Introduction

While the link between oral hygiene and systemic disease has been widely studied, large-scale studies specifically examining the association between oral hygiene or periodontal disease (PD) and colorectal cancer (CRC) remain scarce.

Aims & Methods

We aimed to investigate the association between oral hygiene indicators and the risk of CRC using a nationwide, population-based dataset from the Korean National Health Insurance Service (NHIS). The first was based on the National Health Screening (NHS) database, incorporating self-reported oral hygiene behaviors and dentist-conducted clinical dental examination findings. The second analysis utilized claims data from the NHIS database, focusing on PD as the primary exposure. We identified individuals aged ≥19 years newly diagnosed with CRC between January 2012 and December 2019, and controls without any history of cancer, matched at a 1:4 ratio using extensive propensity score (PS) matching. Multivariable conditional logistic regression was performed to adjust for potential confounders, including demographics, comorbidities, lifestyle factors, and laboratory values.

Results

In the NHS-based analysis, a total of 2,188,968 individuals were analyzed. Following PS matching, the matched dataset comprised 35,668 CRC cases and 141,850 controls. Several oral health indicators were significantly associated with increased CRC risk, including objective dental findings such as decayed teeth (adjusted odds ratio [aOR], 1.08; 95% confidence interval [CI], 1.05–1.11), missing teeth (aOR, 1.14; 95% CI, 1.11–1.17), severe gingivitis (aOR, 1.21; 95% CI, 1.15–1.26), and dental calculus (aOR, 1.10; 95% CI, 1.07–1.12), as well as poor oral hygiene-related behaviors or symptoms such as infrequent dental visits (aOR, 1.04; 95% CI, 1.02–1.07), poor perceived oral health (aOR,1.06; 95% CI, 1.02-1.10),
infrequent daily toothbrushing (aOR,1.20; 95% CI, 1.14–1.24), infrequent brushing before bedtime (aOR, 1.05; 95% CI, 1.02–1.08), non-use of interdental cleaning devices (aOR, 1.10; 95% CI, 1.07–1.13), and tooth pain (aOR, 1.03; 95% CI, 1.00–1.06). In the claims-based analysis, among 5,266,776 individuals, 133,482 CRC cases and 528,559 matched controls were included after PS matching. In the multivariable analysis, PD was independently associated with an increased risk of CRC (aOR, 1.03; 95% CI, 1.01–1.04). Additionally, in subgroup analyses stratified by age, sex, alcohol consumption, smoking status, and obesity, objective dental examination findings consistently showed a significant association with increased CRC risk across all subgroups.

Conclusion

Poor oral hygiene and PD were significantly associated with an elevated risk of CRC in this large-scale, population-based study. These findings highlight the potential importance of oral health in screening and prevention of CRC.

Introduction

Acetaminophen (APAP) overdose is a primary cause of drug-induced liver injury (DILI). Although the inflammatory microenvironment plays a critical role in APAP-induced liver injury (AILI), its cellular interaction network and molecular regulatory mechanisms remain incompletely elucidated. Krüppel-like factor 4 (KLF4), a zinc finger transcription factor, is known to regulate monocyte differentiation, but its functional role in the AILI inflammatory microenvironment remains unclear. This study aims to investigate the regulatory effects of myeloid KLF4 deletion on the AILI microenvironment.

Aims & Methods

By integrating multidimensional omics analysis and a myeloid-specific Klf4 knockout mouse model, we dynamically dissected microenvironmental remodeling during AILI progression. Liver samples were collected for RNA sequencing, combined with single-cell transcriptomics, flow cytometry, and molecular interaction validation to clarify the KLF4-dependent cellular subpopulation interaction network. In vivo liver imaging, histology, biochemical assays, and molecular experiments were performed to validate KLF4-dependent intercellular interactions. Primary hepatocytes and hepatocyte cell lines were used for in vitro verification.

