Anti-tumor necrosis factor (TNF) therapy is widely used for inflammatory bowel disease, yet primary non-response and secondary loss of response remain challenges in clinical practice. In this study, we demonstrate that bacterial phosphoketolase improves the primary response to anti-TNF antibodies during induction therapy by enhancing Treg-mediated immunosuppression and maintaining higher serum drug concentrations. Mechanistically, phosphoketolase acts as a microbial host enzyme in macrophages, increasing phosphoketolase pathway flux and lactate production. Elevated lactate induces histone H4K12 lactylation, leading to the upregulation of the serotonin transporter, which mediates serotonin uptake for subsequent conversion to 5-hydroxyindoleacetic acid, a potential inhibitor of TNF-α-converting enzyme. This increases surface transmembrane TNF levels, thereby enhancing TNFR2 signaling in Tregs and promoting their proliferation and differentiation. In a prospective clinical trial, phosphoketolase-producing Bifidobacterium enhanced anti-TNF antibody efficacy during induction therapy. These findings support phosphoketolase-producing probiotics as an effective adjunct to anti-TNF therapy in inflammatory bowel disease.

Disturbances in the gut microbiota (GM) contribute to the pathogenesis of various prevalent metabolic disorders. Short-chain fatty acids act as signaling molecules and donors for host post-translational modifications. Here, we report a novel type of lysine modification, phenylacetylation (Kpaa), derived from the phenylalanine-dependent phenylacetic acid (PAA) metabolic pathway of the GM. Hepatic Kpaa levels were significantly elevated in mice with high-fat-diet-induced obesity and were reduced by the deacetylase sirtuin 3 (SIRT3). Proteome-wide substrates were significantly associated with mitochondria. PAA disrupted mitochondrial function and impaired insulin signaling. Mechanistically, PAA-induced K481paa of HSP60 triggered the mitochondrial unfolded protein response, which could be reversed by SIRT3. Finally, relatively low levels of hepatic SIRT3 in adults with obesity and metabolic dysfunction-associated steatohepatitis (MASH) were negatively correlated with increased Kpaa levels. Together, our study uncovered a microbiota-derived lysine acylation modification underlying its biological relevance in the development of metabolic dysfunction-associated steatotic liver disease (MASLD)/MASH.

Inflammatory bowel disease (IBD) is a chronic relapsing and remitting disorder in which loss of intrinsic enteric neurons (iENs) has been documented. However, the contribution of gut microbiota to the loss of iENs in IBD remains poorly defined. Here, we identify an IBD-enriched intestinal pathogen, Clostridium symbiosum (C. symbiosum), which exacerbates iEN loss and colitis. Mechanistically, C. symbiosum-derived succinate, emerging as a central mediator, drives macrophage glycolysis via the H3K79succ/HK2 axis, thereby sustaining IL-1β secretion, which, in turn, promotes neuronal-specific NLRP3 inflammasome activation and consequent neuronal loss. We further demonstrated that preventing iEN loss effectively improves outcomes in C. symbiosum-exacerbated colitis. Importantly, we identified phiCS-1, an endolysin from C. symbiosum-specific bacteriophages, which efficiently lyses C. symbiosum and markedly attenuates C. symbiosum-mediated iEN loss and colitis. Together, our study provides insights into the intricate interplay between gut microbiota and immune-neuron crosstalk, offering avenues for targeted therapeutic interventions in IBD.

ARTICLE HIGHLIGHTS:A rare loss-of-function variant in ZNRF3 (p.V228L) is enriched in individuals with obesity and is associated with increased subcutaneous white adipose tissue (sWAT) accumulation and lower fasting glucose levels. Both adipocyte-specific Znrf3 knockout and global variant knock-in impair sWAT browning, increase sWAT expansion, and improve glucose tolerance in mice. These findings establish ZNRF3 as a genetic regulator of fat distribution and thermogenic capacity, informing precise phenotyping of obesity. GWAS has implicated ZNRF3 in human fat distribution, yet its role in adipose tissue biology remains unknown.

Inflammatory bowel disease is shaped by complex microbial communities, yet the contribution of fungal-bacterial interactions to disease progression remains poorly defined. Here, we identify Cladosporium tenuissimum (C. tenuissimum) as a gut fungus with potent colitis-alleviating activity. Mechanistically, C. tenuissimum restrains Candida albicans (C. albicans) overgrowth through nutrient competition, particularly via the utilization and subsequent limitation of the amino acid ornithine. C. albicans can evade this suppression and potentiate intestinal inflammation through nutrient escape by preferentially exploiting specific amino acids, such as threonine. We further reveal a bacterial-fungal metabolic axis in which threonine-producing Bacteroides fragilis facilitates C. albicans escape from gut microbiome-mediated fungal control, thereby exacerbating colitis. Notably, dietary threonine restriction markedly attenuates C. albicans-driven colitis in mice. Together, our findings uncover a cross-kingdom metabolic network that determines C. albicans homeostasis and, in turn, governs intestinal inflammatory outcomes, offering new conceptual and therapeutic avenues for IBD.

