Although metabolic rewiring is a defining feature of ICC, most work has centred on glucose and lipid pathways to date.
CCA still suffers from a lack of precision in both clinical and research approaches.
The RFGES is a mammoth study recruiting at least 2000 subjects each from 33 countries worldwide. In the mothership study, that reported on the wider DGBI cohort, functional constipation (11.7%) was the most prevalent, followed by unspecified functional bowel disorders (8.8%), functional dyspepsia (FD) (7.1%), functional diarrhoea (4.7%), irritable bowel syndrome (IBS) (4.1%) and functional bloating (3.5%).
Benign oesophageal strictures, particularly long-segment ones, present major clinical challenges—especially when caused by complex factors such as corrosive injury, radiation, postablation or mucosal resection, surgery or pill-induced damage.
Streptococcus anginosus has been linked with an increasing risk of gastric cancer (GC) and recognised as a signature for GC screening.
To investigate the promotional effect of S. anginosus in terms of its metabolic interactions with the host.
We used the functional profiles of shotgun metagenomic sequencing from stools to detect bioactive molecules relevant to S. anginosus. In vivo and in vitro experiments were used to validate the facilitation of S. anginosus to GC progression. S. anginosus clinical strains were isolated and cultivated from cancerous tissues to verify its promotion of GC via methionine production. S. anginosus metE mutant strains were constructed to confirm the critical role of metE in methionine biosynthesis.
We verified S. anginosus facilitated GC progression in vivo and in vitro. Our functional analysis of metagenomes revealed a significant enrichment of bacterial methionine biosynthesis pathways in GC patients with high S. anginosus abundance. Methionine, identified here as one of the primary microbial metabolites derived from S. anginosus, contributed to GC progression in humans and mice. S. anginosus strains from cancerous tissues were found to promote GC via methionine production. We further observed a higher abundance and prevalence of metE gene in cancer stool metagenomes. By constructing an S. anginosus metE mutant strain, we confirmed the critical role of metE in methionine biosynthesis.
Our results elucidate the role of S. anginosus-derived methionine in GC progression, shedding light on intricate metabolic interplay between S. anginosus and host.
Post-infection disorders of gut-brain interaction (PI-DGBI) are a subset of chronic gastrointestinal disorders triggered by acute infectious gastroenteritis. These conditions impose a significant burden on patients’ quality of life.
This study aimed to determine the prevalence of PI-DGBI and assess associated risk factors among participants in the Rome Foundation Global Epidemiology Study.
Data were extracted from an online survey involving 54 127 participants across 26 countries. PI-DGBI were diagnosed based on self-reported gastrointestinal symptoms following acute gastroenteritis. Statistical analyses included multivariate logistic regression to identify factors associated with PI-DGBI and comparisons with DGBI not associated with infection.
Of 21 713 individuals with at least one DGBI, 987 (10.5%) were classified as having PI-DGBI. PI-DGBI prevalence varied geographically, with the highest rates in Asia (7.1%) and Latin America (6.4%). Younger age, male sex, urban residence, anxiety and higher somatic symptom scores were positively associated with subjects reporting PI-DGBI, while female sex and rural living had negative associations. Subjects with PI-DGBI reported more severe psychological and physical health impairments and distinct gastrointestinal profiles, including higher rates of functional dyspepsia (32.2%), irritable bowel syndrome (23.5%) and anorectal disorders (35.3%).
PI-DGBI represents a significant subset of DGBI, with distinct sociodemographic and clinical characteristics. These findings highlight the role of acute gastroenteritis in triggering the onset of long-term gastrointestinal disorders and underscore the need for targeted interventions to mitigate its impact on patient health.
Eight months earlier, a 71-year-old man developed acute-onset severe abdominal pain following alcohol consumption. Following a 2-day onset, on admission, laboratory testing revealed serum lipase levels exceeding three times the upper limit of normal, and contrast-enhanced CT demonstrated features of acute pancreatitis, including a walled-off fluid collection near the splenic hilum. He improved with conservative management but subsequently developed recurrent postprandial abdominal pain and progressive enlargement of a left upper quadrant mass.
He had no relevant medical or surgical history but reported long-term heavy alcohol consumption and a 12.5-kg unintentional weight loss. Laboratory tests showed hypoalbuminaemia and elevated lactate dehydrogenase (LDH), while serum carbohydrate antigen 19-9 (CA19-9) and IgG4 were within normal limits.
Repeat CT demonstrated enlargement of the pancreatic cystic lesion to 9 cm with splenic involvement (
Dipeptidyl peptidase-4 inhibitors (DPP-4is) have been reported to exhibit therapeutic effects in Parkinson’s disease (PD), increasing their potential for drug repurposing. One aspect of PD pathogenesis is thought to be associated with the gut-brain axis, where α-synuclein from the gut is transmitted to the brain via the vagus nerve (VN).
