid concentration of 0.49 µmol/g distinguished IBD patients from controls, achieving a sensitivity of 71% and a specificity of 82%. Fecal nervonic acid levels showed a positive correlation with both C-reactive protein and fecal calprotectin and increased proportionally with rising fecal calprotectin levels. IBD patients treated with corticosteroids or interleukin-12/23 antibodies had higher levels of fecal nervonic acid than those in other therapies, with no difference in serum C-reactive protein and calprotectin levels between these groups. Conclusions: In summary, this analysis indicates that fecal nervonic acid may emerge as a novel specific biomarker for IBD diagnosis and disease monitoring.

Predicting responses and monitoring the severity of inflammatory bowel disease (IBD) is challenging due to a lack of specific biomarkers. This study identifies urinary hydroxyproline, a marker of collagen turnover elevated in experimental colitis, as independent of conventional biomarkers like creatinine, glomerular filtration rate, C-reactive protein, and fecal calprotectin. Among 71 IBD patients, urinary hydroxyproline levels were significantly higher compared with 36 controls, with an area under the receiver operating characteristic curve of 0.814, highlighting its potential as a diagnostic tool. No significant difference in hydroxyproline levels was observed between the 50 Crohn’s disease and 21 ulcerative colitis patients, nor was there a correlation with kidney function markers, gastrointestinal symptom severity, or stool consistency. Disease localization was not associated with urinary hydroxyproline levels. Interestingly, 14 patients with primary sclerosing cholangitis and IBD also exhibited elevated urinary hydroxyproline levels, comparable to IBD patients but higher than healthy controls. This underscores the role of urinary hydroxyproline as an independent biomarker for IBD diagnosis, without association with disease severity or established markers like fecal calprotectin.

Metastatic Crohn’s disease is a rare disorder characterized by various granulomatous skin lesions that occur independently of gastrointestinal tract involvement. However, currently there is no standardized care or specific treatment. Therapeutic approaches include immunosuppressive agents, such as corticosteroids, azathioprine, and monoclonal antibodies targeting inflammatory cytokines like tumor necrosis factor (TNF). We present a case of a 29-year-old western European woman with significant blind ending abdominal subcutaneous fistulas and abscesses, who sought evaluation in the dermatology department. Histological examination revealed multiple epithelioid cell granulomas. There was no evidence of infectious or rheumatologic diseases such as sarcoidosis. The tentative diagnosis was metastatic Crohn’s disease, which was not related to an intestinal manifestation of the disease. The patient responded to infliximab but had to discontinue it due to an allergic reaction. Subsequent adalimumab treatment failed to induce clinical remission; thus, therapy was switched to ustekinumab, resulting in a positive response. Written informed consent for publication of their clinical details and clinical images was obtained from the patient. For our study more than 1600 publications were screened for cases of metastatic Crohn’s disease on PubMed database. 59 case reports with 171 patients were included in the analysis and evaluated for localization, diagnostic and therapeutic approaches, and complications and were summarized in this review. The successful ustekinumab treatment of a patient with metastatic Crohn's disease underscores the potential of this minimally investigated therapeutic option, highlighting the need for future treatment guidelines given the increasing prevalence of such cases.