AIMS:To evaluate the impact of applying the International Diabetes Federation (IDF) 1-hour plasma glucose (1h-PG) criteria on diagnosing dysglycaemia in young Chinese adults with obesity, and to validate the metabolic basis and diagnostic performance of these criteria in this high-risk population. METHODS:This Cross-Sectional Study Included 2484 Obese Individuals (Aged 18-40 Years, BMI ≥ 28 kg/m2). Participants underwent a 75-g oral glucose tolerance test (OGTT). Glycaemic status was classified using both traditional American Diabetes Association (ADA) criteria (fasting and 2-hour PG) and the IDF criteria (1h-PG cutoffs: 8.6 mmol/L for intermediate hyperglycaemia, 11.6 mmol/L for diabetes). Insulin sensitivity, secretion and β-cell function indices were calculated. Reclassification patterns were assessed, and the diagnostic accuracy of the 1h-PG cutoffs was evaluated using receiver operating characteristic (ROC) curve analysis against the ADA criteria. RESULTS:Applying IDF criteria doubled the prevalence of diabetes (from 12.0% to 22.7%) and significantly increased total dysglycaemia. This newly identified dysglycaemic population exhibited an intermediate metabolic phenotype with worsening insulin resistance and impaired early-phase β-cell function. ROC analysis demonstrated excellent diagnostic accuracy for the IDF diabetes cutoff (11.6 mmol/L; AUC 0.927), which matched the population-optimal cutoff. The cutoff for intermediate hyperglycaemia (8.6 mmol/L) showed high sensitivity (86.8%) for detecting ADA-defined prediabetes. CONCLUSIONS:The IDF 1h-PG criteria uncover a substantial, previously unrecognised burden of dysglycaemia in young Chinese adults with obesity, supported by clear metabolic defects and strong diagnostic performance. These findings support the use of 1h-PG as a practical tool for earlier risk stratification in this vulnerable population.

Obesity exhibits a high heritability with heterogeneity; however, the genetic variants identified as obesity-causing factors are still underexplored. By performing deep sequencing on 2295 cases of young-onset obesity from East Asian populations and 2292 lean controls, we identified five genes (TUB, NR4A3, HIST1H4D, DXO, and TELO2) with an excess burden of rare predicted loss-of-function (LoF) variants in cases. Among the variants, TUB p.R364G was identified as a potential deleterious variant that disrupted TUB protein's subcellular localization. Knock-in mice carrying the homologous p.R363G variant exhibited hyperphagia and obesity in an allele dose-dependent manner when fed a high-fat diet. The TUB p.R363G variant also blunted responses to leptin-induced suppression of food intake, leading to leptin resistance in mice. Furthermore, we demonstrated that TUB acted as a positive regulator of the leptin pathway through its interaction with STAT3, and this interaction was impaired by the p.R364G variant. TUB silencing mitigated the inhibitory effects of leptin on the activities of agouti-related protein (AgRP)-expressing neurons. Consistently, conditional ablation of TUB in AgRP+ neurons in mice led to hyperphagic obesity and attenuated leptin-induced appetite suppression in mice. Thus, our study demonstrates that rare LoF variants in TUB predispose to young-onset obesity in humans, likely through impairing leptin sensitivity in AgRP+ neurons.

Crosstalk between gut microbiota and adipose tissue critically shapes immunotherapy responses in patients with cancer. An obesity-associated microbial signature enriched in riboflavin-producing taxa was identified, along with increased microbial riboflavin biosynthesis pathway and elevated levels of flavin adenine dinucleotide (FAD), in obese responders to immune checkpoint blockade (ICB). In diet-induced obese (DIO) mice, fecal microbiota transplantation (FMT), administration of Lachnospiraceae bacterium, or FAD supplementation significantly enhanced the therapeutic efficacy of anti-PD-1 therapy. These interventions increased the cytotoxicity of tumor-infiltrating CD8+ T cells via mesenteric adipocyte-driven synthesis of polyunsaturated fatty acids (PUFAs). Inhibiting fatty acid desaturase 2 (FADS2) eliminated the benefits of FAD, underscoring a critical role for adipocyte-intrinsic lipid remodeling in mediating immune responses. Clinically, elevated systemic levels of PUFAs, particularly docosahexaenoic acid (DHA), were positively correlated with intratumoral CD8+ T cell infiltration and favorable immunotherapy outcomes. Dietary DHA supplementation improved ICB responses in lean mice. This study highlights that a microbiota-adipose axis shapes antitumor immunity, enabling potential personalized metabolic and microbial immunotherapy strategies.

