Dysregulated cholesterol metabolism is a recognized metabolic hallmark of cancer. While the transcription factor SREBP2 is a master regulator of this pathway, how its activation converts metabolic stress into the development of carcinogenic signals in colorectal cancer (CRC) remains unclear. Through clinical and preclinical analyses, we first confirmed that hypercholesterolemia and elevated tumoral SREBP2 are hallmarks of CRC. Using multi-omics integration, we identified CNPY3 as a direct transcriptional target of SREBP2. Functionally, CNPY3 drives CRC cell proliferation, invasion, and tumor growth via a cholesterol synthesis-independent oncogenic program. Clinically, high CNPY3 expression robustly correlated with advanced disease and poor patient survival. Mechanistically, we discovered that CNPY3 undergoes liquid-liquid phase separation (LLPS), a property dependent on its intrinsically disordered C-terminal region. This LLPS capacity is essential for its oncogenic function, as it enables CNPY3 to enhance MDM2 phosphorylation at the activating Ser166 site and promote its nuclear translocation. Consequently, CNPY3 potentiates MDM2-mediated ubiquitination and degradation of the tumor suppressor p53. Genetic ablation of p53 completely abolished the pro-tumorigenic effects of CNPY3, confirming p53 as the critical downstream effector. Crucially, this axis specifically targets wild-type p53, having no effect on common p53 mutants. Pharmacological disruption of the MDM2-p53 interaction with Nutlin-3 effectively reversed CNPY3-driven malignancy both in vitro and in vivo. Our work unveils a SREBP2-CNPY3-MDM2-p53 signaling axis that links cholesterol metabolic dysregulation to p53 pathway inactivation in CRC. We further established that the oncogenic activity of CNPY3 is mediated through its biophysical property of LLPS. These findings nominate CNPY3 as a novel prognostic biomarker and a compelling therapeutic target for p53-wild-type CRC.

BACKGROUND:Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are at increased risk of both hepatic and extrahepatic adverse outcomes. However, the evidence regarding lean MASLD and its prognosis remains controversial. OBJECTIVE:To comprehensively investigate the long-term prognosis of lean patients with MASLD versus non-lean MASLD in Western and Asian populations. DESIGN:This prospective multicohort study included 153 192 patients with MASLD from UK Biobank (UKB), 29 700 from Kailuan cohort and 3329 from China Kadoorie Biobank (CKB). Lean MASLD was defined as body mass index (BMI)<23 kg/m² in Kailuan and CKB and <25 kg/m² in UKB. Primary endpoints were liver-related events (LREs), all-cause mortality, liver-related mortality (LRM), cardiovascular disease (CVD) mortality, CVD, hepatocellular carcinoma (HCC) and extrahepatic cancer. RESULTS:Overall, 181 191 non-lean and 5030 lean patients with MASLD were included. During a median of 14.2-year follow-up (median 14.1, 14.8 and 13.4 years in UKB, Kailuan and CKB), 2501 incident LREs, 22 482 all-cause deaths, 28 722 incident CVD cases, 326 HCC and 25 258 extrahepatic cancer cases were identified, with 375 LRM and 4511 CVD deaths. Pooled analysis of three cohorts showed lean MASLD had higher risks of LREs (HR=2.14; 95% CI 1.27 to 3.62), all-cause mortality (HR=1.26; 95% CI 1.14 to 1.39), LRM (HR=2.31; 95% CI 1.54 to 3.46) and CVD mortality (HR=1.22; 95% CI 1.05 to 1.41). By contrast, lean MASLD exhibited comparable HCC risk (HR=1.76; 95% CI 0.84 to 3.71) and extrahepatic cancer risk (HR=1.14; 95% CI 0.88 to 1.48), but reduced CVD risk (HR=0.89; 95% CI 0.83 to 0.95) versus non-lean MASLD. CONCLUSION:Lean patients with MASLD have worse liver outcomes and greater risk of all-cause mortality, but similar risk of HCC and extrahepatic cancer, and lower CVD risk.