We explored whether sitagliptin, a DPP-4i, exhibits a protective effect in a low-dose rotenone-treated gut-brain axis-associated PD model.
To explore the effect of sitagliptin, we used the oral rotenone-treated mouse model, which showed spreading of pathological α-synuclein from the intestine in a stereotypic manner via the VN into the midbrain with motor deficits.
Sitagliptin mitigated rotenone-induced gut inflammation and toll-like receptor 2 (TLR2) expression, reduced α-synuclein accumulation in the gut, VN and brain and lessened neuronal loss in the medulla and midbrain with recovery of motor performance. In addition, sitagliptin suppressed inflammation in response to a TLR2 agonist and rotenone in macrophages, enteric glial cells and enteroendocrine cell lines in vitro. In secretin tumour cell 1, an enteroendocrine cell line, sitagliptin also decreased rotenone-induced endogenous α-synuclein levels. The beneficial effects of sitagliptin were maintained even under glucagon-like peptide-1 receptor blockade. Notably, sitagliptin significantly altered the gut microbiome, shifting towards a profile that may counteract PD pathology.
These findings demonstrated that sitagliptin alleviated α-synuclein deposition in the gut and brain through modulation of TLR2-mediated inflammation and altered the gut microbiome composition towards a more favourable profile, which indicates that DPP-4is can offer a novel therapeutic avenue for managing PD.
Late-onset diarrhoea remains a poorly managed concern for clinical irinotecan therapy. Although bacterial β-glucuronidases (β-GUS) mediated SN-38 production is prevailingly thought to mediate intestinal toxicity, β-GUS inhibitors confer limited benefits in the clinic.
This study aimed to explore the role and mechanism of endogenous bacterial metabolites in susceptibility to irinotecan toxicity.
Gut microbiota profiles and metabolites in patients with colorectal cancer (CRC) with or without diarrhoea were investigated via 16S rRNA sequencing, shotgun metagenomics and metabolomics. The role of microbial metabolites was investigated in mice by metabolic bioengineering and intestinal organoid culture. The mechanism of microbial metabolites on intestinal stem cells was investigated by transcriptional profiling and chemical intervention.
Gut microbial configuration was differentially remodelled in diarrhoea and non-diarrhoea patients with irinotecan therapy, and the susceptibility was transmissible to recipient mice via transplantation of baseline faecal microbiome. Bacteroides intestinalis (B. intestinalis) was notably expanded in the diarrhoea-prone cohorts as well as in irinotecan-treated mice. B. intestinalis colonisation sensitised intestinal epithelia to irinotecan-induced chemical injury, partially via tryptophan metabolite indole-3-acetate (IAA). Both B. intestinalis and bioengineered bacteria that produce IAA exacerbated irinotecan-induced intestinal epithelial injury in mice. Mechanistically, IAA suppressed PI3K-Akt signalling, thereby impairing the renewal of intestinal epithelia under the insult of irinotecan. In clinical patients receiving irinotecan therapy, faecal IAA level was closely associated with the diarrhoea severity.
Our study uncovers the mechanism of endogenous bacterial metabolite in shaping the individual susceptibility to irinotecan toxicity and suggests IAA as a potential predictive biomarker.
Dysosmobacter welbionis is a recently discovered butyrate producer whose presence in stool correlates with improved metabolic health. Whether its abundance is reduced in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unknown. Mechanistic insight into its butyrate production from myo-inositol, a dietary compound from fruits, beans, grains and nuts with metabolic benefits, is also limited.
To assess population-level distribution, relative abundance and strain diversity of D. welbionis in humans, and to elucidate its metabolic capacity to ferment myo-inositol into butyrate.
We analysed several human cohorts for associations with liver health and evaluated D. welbionis J115T supplementation in a diet-induced steatosis mouse model. An antibody-guided anaerobic cell-sorting strategy enabled isolation of distinct strains. We combined 13C-labelled inositol isotopes with NMR, mass spectrometry, genomics and proteomics.
We found that D. welbionis and two related species (D. hominis and D. segnis) are prevalent gut bacteria in the human gut. D. welbionis abundance was reduced in MASLD across two cohorts and inversely correlated with fibrosis score in a third cohort. Treatment with D. welbionis J115T improved glycaemia and hepatic steatosis in high-fat diet fed mice. We identified a non-canonical myo-inositol-to-butyrate fermentation pathway. 19 human strains were isolated, comparative genomics of 23 strains revealed an open pangenome (about 2100 core genes) including the full myo-inositol fermentation pathway.
D. welbionis possesses a unique, conserved route to convert dietary myo-inositol into butyrate, distinguishing it from other commensals and supporting its potential as a next-generation probiotic for metabolic and liver health.