OBJECTIVE: To identify predictive biomarkers from the perspectives of gut microbiota and bile acid metabolites for polycystic ovary syndrome (PCOS) remission following metabolic bariatric surgery in patients with PCOS and obesity. METHODS: We conducted a one-year follow-up of patients with obesity and PCOS who underwent sleeve gastrectomy (SG) to assess their PCOS remission status. Metagenomics and bile acid metabolomics were performed and compared between the remission and non-remission groups to identify differential microbial species and bile acid metabolites. The associations between these biomarkers and PCOS remission was then evaluated using Generalized Estimating Equations (GEE) models and Receiver Operating Characteristic (ROC) analysis. RESULTS: SG led to marked improvements in metabolic parameters and hyperandrogenemia. These changes were accompanied by substantial shifts in the gut microbiome, which correlated with alterations in gonadal hormone levels. Based on PCOS outcomes, patients were categorized into remission and non-remission groups. The remission group showed a higher abundance of A. equolifaciens and Clostridium sp CAG 299, along with lower baseline circulating levels of ursodeoxycholic acid (UDCA). These factors were positively associated with PCOS remission. ROC analysis demonstrated that the combination of A. equolifaciens, Clostridium sp CAG 299, UDCA, and average follicle number yielded an AUC of 0.93 for predicting remission. CONCLUSION: A composite biomarker signature incorporating specific gut microbiota profiles, circulating UDCA levels, and ovarian follicle count shows strong potential as an effective predictor of PCOS remission after SG.

To characterize the multimodal imaging features of pachychoroid-associated choroidal ossification (PACO), a newly proposed entity, in eyes with pachychoroid diseases. This retrospective case series included 12 eyes in 11 patients with PACO and 14 age-matched eyes with choroidal osteoma as a control group. Lesions were characterized using multimodal fundus imaging, which included B-scan ultrasonography. The subfoveal choroidal thickness (SFCT) and the maximum choroidal vessel diameter (MCVD) were manually measured on optical coherence tomographic images. PACO lesions exhibited a hyperechoic appearance with posterior shadowing on B-scan ultrasonography. Distinct multimodal imaging features included tortuous vascular tufts on indocyanine green angiography and an abnormal vasculature within the lesion on optical coherence angiography. Among the 12 eyes, 7 eyes had ossified lesions at initial presentation, including 6 eyes with chronic central serous chorioretinopathy (CSC) and 1 eye with polypoidal choroidal vasculopathy, whereas PACO developed during follow - up in the remaining 5 eyes. In 3 eyes with CSC, PACO lesions developed on fibrin sites over microtears in the retinal pigment epithelium accompanied by dilation of the underlying choroidal vessels. PACO was more frequent in males (P = 0.023) and was characterized by a longer interval from symptom onset to presentation of PACO lesions (P = 0.004), shorter maximum tumor linear dimension (P = 0.004), decreased tumor thickness (P < 0.001), increased SFCT (P < 0.001), and larger MCVD (P < 0.001) compared with the control eyes with osteoma. During the mean follow-up period of 42.50 ± 44.35 months (range 3‒131 months), 10 lesions decreased in height but increased in length. New ossified lesions emerged in the contralateral eye in 2 patients. PACO is an acquired choroidal ossification secondary to pachychoroid diseases, distinct from choroidal osteoma and fibrosis. Despite the lack of histologic investigation, our findings may enhance our understanding and recognition of the pathophysiological mechanisms involved in choroidal ossification.