The global incidence of obesity and inflammatory bowel disease (IBD) has been rising during recent decades. We aimed to investigate the prospective association between general and central obesities with IBD in a large-scale, long-term follow-up, population-based cohort. Participants free of IBD at baseline were enrolled in UK biobank from 2006 to 2010. Multiple baseline general and central obesity indices were assessed (i.e., body mass index [BMI], waist circumference [WC], etc.]. Primary outcome was incident IBD, including ulcerative colitis (UC) and Crohn's disease (CD). Cox proportional hazard model was conducted to investigate the association. Overall, 438,172 participants (aged 56.19 +/- 8.10 years; 46.6% male) were included. Based on baseline BMI, 141,464 (32.3%), 187,040 (42.7%), and 107,562 (24.5%) were categorized as normal weight, overweight, and obesity, respectively. During a median of 14.6 years' follow-up, 2856 incident IBD developed. After multivariable adjustment, individuals with obesity had an 18% higher risk of incident IBD compared to those with normal BMI (hazard ratio [HR] = 1.18, 95% confidence interval [CI]: 1.07-1.30). Similarly, participants in the highest WC quartile had a 28% higher IBD risk compared to the lowest quartile (HR = 1.28, 95% CI: 1.13-1.45). Other central obesity measures showed similar patterns, with 13%-39% higher risk of IBD occurrence in the highest quartile versus the lowest quartile. Similar greater risk of UC and CD was also identified in those with general or central obesity. General and central obesities are both associated with an elevated risk of developing IBD, CD, and UC, emphasizing the critical role of obesity management in preventing IBD.

BACKGROUND:Long-term adverse liver and oncological risks across steatotic liver disease (SLD) subtypes remain uncertain, and alcohol underreporting may cause misclassification. AIMS:To evaluate long-term risks of major adverse liver outcomes (MALO) and cancer across SLD subtypes by the MetALD-ALD Prediction Index (MAPI) and self-reported alcohol intake. METHODS:Participants with SLD at baseline and free of cancer in the UK Biobank were classified as MASLD, MetALD, or ALD. The primary outcome was incident MALO. Secondary outcomes included incident all cancers, cancer-related death, hepatocellular carcinoma (HCC), extrahepatic cancers, digestive cancers excluding HCC, and site-specific digestive cancers. Multivariable Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), with MASLD as the reference group. RESULTS:Among 138,996 participants, 51,633 were classified as MASLD, 27,231 as MetALD, and 60,132 as ALD. Compared with MASLD, MetALD exhibited higher risks of all cancers (HR, 1.07; 95% CI, 1.04-1.11) and extrahepatic cancers (HR, 1.07; 95% CI, 1.03-1.11), but not of MALO, cancer-related death, HCC, or digestive cancers excluding HCC. ALD showed the greatest risks, with increased risks of MALO (HR, 1.70; 95% CI, 1.54-1.88), all cancers (HR, 1.12; 95% CI, 1.08-1.15), cancer-related death (HR, 1.07; 95% CI, 1.01-1.14), HCC (HR, 3.07; 95% CI, 2.23-4.23), extrahepatic cancers (HR, 1.11; 95% CI, 1.08-1.14), and digestive cancers excluding HCC (HR, 1.20; 95% CI, 1.11-1.29). CONCLUSIONS:MAPI-informed SLD subtypes showed distinct risk profiles. MetALD exhibited higher risks of all cancers and extrahepatic cancers, whereas ALD conferred the highest risks across MALO and cancer outcomes, particularly for HCC and digestive cancer.