Results

Myeloid-specific KLF4 deletion led to an increase in CXCL2⁺CXCL3⁺CD24⁺ monocytes, which activated the NF-κB signaling pathway to secrete CXCL2/CXCL3 chemokines. These chemokines bound to the CXCR2 receptor on neutrophils, driving neutrophil infiltration and neutrophil extracellular traps (NETs) formation, while amplifying the TNF-α signaling pathway. Concurrently, myeloid KLF4 knockout induced enrichment of CXCL1⁺IL17RA⁺ endothelial cells. Neutrophil-derived NETs promoted endothelial phenotypic switching toward pro-inflammatory polarization, while endothelial-derived CXCL1 further recruited neutrophils, establishing a "monocyte-neutrophil-endothelial" cellular subpopulation interaction that perpetuated microenvironmental inflammation.

Conclusion

This study reveals the molecular mechanism by which KLF4 drives inflammatory cascades in the AILI microenvironment through regulation of the myeloid-endothelial interaction network. We propose therapeutic strategies targeting NETs formation or the CXCL2/CXCL3-CXCR2 axis, providing novel targets for precise intervention in AILI.

Introduction

Acetaminophen-induced liver failure (AILF) has a high fatality rate and limited therapeutic approaches at present. Type 1 conventional dendritic cells (cDC1) are one of the major subgroups of cDCs in the liver, which is not only an important type in initiating adaptive immune response, but also can promote the generation, stability and function of Regulatory T (T_reg) cells through various mechanisms. cDC1 maintains liver immune homeostasis by regulating the balance between immune activation and tolerance. Nevertheless, the precise involvement and mechanistic contributions of hepatic cDCs in AILF remain to be elucidated.

Aims & Methods

Multiplex Immunohistochemistry (mIHC), flow cytometry, spatial transcriptomics (ST), single-cell RNA sequencing (scRNA-seq) and intravital 3D imaging were used to characterize the distribution and frequency of the cDC1. Bulk RNA-seq, metabolomic analyses, Cleavage Under Targets and Tagmentation (CUT&Tag) and Chromatin immunoprecipitation (ChIP)-qPCR assay were employed to explore the molecular mechanisms. CD11c^creXCR1^f/f, CD11c^creIDO1^f/f, CD11c^creP300^f/f and Foxp3^DTR mice, various mouse primary cells, human liver and serum samples were applied to verify the discoveries of bioinformatics analysis. Intravenous delivery of tolerogenic dendritic cells (tolDCs) was used to elucidate their regulatory effects on T_reg cells and roles in the AILF process.

Results

Our analyses revealed that the amount of cDC1 was significantly reduced across both clinical AILF cohorts and mouse AILF models, with the magnitude of depletion exhibiting dose- and duration-dependent associations with APAP exposure. mIHC, ST, scRNA-seq and intravital 3D imaging delineated that cDC1 depletion impaired T_reg cells priming capacity, ultimately disrupting hepatic immune homeostasis and exacerbating AILF. Intravenous tolDCs injection demonstrated therapeutic efficacy by orchestrating hepatic T_reg cells infiltration, attenuating inflammatory responses, potentiating liver regeneration, and ultimately reversing AILF-associated pathological manifestations. The therapeutic effect of intravenous tolDCs administration was abolished after diphtheria toxin-mediated T_reg cells depletion in Foxp3^DTR mice. CD11c^creXCR1^f/f mice andwild-type mice clearing cDC1 with XCL1-antibody had exacerbated liver pathology. Mechanistically, EP300-mediated histone 3 lysine 27 acetylation (H3K27ac) in IDO1 promoter region enforced stable tolerogenic states of cDC1, these epigenetically programmed cDC1 subsequently initiated tryptophan catabolism, generating kynurenine metabolites that triggered both differentiation and functional maturation of T_reg cells. Both the DC-specific knockout and inhibition of EP300 could reduce the H3k27ac levels of IDO1. And the CD11c^creIDO1^f/f mice with APAP exposure had less T_reg cells recruitment and worse phenotype.

Conclusion

This study elucidated that EP300 orchestrated tolDCs differentiation via H3K27ac/IDO1 signaling axis, this epigenetic-metabolic cascade licensed tolDCs to recruit and activate T_reg cells, thereby preserving hepatic immune homeostasis while promoting hepatocyte proliferation and tissue repair. These findings highlight novel therapeutic targets for reversing AILF pathogenesis.