Sex-dimorphic adipose mitochondrial function (lower activity in males) correlates with visceral adiposity and metabolic risk, yet the underlying mechanisms remain elusive. We find that androgen-androgen receptor (AR) signaling suppresses mitochondrial respiration and thermogenesis in visceral adipose tissue (VAT), promoting visceral fat accumulation. Mechanistically, androgen-AR signaling represses transcription of Pdhb, which encodes a pyruvate dehydrogenase (PDH) subunit, thereby reducing PDH activity, acetyl-CoA levels, H3K27 acetylation, and chromatin accessibility at the promoters of mitochondrial respiration-related genes. Notably, Pdhb overexpression largely reverses these alterations and restores mitochondrial function. Furthermore, sodium dichloroacetate, a PDH activator, enhances mitochondrial respiration and reduces visceral fat in male mice. Multi-omics analyses reveal that the androgen-PDH axis orchestrates a male-specific chromatin-based transcriptional landscape that encompasses mitochondrial and metabolic pathways in visceral adipocytes. Collectively, this study identifies the androgen-PDH axis as a key regulator of sexual dimorphism in mitochondrial metabolism and adipose homeostasis in VAT.

Background:Lifestyle-induced weight loss improves metabolic health, but weight regain is common. Its hepatic consequences, particularly in relation to metabolic dysfunction-associated steatotic liver disease (MASLD), remain insufficiently characterized. Methods:This retrospective observational study included 213 patients categorized as weight regain (≥5% lifestyle-induced weight loss followed by return to or exceeding baseline weight) or weight sustain (weight change within ±5% of baseline) over 3 years. Propensity score matching (PSM) balanced age, sex, weight, and body mass index. Clinical, biochemical, and noninvasive liver indices were compared. In a bariatric surgery subset, liver histology, transcriptomics, quantitative PCR, and immunohistochemistry were performed. Results:No significant differences were found in metabolic parameters between groups. After PSM, the weight regain group showed higher alanine aminotransferase (ALT) (median 59.00 vs 41.00 IU/L, P=0.007) and aspartate aminotransferase (AST) (33.50 vs 26.00 IU/L, P=0.041). In males, ALT (88.00 vs 47.00 IU/L, P<0.001) and AST (46.00 vs 30.00 IU/L, P=0.004) remained higher. Noninvasive indices of hepatic steatosis (Dallas Steatosis Index, DSI) and fibrosis (NFS, FIB-4) did not differ. In male patients with liver biopsy samples available, liver histology showed comparable NAFLD Activity Scores (NAS) and fibrosis stages, whereas transcriptomic analysis revealed immune-related pathway enrichment. Increased hepatic CD11B and CD68 expression was confirmed by quantitative PCR and immunohistochemistry. Conclusion:Weight regain after lifestyle-induced weight loss is associated with early liver-related biochemical abnormalities and hepatic innate immune activation in the absence of advanced fibrosis, underscoring the need for early liver risk assessment in individuals with weight cycling.

OBJECTIVE:Dysregulation of bile acid (BA) profiles is closely associated with obesity and its related metabolic abnormalities. This study aims to investigate the BA alterations between metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) and identify specific BA species associated with MUO. METHODS:We measured serum bile acid profiles in two cross-sectional studies. The discovery cohort included 261 normal-weight, 80 MHO, and 120 MUO individuals. The validation cohort, consisting of 104 MHO and 104 MUO participants (matched for age, sex, and BMI), was used for confirmation. RESULTS:Individual primary bile acids (PBAs), including cholic acid, glycocholic acid, chenodeoxycholic acid, and total PBA concentration, were markedly increased in MUO compared with both normal-weight and MHO subjects. Total secondary bile acids were decreased in both obesity phenotypes compared with normal-weight subjects, but did not differ between MUO and MHO. Among individuals with obesity, either individual PBA or total PBA levels were positively correlated with metabolic deterioration parameters such as WHR, HOMA-IR, HbA1c, and TG. Moreover, a higher total PBA level was associated with an increased proportion of MUO. These findings were further replicated in the validation cohort. CONCLUSIONS:Serum individual PBAs and total PBAs were significantly elevated in MUO compared with MHO. Higher PBA levels were associated with adverse metabolic parameters and an increased proportion of MUO. This study characterizes the distinct BA profiles across obesity phenotypes and highlights the associations between PBAs and MUO.

AIMS:To determine whether 1-hour plasma glucose (1-h PG) during an OGTT outperforms other glycemic markers (FPG, 0.5-h PG, 2-h PG, HbA1c) in identifying impairments in insulin secretion, sensitivity, and β-cell compensation. METHODS:We analyzed 2178 Chinese young adults (18-40 years) with obesity (BMI ≥ 28 kg/m2) and without diabetes. Associations between glycemic markers and OGTT-derived indices were assessed using adjusted correlations, regression, and ROC analyses. In a subcohort (n = 495) with frequently sampled intravenous glucose tolerance test (FSIVGTT) data, markers were evaluated against minimal-model estimates of first-phase secretion (AIRg), insulin sensitivity (SI), and disposition index (DI). RESULTS:1-h PG showed superior performance over other glycemic markers for identifying early-phase insulin secretion defects. Among these markers, it demonstrated the strongest correlation with IGI30 (ρ =  - 0.413) and the highest discriminatory accuracy (AUC = 0.702); this was supported by FSIVGTT-derived AIRg. For insulin sensitivity, 1-h PG correlated more strongly with the Matsuda index, whereas 2-h PG was more strongly associated with FSIVGTT-derived SI. Elevated 1-h PG (≥8.6 mmol/L) identified individuals with impairments across all traits. CONCLUSIONS:1-h PG is a specific physiological marker of early-phase insulin secretion defects, supporting its role in early phenotyping and risk stratification in young adults with obesity.