OBJECTIVE:To examine the association between sleep pattern, which integrates sleep duration, chronotype and quality, with risk of bowel resection and all-cause mortality in patients with inflammatory bowel disease (IBD) based on a long-term prospective cohort. DESIGN:Prevalent patients with IBD were categorised into poor (0-2 score), intermediate (3 score) and healthy (4-5 score) based on sleep score. The score assigned 1 point for each of five low-risk sleep behaviours: sleep 7-8 hours per day, early chronotype, no snoring, never/rarely insomnia symptoms and no frequent daytime sleepiness. The primary outcome was all-cause death, with bowel resection as a secondary outcome. Multivariable Cox proportional hazards models were used to explore the association. SETTING:This study used the data from the UK Biobank with participants recruited in 2006-2010. PARTICIPANTS:Among 502 411 participants recruited in UK biobank, 4262 cancer-free patients with IBD at baseline were finally included. RESULTS:During a median of 14.6-year follow-up, 793 received bowel resection and 498 deaths developed. Compared with poor sleep pattern, both healthy (HR=0.75, 95% CI 0.59 to 0.94) and intermediate (HR=0.77, 95% CI 0.66 to 0.95) sleep groups had reduced mortality risk, with a dose-response relationship across sleep scores (HR=0.89, 95% CI 0.82 to 0.98). Specifically, appropriate sleep duration (HR=0.79, 95% CI 0.66 to 0.95) and early chronotype (HR=0.82, 95% CI 0.68 to 0.98) were associated with 21% and 18% lower mortality risk, respectively. Marginally significant lower risk of bowel resection was observed with healthy (HR=0.86, 95% CI 0.72 to 1.04) and intermediate (HR=0.87, 95% CI 0.73 to 1.03) sleep pattern, with 22% lower risk associated with never/rarely insomnia symptoms (HR=0.78, 95% CI 0.65 to 0.94). CONCLUSIONS:A healthy sleep pattern, particularly sleep duration and early chronotype, is associated with reduced all-cause mortality risk in patients with IBD, with probably beneficial effect on lowering risk of bowel resection, highlighting the importance of maintaining healthy sleep behaviours for long-term prognosis in IBD.

The clinical use of irinotecan (CPT-11), a first-line chemotherapeutic agent for solid tumors, is severely compromised by the side effect of diarrhea and enterotoxicity. This toxicity is largely driven by the reactivation of the metabolite SN-38G to cytotoxic SN-38 by bacterial β-glucuronidases (GUS) in the gut. In this study, we investigated the protective effects of Pterostilbene (PTE), a natural active compound extracted from blueberry and grape, against CPT-11-induced intestinal injury in mice. We found that oral administration of PTE significantly alleviated CPT-11-induced weight loss, diarrhea, and colonic pathological damage. PTE treatment preserved the integrity of the intestinal mucosal barrier as restoring tight junction proteins and preventing goblet cell depletion, while concurrently suppressing pro-inflammatory cytokines. Metagenomic sequencing and functional assays revealed that PTE administration partially restores gut microbial homeostasis, most notably by significantly reducing the abundance and activity of GUS-expressing bacteria such as Enterococcus faecalis. Furthermore, PTE exerted direct inhibitory activity against Enterococcus faecalis both in vitro and in vivo, thereby significantly reducing the intestinal accumulation of the toxic metabolite SN-38. Importantly, PTE mitigated enterotoxicity without compromising the anti-tumor efficacy of CPT-11 in a colorectal cancer xenograft model. Collectively, our findings suggest that PTE represents a natural functional food ingredient to enhance the tolerability of irinotecan-based chemotherapy.

BACKGROUND:Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder; however, evidence regarding its association with early-life factors is lacking. OBJECTIVES:We aimed to examine the association between early-life factors, including maternal smoking and lactation, and risk of incident IBS in offspring within a large prospective cohort. METHODS:Participants free of IBS at baseline and with available data on maternal smoking and lactation were included. Maternal smoking was defined as regular cigarette smoking during the perinatal period, and lactation was defined as any breastfeeding during the infant period. Participants exposed to maternal smoking or to lactation during infancy were defined as exposure groups. The primary outcome was incident IBS. Cox proportional hazards model was conducted to estimate the associated risk. RESULTS:Among 290,962 participants, 81,186 (27.90%) participants were exposed to maternal smoking and 211,954 (72.85%) were exposed to lactation as infants. Over a median of 14.6 y of follow-up, 6222 incident IBS cases were identified. After multivariable adjustment, participants with maternal smoking had a 16.0% higher risk of incident IBS compared with those without maternal smoking [hazard ratio (HR): 1.16; 95% confidence interval (CI): 1.09, 1.22], whereas those exposed to lactation had a 9% lower risk of IBS than those not exposed to lactation (HR: 0.91; 95% CI: 0.86, 0.97). Notably, participants exposed to both maternal smoking and no lactation exhibited an even higher risk of developing IBS compared with those with lactation exposure but without maternal smoking (HR: 1.23; 95% CI: 1.14, 1.34). Additionally, an evidently higher IBS risk was observed in those with both maternal smoking and individual previous/current smoking (HR: 1.30; 95% CI: 1.21, 1.41). CONCLUSIONS:Maternal smoking is associated with a higher risk of incident IBS, whereas exposure to lactation is associated with a lower risk. These findings underscore the potential impact of early-life exposures on gastrointestinal health.