Germline RNF43 mutations cause a dominantly inherited syndrome of colorectal cancer (CRC) and serrated polyps. However, these data originate from highly selected families.
We assessed germline RNF43 variants in patients more representative of the general population and compared these with somatic RNF43mutations in CRCs.
We studied 49 823 CRC and/or polyp cases from the CORGI study, 100 000 Genomes (100kGP) and UK Biobank (UKB), alongside 165 250 controls. Somatic mutations were analysed in 2722 CRCs.
Consistent with the literature, a germline loss-of-function RNF43 variant (p.Thr158ProfsTer6) was found in a multigenerational CORGI family with early-onset CRC and serrated and/or filiform polyps. However, while 23 CRC/polyp cases and 47 controls from 100kGP or UKB had germline RNF43 mutations, cases often lacked multiple polyps or a notable family history. Sometimes, CRCs developed independently of the germline RNF43 mutation. In case-control analyses, germline RNF43 variants were associated with CRC risk (OR=2.696, p=0.010), but penetrance was much greater for germline mutations in the N-terminal half of the gene. Germline C-terminal mutations conferred no increased CRC risk. However, somatic C-terminal mutations were pathogenic, perhaps because their relatively weak effects are supplemented by accompanying mutations in Wnt genes, including ZNRF3 and a new driver, SFRP4.
RNF43 is a CRC predisposition gene, but risks are moderate, the reported polyposis phenotype is often absent and molecular phenocopies can occur. N-terminal germline RNF43 variants confer higher risk, although weak effects of C-terminal variants cannot be excluded. Genetic testing and patient management should incorporate these factors.
Accumulating evidence has demonstrated that distinct tumour-promoting and tumour-restraining cancer-associated fibroblast (CAF) subtypes coexist in pancreatic ductal adenocarcinoma.
To develop targeted CAF therapeutic strategies by reprogramming tumour-promoting CAF subtypes.
We leveraged multiomics technologies to systematically identify and characterise CAF subtypes transcriptionally, epigenetically and spatially and correlate them with clinicopathological features.
We found that complement-secreting CAFs (csCAFs), initially identified by our group and inflammatory CAFs (iCAFs) share significant overlap in their transcriptional profiles and chromatin accessibility. iCAFs specifically express transcription factors from the heme and oxidative homeostasis pathway and the activator protein 1 family, which are both involved in cellular response to oxidative stress. Notably, the composition of csCAFs among all CAFs declined during pancreatic carcinogenesis, while trajectory analysis showed that csCAFs could potentially differentiate into iCAFs. Spatially resolved analysis indicated that tumour regions with a higher csCAF composition were associated with lower levels of TGF-β ligands, fewer M2 tumour-associated macrophages and increased levels of lipid mediators. Additionally, we identified a spatially defined CXCL12-CXCR4 ligand–receptor interaction between csCAFs and T cells, but in distinct patterns between different metastatic organs. Patients with a higher composition of csCAFs have significantly longer overall survival and recurrence-free survival through multiplex immunohistochemistry and bulk RNA-seq deconvolution.
Our study demonstrates that csCAFs may represent an early-stage iCAF subtype and suggests a promising strategy for reprogramming iCAFs into csCAFs.
SIRT6 acts as a tumour suppressor in multiple cancers by regulating glucose and lipid metabolism, but its role in intrahepatic cholangiocarcinoma (ICC) remains unclear.
We investigated the role and molecular mechanisms of SIRT6 in ICC development and progression.
Spatial transcriptome and single-cell sequencing data from public ICC cohorts and clinical specimens were used to establish the clinical relevance of SIRT6 overexpression. B/R cell-established allografts and AKT/YAP-induced primary ICC mouse models were used to investigate the oncogenic role of SIRT6. The function of SIRT6 in metabolic regulation was assessed using seahorse analysis, metabolomics and isotope tracing. The transcriptional targets of SIRT6 were screened by RNA sequencing and confirmed by dual-luciferase assay and chromatin immunoprecipitation, and the molecular interactions and deacetylation activity of SIRT6 were analysed via co-immunoprecipitation.
SIRT6 was highly expressed in both human and mouse ICC tissues and cell lines. SIRT6 knockdown significantly inhibited ICC cell growth in vitro and ICC development in mouse models. Hydrodynamic co-injection of SIRT6 and AKT resulted in ICC formation in mice. SIRT6 promoted glutamine synthesis by enhancing GLUL transcription and stabilising GLUL protein degradation. SIRT6 silencing decreased glutamine levels, subsequently reducing the levels of nucleotides and amino acids in ICC cells. Thus, SIRT6 or GLUL inhibitors can suppress ICC progression and significantly enhance the sensitivity to chemotherapy.