Introduction

In Crohn’s disease (CD), an exposure-response relationship is suggested for ustekinumab, with higher serum levels associated with better outcomes. Pharmacokinetic data are scarce, with suggested target maintenance trough level associated with remission at 0.8-1.4 µg/mL. ^{1, 2} The REScUE study (NCT04245215) investigated the effect of two different re-induction regimens with ustekinumab in patients with CD. No significant difference was observed on clinical, endoscopic and biological outcomes.³ Here we present the pharmacokinetic and pharmacodynamics results of the REScUE study.

Aims & Methods

This Belgian multicentre prospective double-blind randomized placebo-controlled trial included adult patients with CD treated with ustekinumab who presented with secondary loss of response to ustekinumab after documented primary response. All patients received a single IV re-induction with ustekinumab (≈6mg/kg) and were then randomized 1:1 to blinded maintenance ustekinumab 90 mg SC Q4W (intervention) or 90 mg SC Q8W (control) for 48 weeks. PK samples were obtained at baseline, week 4-8-12-20-28-36-48.

Results

In total, 108 patients were included: 67% female, median [IQR] age 41 [32-54] year, median disease duration 14 [7-22] years. Prior anti-TNF exposure was reported in 92% of the patients. Baseline ustekinumab trough levels at moment of loss of response were similar in both groups and at the suggested target level of 0.8-1.4 µg/mL ¹: median (IQR) q4 week 1.39 (0.84-2.74) µg/mL and q8 week 1.31 (0.91-2.34) µg/mL (p>0.9). Eight weeks after induction, there was a statistically significant difference in ustekinumab trough levels between both groups 10.8 (8.0-15.9) µg/mL versus 8.2 (4.9-11.1) µg/mL for q4weeks vs q8weeks respectively (p=0.002). After 48 weeks of treatment the statistically significant difference persisted with 6.0 (4.8-9.6) µg/mL versus 2.1 (1.6-2.9) µg/mL (p<0.001). No significant association between baseline/week 8/week 48 ustekinumab trough levels and (steroid free) clinical remisison [PRO2 (AP ≤ 1 AND SF ≤ 3) and FCP <250µg/g and no steroids for 90 days prior to week 48] or endoscopic remission [SES-CD <3 at week 48] was seen. However, there was a significant association between baseline/week 8/week 48 ustekinumab trough levels and biomarker remission [CRP <5 mg/L and FCP <250 µg/g at week 48]; OR (95% CI) 2.98 (1.85, 5.23), 1.12 (1.06, 1.19) and 1.35 (1.13, 1.66) (all p<0.01) respectively. As per quartile analysis of the ustekinumab trough levels at week 48, the lowest quartile (ustekinumab <0.9 µg/mL) had the lowest steroid free clinical remission in each treatment group.

Conclusion

In patients with CD experiencing secondary loss of response to ustekinumab, baseline ustekinumab levels are low. Dose optimization with a single IV re-induction followed by intensified maintenance dosing (90 mg SC q4W) leads to higher ustekinumab levels compared to IV re-induction followed by conventional maintenance dosing (90 mg SC q8W). No association was found between ustekinumab levels and different outcomes except for biomarker remission. This suggests that treatment with ustekinumab should be personalized on a patient level, guided by drug-clearance rather than guided by target trough levels.

References

¹ Adedokun O. et al Gastroenterology 2018;154:1660–1671
² Schreiber S. et al ECCO 2023 Copenhagen; P436
³ Bossuyt P. et al ECCO 2025 Berlin; OP35

Disclosure

PB: Financial support for research: AbbVie, EG. •Lecture fees: AbbVie, AMC ICP, Amgen, Bristol Myers Squibb, Celltrion, Dr Falk Benelux, EG, Galapagos, Globalport, Lilly, Medtalks, Materia Prima, Pentax, Springer Media. •Advisory board: AbbVie, Bristol Meyers Squibb, CIRC, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda, Tetrameros.