The impact of adverse childhood experiences (ACEs), adverse adulthood experiences (AAEs), and their combined effects on the risk of incident irritable bowel syndrome (IBS) remains unclear. We aimed to investigate the risk of IBS associated with ACEs and AAEs. Participants free of IBS with available ACEs and AAEs data were included (N = 126,735). ACEs and AAEs were assessed separately using the Childhood Trauma Screener-5 item and custom-built questions, with different patterns identified through latent profile analysis. The primary endpoint was incident IBS. Cox proportional hazards models were used to estimate the relationship. During a median follow-up of 14.5 years, 2492 (2.0%) incident IBS cases were identified. Overall, 95,040 (75.0%), 3011 (2.4%), 17,409 (13.7%), and 11,275 (8.9%) participants were classified as low ACEs, high physical neglect, high emotional neglect, and high abuse patterns, respectively. Compared with low ACEs, those with high emotional neglect (HR = 1.38, 95%CI: 1.24-1.54) and abuse (HR = 1.64, 95%CI: 1.46-1.84) patterns during childhood showed an increased IBS risk. Similarly, 111,776 (88.2%), 7039 (5.6%), and 7920 (6.2%) participants were classified as low AAEs, high physical neglect, and high abuse. Compared to low AAEs, high physical neglect and abuse in adulthood had a 1.34-fold (95%CI: 1.15-1.56) and 1.54-fold (95%CI: 1.36-1.77) increased IBS risk. Joint analysis indicated that individuals with high abuse or emotional neglect in ACEs, combined with any pattern in AAEs, had a 39-161% higher IBS risk compared to those with low ACEs and AAEs. Both ACEs and AAEs are associated with higher IBS risk, with their joint effects aggravating the risk.

Non-alcoholic fatty liver disease (NAFLD), recently redefined as metabolic dysfunction-associated steatotic liver disease (MASLD), is strongly associated with metabolic dysfunction and altered body fat distribution. However, MASLD-based reclassification was not performed due to incomplete cardiometabolic data. Transient elastography non-invasively assesses hepatic steatosis and stiffness, but its metabolic associations remain unclear. In this retrospective cross-sectional study, 238 NAFLD patients and 165 non-NAFLD controls were analyzed. Clinical, biochemical, and body composition data (bioelectrical impedance analysis) were collected. Liver steatosis (CAP) and stiffness (E value) were measured using FibroScan®. Group comparisons, correlation analyses, and multivariable regression models were performed. Logistic regression identified independent factors associated with NAFLD, and model performance was evaluated using ROC analysis. NAFLD patients showed significantly higher BMI, blood pressure, triglycerides, total cholesterol, LDL-C, and regional fat mass (including trunk and limb compartments) compared with controls (all P < 0.05). CAP was positively correlated with HbA1c, total cholesterol, and LDL-C (all P < 0.05). In multivariable analysis, total cholesterol (β = 9.26, P = 0.018) and LDL-C (β = 6.55, P = 0.021) were independently associated with CAP. Logistic regression identified sex, hypertension, BMI, LDL-C, left upper-limb fat mass, and liver stiffness as independent factors associated with NAFLD. The combined clinical model achieved the highest discriminatory performance (AUC = 0.91, 95