Our findings establish SIRT6 as an oncogenic driver in ICC by orchestrating glutamine metabolic reprogramming and highlight the SIRT6-GLUL axis as a potential therapeutic target for ICC.
Chronic hepatitis B virus (HBV) infection disproportionately affects people living with HIV, who are often excluded from functional cure studies.
This study investigates CD8+ T cell profiles in HBV mono-infection versus HBV/HIV co-infection, examining the impact of long-term therapy on virus-specific responses to inform therapeutic strategies for immune restoration.
We analysed CD8+ T cell responses in 61 participants (HBV n=20, HBV/HIV n=20, HIV n=21), on suppressive antiviral therapy, assessing transcriptomic and proteomic profiles, focusing on exhaustion markers alongside virus-specific functional capabilities.
Transcriptomic analysis revealed distinct signatures in co-infection, with upregulation of TCR signalling genes, inhibitory pathways and progenitor-exhausted markers (XCL2, TCF7, PDCD1, IL7R). This profile scored highly for a precursor exhausted (Tpex) CD8+ T cell signature, reflecting stemness that maintains plasticity despite chronic antigen exposure. Proteomic analysis confirmed higher frequencies of Tpex (TCF-1+CD127+PD-1+) CD8+ T cells in co-infection, while HBV mono-infection showed predominance of terminally exhausted ToxhighTCF-1-CD127- cells. Tpex enrichment extended to HBV-specific populations corresponding with more robust, polyfunctional HBV-specific responses in co-infection against surface and core antigens. HBV-specific CD8 T cells maintained enhanced proliferative capacity and checkpoint responsiveness to anti-PDL1 blockade compared with HBV mono-infection. While co-infection was characterised by lower HBsAg levels and longer treatment duration, these factors alone did not account for the distinct immunological profiles.
People with well-controlled HBV/HIV co-infection maintain robust CD8+ T cell responses with preserved stem-like properties supporting antiviral function. These results challenge assumptions about additive immune dysfunction in dual chronic infections and highlight the need for tailored immune-modulatory therapies.
Most patients with biliary tract cancer (BTC) do not derive durable clinical benefit (DCB) from immune checkpoint inhibitors (ICIs), underscoring the urgent need for predictive biomarkers. While urinary proteomics represents a non-invasive approach for biomarker discovery and mechanism exploration, its utility in ICI-treated patients with cancer remains unexplored.
We aimed to establish urinary proteomics as a predictive tool for ICI responsiveness and to elucidate its relationship with tumour dynamics and tumour microenvironment (TME) remodelling in BTC.
We performed a staged mass spectrometry (MS)-based discovery-validation proteomics workflow in 211 urine samples from 97 treatment-naïve patients with BTC undergoing ICI-based therapy. A machine learning model was developed based on baseline proteomic features for ICI response prediction. Single-cell transcriptomics of 11 pretreatment tumour biopsies and spatial transcriptomics were integrated to explore the link between urinary proteomics and TME.
Patients achieving DCB exhibited enrichment of immune activation and systemic inflammatory pathways, whereas non-durable benefit was correlated with protumourigenic processes. Longitudinal urinary proteomic dynamics could mirror TME remodelling and tumour evolution. A machine learning-derived 4-urinary protein panel (protein tyrosine phosphatase non-receptor 13 (PTPN13), SUB1, MICAL-L1, VARS1) robustly predicted DCB and early responses. Subsequent external validation in an independent cohort (n=24) using parallel reaction monitoring-MS further confirms its generalisability. PTPN13+ malignant cells were identified as key regulators of proapoptotic TME states, contributing to sustained ICI responsiveness.
This study pioneers the application of urinary proteomics in immuno-oncology, providing a non-invasive approach to predict and monitor ICI responsiveness, while offering mechanistic insights into TME dynamics in BTC.
Chen X, Yang M, Chen Y, et al. Genetic engineering of systemically injectable oncolytic viruses for pyroptosis-accelerated cancer virotherapy. Nat Cancer 2026; 7(1): 207–223. doi: 10.1038/s43018-025-01078-y.
Delivering therapy specifically to cancer is a major challenge which promises to unlock effective cancer therapies without the detrimental systemic or local off-target effects. Oncolytic virus therapy is an exciting form of targeted immunotherapy which uses genetically engineered or natural viral particles to infect and destroy cancer cells. However, their detection and destruction by the patient’s immune system still offers a barrier to their delivery.
Chen et al set out to engineer oncolytic viruses to express gasdermin, a protein which forms pores in the host cell resulting in cell death through pyroptosis. Alongside this, they created engineered human cell membranes which act to cloak the oncolytic virus from cells which lack key...]]>
Five French laboratories offering microbiome analysis without prior consultation were selected via standard internet searches...]]>