This study examines the association between the aggregate index of systemic inflammation (AISI) and mortality among individuals with abdominal obesity, aiming to provide a scientific basis for accurate identification of high-risk individuals and the implementation of early interventions. This study utilized data from the National Health and Nutrition Examination Survey (NHANES) 1999-2016 to include adults with abdominal obesity. The AISI was calculated as (neutrophil count × platelet count × monocyte count)/lymphocyte count. Participants were linked to the National Death Index to determine vital status, with mortality follow-up extending through December 31, 2019. The association between the AISI and mortality risk in individuals with abdominal obesity was examined through Kaplan-Meier survival analysis, weighted Cox proportional hazards regression, subgroup stratification, and restricted cubic spline modeling. This cohort study enrolled 15,839 adult participants with abdominal obesity. During a median follow-up of 119 months, 2223 deaths were recorded. Kaplan-Meier survival analysis showed that elevated levels of the AISI were significantly associated with reduced survival probability. After comprehensive adjustment for multiple potential confounders, multivariate Cox proportional hazards regression revealed a significant positive association between AISI levels and all-cause mortality risk in individuals with abdominal obesity. When AISI was treated as a continuous variable, each 1-unit increase was associated with a 1% higher risk of death (fully adjusted HR = 1.01, 95% CI: 1.01-1.01, P < .001). When dichotomized at the median, the high AISI group exhibited a 16% increased risk of mortality compared to the low AISI group (fully adjusted HR = 1.16, 95% CI: 1.04-1.30, P = .010). Restricted cubic spline analysis confirmed a statistically significant linear relationship (P for overall < .001; P for nonlinearity = .192). Subgroup analyses indicated heterogeneity in this association across marital status subgroups (interaction P = .017). This study demonstrates that elevated AISI levels are associated with increased mortality risk among individuals with abdominal obesity. These findings underscore the value of AISI as a prognostic indicator for mortality in this at-risk population. The integration of AISI into clinical inflammatory assessment frameworks may facilitate the establishment of dynamic surveillance strategies for identifying and monitoring high-risk individuals.

Intraoperative high end-tidal carbon dioxide (ETCO₂) during endoscopic resection (ER) of gastric submucosal tumors (SMTs) may cause respiratory compromise. Preoperative identification of risk factors and development of a scoring model to predict intraoperative high ETCO₂ may aid in preoperative planning. A total of 1,368 patients were retrospectively enrolled and divided into a training cohort (TC, n = 690), an internal validation cohort (IVC, n = 296), and an external validation cohort (EVC, n = 382). Preoperative variables were compared between the high ETCO₂ and normal groups in the TC. Multivariate logistic regression was performed to identify independent risk factors for intraoperative high ETCO₂ and to construct a simplified scoring system. The model’s performance was assessed using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy in the TC, IVC, and EVC. Intraoperative high ETCO₂ was documented in 341 (24.9%) patients. Multivariate analysis identified age ≥ 65 years (1 point), BMI ≥ 24.0 kg/m² (1 point), tumor size ≥ 3.0 cm (1 point), and invasion depth beyond muscularis propria (2 points) as independent predictors, which were incorporated to build a weighted scoring model. The model showed good discrimination, with AUCs of 0.832 (IVC) and 0.807 (EVC) and high NPVs of 90.0% and 88.7%. The incidence of intraoperative high ETCO₂ increased significantly with risk stratification: low-risk (score 0–1), intermediate-risk (score 2–3), and high-risk (score 4–5) groups exhibited rates of 11.0%, 52.7%, 85.7% (TC); 10.0%, 42.1%, 89.5% (IVC); and 11.3%, 39.3%, 85.7% (EVC), respectively. This preoperative scoring model based on four readily available clinical variables shows good discrimination for predicting intraoperative high ETCO₂. It may help raise preoperative awareness and guide the intensity of intraoperative monitoring. However, prospective validation is required before clinical implementation.

Background: Social isolation and loneliness are common among older adults and have been linked to metabolic disorders, psychological conditions, and unhealthy lifestyle behaviors. However, their associations with incident irritable bowel syndrome (IBS) remain unclear. Objective: To investigate the associations of social isolation and loneliness with incident IBS risk, and the mediating roles of anxiety or depression. Design: Population-based prospective cohort study. Methods: Participants without IBS and with available social isolation and loneliness data at recruitment were included ( N = 394,458). Social isolation was assessed using household size, social contact frequency, and weekly social activities, while loneliness was measured by self-reported feelings of loneliness and willingness to confide. The primary outcome was incident IBS. Cox regression with sequential mediation analysis was conducted to estimate the effect. Results: During a median follow-up of 14.5 years, 8307 (2.1%) incident IBS cases were identified. Overall, 209,081 (53.0%), 149,729 (38.0%), and 35,648 (9.0%) participants were classified as least, moderately, and most isolated, respectively. The 14-year cumulative incidence of IBS increased from 2.0% (95% confidence interval (CI): 2.0–2.1) in the least isolated group to 2.2% (95% CI: 2.2–2.3) and 2.6% (95% CI: 2.4–2.8) in the moderately and most isolated groups (population-attributable fraction (PAF) = 3.6%). Compared with the least isolated group, most isolated individuals had a 20.0% higher IBS risk (hazard ratio (HR) = 1.20, 95% CI: 1.11–1.29), with 24.7% of the effect mediated by depression or anxiety. The 14-year cumulative incidence of IBS was 3.1% (95% CI: 2.9–3.4) in the lonely group versus 2.1% (95% CI: 2.1–2.1) in the non-lonely group (PAF = 2.1%). Compared with non-lonely individuals (95.2%), lonely individuals (4.8%) showed a 46.0% increased IBS risk (HR = 1.46, 95% CI: 1.34–1.59), with 26.5% of the effect mediated by depression or anxiety. In addition, one increment in social isolation score (HR = 1.08, 95% CI: 1.04–1.11) and loneliness score (HR = 1.27, 95% CI: 1.23–1.32) were associated with 8.0% and 27.0% higher IBS risk, respectively. Particularly, most isolated and lonely individuals exhibited a 60.0% greater IBS risk versus their non-lonely and least isolated counterparts (HR = 1.60, 95% CI: 1.35–1.89). Conclusion: Both social isolation and loneliness are associated with increased IBS risk, partially mediated by depression or anxiety. Multi-level psychosocial and environmental interventions may help reduce IBS burden.

Background:While irritable bowel syndrome (IBS) and psoriasis share some pathophysiological features, it remains unclear whether they are associated with one another. Therefore, we aimed to investigate the long-term risk of incident psoriasis in a large prospective cohort of patients with IBS. Methods:We retrieved data on 437,170 participants from the UK Biobank without psoriasis at baseline. Using ICD-10 codes, we classified these participants into IBS and non-IBS groups based on recruitment status and assessed them for incident psoriasis at follow-ups as the primary outcome. We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results:We identified 21,748 (5.0%) IBS patients among the 437,170 participants. There were 4325 (1.0%) incident psoriasis cases during a median follow-up period of 14.4 years, amounting to a cumulative incidence of 0.88% (95% CI = 0.73-1.02) in the IBS group vs. 0.69% (95% CI = 0.66-0.72) in the non-IBS group. Compared with non-IBS patients, patients with IBS had a 35.0% higher risk of developing psoriasis (HR = 1.35; 95% CI = 1.19-1.52). In subgroup analyses, a higher psoriasis risk associated with IBS was generally observed across age, sex, Townsend deprivation index, smoking status, non-steroidal anti-inflammatory drug use, C-reactive protein, and polygenic risk score of psoriasis subgroups. Conclusions:The IBS patients in our sample had an increased long-term risk of incident psoriasis. This finding highlights the importance of monitoring psoriasis in IBS patients and suggests a potential shared pathophysiological mechanism between the two conditions which may inform future preventive and therapeutic strategies.

BACKGROUND:Limited evidence has investigated the effect of a healthy lifestyle on mortality in patients with inflammatory bowel disease (IBD). We aimed to assess the relationship between a healthy lifestyle and all-cause mortality in IBD, as well as the underlying metabolic mechanisms in a prospective cohort. METHODS:Overall, 5052 IBD patients free of cancer (aged 57.0±8.0 years, 48.5% men) were included from UK Biobank cohort. A healthy lifestyle was defined as a normal body mass index, never smoking, moderate alcohol consumption, regular physical activity, adequate sleep duration and healthy diet. The primary outcome was all-cause mortality. Lifestyle-related metabolic signatures were constructed by linear regression and elastic net regression in patients with metabolomics data. A multivariable Cox proportional hazards model was used to assess associations between lifestyle, metabolic signature and all-cause mortality. The mediation effect of lifestyle-related metabolic signatures was estimated through the Cox marginal structural model. RESULTS:During a median of 14.6 years' follow-up, 583 deaths were identified. Compared with unfavourable lifestyle, those with favourable lifestyle showed significantly lower risk of all-cause mortality in IBD (HR=0.56, 95% CI 0.46 to 0.68), ulcerative colitis (UC) (HR=0.61, 95% CI 0.48 to 0.79) and Crohn's disease (HR=0.49, 95% CI 0.36 to 0.67), and 18.9% of the reduced risk was mediated by metabolic signature. Metabolic signature was significantly associated with lower all-cause mortality, with HR of 0.65 (95%CI 0.49 to 0.85) for values above versus below the median and 0.73 (95%CI 0.64 to 0.83) for per SD increase. Subgroup and sensitivity analyses demonstrated similar results. CONCLUSION:A healthy lifestyle is associated with lower mortality in IBD patients. This beneficial effect may be mediated by metabolic signatures and related to favourable metabolic alterations.

BACKGROUND:Vitamin D is considered as a potential immunomodulator in inflammatory bowel disease development; however, emerging evidence remains inconsistent. We aimed to investigate the prospective association between serum vitamin D level and long-term risk of elderly-onset inflammatory bowel disease in a large-scale cohort. METHODS:Participants without inflammatory bowel disease at enrollment from the UK Biobank were included. Baseline blood samples were collected and serum 25-hydroxyvitamin D (25[OH]D) levels were measured. Participants were classified as having vitamin D deficiency (< 50 nmol/L), insufficiency (50-75 nmol/L) or sufficiency (≥ 75 nmol/L) based on predefined cutoffs. Primary outcome was incident elderly-onset inflammatory bowel disease, including ulcerative colitis and Crohn disease. Hazard ratio (HR) and 95% confidence intervals (CIs) of related associations were determined using multivariable Cox regression. RESULTS:Among 357,656 participants (mean age, 57.9±6.9 years), 196,499 (54.9%) and 121,035 (33.8%) had vitamin D deficiency and insufficiency, respectively. During a median 13.3 years follow-up, 1622 elderly-onset inflammatory bowel disease cases were identified. Compared with vitamin D sufficiency, no associations with vitamin D deficiency (HR = 0.91; 95% CI, 0.78-1.07) or insufficiency (HR = 0.86; 95% CI, 0.73-1.01) were observed for elderly-onset inflammatory bowel disease. Similarly, no associations with per 10 nmol/L increase of serum 25(OH)D were detected for elderly-onset inflammatory bowel disease (HR = 1.00; 95% CI, 0.98-1.03), ulcerative colitis (HR = 1.00; 95% CI, 0.97-1.03), or Crohn disease (HR = 1.01; 95% CI, 0.97-1.05). Compared with the lowest quartile, no associations with higher quartiles of serum 25(OH)D were observed for inflammatory bowel disease (HRQ4VSQ1 = 1.03; 95% CI, 0.89-1.19), ulcerative colitis (HRQ4VSQ1 = 1.06; 95% CI, 0.90-1.26), or Crohn disease (HRQ4VSQ1 = 0.93; 95% CI, 0.73-1.20). Further sensitivity and subgroup analyses demonstrated similar results. CONCLUSIONS:Serum vitamin D level or deficiency status is not associated with the development of elderly-onset inflammatory bowel disease, ulcerative colitis, or Crohn disease.

BACKGROUND AND AIMS:Type 2 diabetes (T2DM) and inflammatory bowel disease (IBD) are 2 distinct diseases that share a similar pathophysiology; however, the association between the 2 diseases remains elusive. We aimed to investigate the bidirectional association between T2DM and IBD in a large prospective population cohort. METHODS:Participants were recruited from the prospective cohort of UK Biobank. We included 4921 patients with IBD and 438,948 non-IBD to assess the incident risk of T2DM, and 11,649 patients with T2DM and 438,948 non-T2DM to assess the incident risk of IBD. Multivariable Cox proportional hazards regression model was used to calculate adjusted hazard ratio (HR). RESULTS:A total of 27,373 incident T2DM and 2696 incident IBD cases were identified during a median of 12.6- and 12.9-years' follow-up, respectively. After adjustment for potential confounders, participants with IBD, UC, or CD showed an excess risk of incident T2DM (HR=1.44, 95% CI: 1.31-1.59 for IBD, HR=1.41, 95% CI: 1.26-1.58 for UC, and HR=1.62, 95% CI: 1.39-1.89 for CD, respectively), compared with non-IBD. By contrast, compared with non-T2DM, participants with T2DM also showed higher risk of incident IBD (HR=1.40, 95% CI: 1.15-1.69), UC (HR=1.41, 95% CI: 1.13-1.76), or CD (HR=1.48, 95% CI: 1.08-2.04). Furthermore, the increased risk of incident T2DM was more evident when accompanied with the severity of IBD, and vice versa. Sensitivity analyses and subgroup analyses according to age, sex, and body mass index demonstrated similar results. CONCLUSION:IBD and T2DM are bidirectionally associated with higher comorbidity risks. Further investigations are needed to elucidate the shared pathogenesis underlying these 2 diseases.

OBJECTIVES:To investigate the bidirectional prospective association between inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) in a large-scale, long-term follow-up, population-based cohort. METHODS:Participants free of any cancer at baseline were included and divided into two prospective cohorts: baseline IBD and incident RA (cohort 1), and baseline RA and incident IBD (cohort 2). The primary outcome was incident RA in cohort 1 and incident IBD, including ulcerative colitis (UC) and Crohn's disease (CD), in cohort 2, separately. Cox proportional hazard regression models were used to investigate the bidirectional relationship between RA and IBD. RESULTS:Overall, 449 662 and 450 534 participants were included in cohort 1 and cohort 2, respectively, with 5015 prevalent IBD and 5887 prevalent RA cases at baseline, respectively. During a median of 14.3- and 14.6-year follow-up, 6001 (1.3%) cases of RA and 2988 (0.7%) cases of IBD were identified in cohort 1 and 2, respectively. Compared with non-IBD, IBD patients (hazard ratio [HR] = 1.44; 95% CI: 1.15, 1.79) showed a significantly higher risk of incident RA, particularly in UC patients (HR = 1.36; 95% CI: 1.06, 1.75) after multivariable adjustment. Similarly, RA patients had a 1.65-fold higher risk (95% CI: 1.31, 2.09) of incident IBD, with a 60% and 65% excess risk of developing UC (HR = 1.60; 95% CI: 1.20, 2.13) and CD (HR = 1.65; 95% CI: 1.12, 2.42), respectively. Further sensitivity analysis and subgroup analysis indicated similar results. CONCLUSION:IBD is associated with an increased risk of RA, and vice versa. Further studies are warranted to confirm the findings and elucidate the underlying biological mechanisms.

ABSTRACT Background Creatine is essential for energy storage and transfer within and outside cells. However, its relationship with cerebrovascular disease has not been fully explored. This study examined the association between serum creatine levels and postoperative cerebrovascular events, including transient ischemic attack (TIA), ischemic stroke, and hemorrhagic stroke, in patients with moyamoya disease (MMD). Methods Serum creatine and disodium creatine phosphate levels were quantified in 352 patients with MMD using liquid chromatography–tandem mass spectrometry. Kaplan–Meier (KM) curves were used to analyze the impact of serum creatine levels on cerebrovascular event risk, whereas univariate and multivariate Cox regression analyses were used to identify predictors of postoperative outcomes. A prognostic nomogram was developed to predict stroke‐free survival at 12, 24, and 36 months postoperatively. Results In patients with MMD, serum creatine showed a negative correlation with creatinine (r = −0.22; p < 0.001) and homocysteine (r = −0.10; p < 0.05) but not with disodium creatine phosphate (r = −0.08; p = 0.15). When patients were divided into high and low groups based on the median serum creatine concentration, KM curve analysis revealed that patients in the high concentration group had a lower relative risk of cerebrovascular events than those in the low concentration group (hazard ratio: 0.55; 95% confidence interval, 0.33–0.94; p = 0.026). Furthermore, when patients were categorized into three levels based on creatine concentration, the overall KM curve analysis showed a significant difference (p = 0.038), such that the highest creatine concentration group (third tertile) showed a significantly reduced risk compared with the lowest concentration group (first tertile; p = 0.04). Conclusion Lower preoperative serum creatine levels were associated with a higher risk of postoperative cerebrovascular events in patients with MMD. Therefore, creatine supplementation may be an effective means of preventing adverse outcomes in patients with MMD.

Despite the increased irritable bowel syndrome (IBS) risk associated with hepatic steatosis demonstrated in prior evidence, it is still unclear whether the newly coined metabolic dysfunction-associated steatotic liver disease (MASLD), could in reverse impact IBS development. We prospectively assessed the association of MASLD, MASLD type and different cardiometabolic risk factors (CMRFs) with incident IBS in a nationwide population-based cohort. Participants free of IBS at baseline in UK Biobank were included (N = 380,619). MASLD, MASLD type [pure MASLD, MASLD with increased alcohol intake (MetALD)] and CMRFs were defined based on the new criteria in America and Europe. Cox proportional hazard model was used to assess the associated risk of incident IBS. Overall, 143,857 (37.8