IntroductionElevated cortisol levels have been linked to arterial stiffness, but the evidence for this association remains controversial. We aimed to elucidate this relationship and to explore potential mediation pathways.MethodsTo investigate the relationship between morning cortisol and arterial stiffness, two approaches were employed. First, we used linear mixed-effects (LME) models and mediation analysis in a prospective cohort study (n=1,235; average follow-up of 3.5 years) in type 2 diabetes (T2D), featuring repeated brachial-ankle pulse wave velocity (baPWV) measurements (2–8 per participant; 4,143 total) to assess arterial stiffness. Second, a two-step Mendelian randomization (MR) study was conducted using summary data of genome-wide association studies (GWAS) of CORtisol NETwork (CORNET) and UK Biobank (UKB). Arterial stiffness was measured by baPWV in the cohort study, with coronary atherosclerosis from UKB serving as the validation outcome.ResultsThe prospective study included participants with a mean age of 54.3 ± 11.3 years (65.3% male) and a mean baseline baPWV of 16.06 ± 3.23 m/s. It revealed that each 1-unit increase in log10Cortisol was associated with a 0.67 m/s (95% CI: 0.25–1.10, P = 0.002) increase in baPWV. Mediation analysis indicated that systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) all partially mediated the association between morning cortisol and arterial stiffness, with SBP contributing the largest proportion (18.68%, 95% CI: 16.48–23.66%; P = 0.033). The two-step MR analysis further supported that SBP could mediate the positive relationship between morning cortisol and coronary atherosclerosis.ConclusionsThis research provides both observational and genetic evidence indicating a potential causal relationship between morning cortisol and arterial stiffness, with SBP as a key mediator.

Precision nutrition is pivotal to preventing cardiometabolic diseases. However, almost no single blood biomarker capable of predicting the metabolic benefits of specific dietary patterns has yet been identified. Here, we revealed the associations of plasma levels of the secreted protein acidic and rich in cysteine (SPARC), an inflammatory factor highly expressed in fat tissues, and insulin sensitivity improvement in a 6-month randomized controlled, calorie-restricted feeding trial recruiting 235 Chinese adults with overweight/obesity and prediabetes: the Mediterranean diet (MD) group (n = 81), the traditional Jiangnan diet (TJD) group (n = 81), and the control diet (CD) group (n = 73). The 1-h post-glucose loading plasma SPARC levels (SPARC-1H) decreased significantly from baseline to 3 months and 6 months in the MD group, whereas no significant changes were observed in the TJD or CD groups. Further analyses revealed that the individuals with higher baseline SPARC-1H levels were associated with fewer improvements in fasting insulin (β ± SE: 1.54 ± 0.43; P = 0.0007), fasting glucose (0.10 ± 0.04; P = 0.013), the homeostasis model assessment of insulin resistance (HOMA-IR, 0.47 ± 0.12; P = 0.0002), and the homeostasis model assessment of β-cell function (HOMA-β, 7.63 ± 3.27; P = 0.023) after 6 month in MD group. Moreover, baseline SPARC-1H levels were positively correlated with changes in lipidomic profiles, including three alkenylphosphatidylethanolamines (PE(P)s), which potentially mediate the cardiometabolic benefits of the MD group. No significant associations were observed in the other two diet groups. Our findings suggest postprandial SPARC as a predictor for the metabolic benefits of MD, offering a potential biomarker for individualized nutrition interventions against cardiometabolic diseases.

The role of hypothalamic branched-chain amino acid (BCAA) catabolism in the maintenance of energy homeostasis remains elusive. By using Mendelian randomization, we found that genetically predicted branched-chain keto acid dehydrogenase E1α subunit (BCKDHA) expression in the hypothalamus was negatively associated with fat mass. Hypothalamic deletion of BCKDHA (Bckdhaf/f;RIP-Cre) leads to increased fat mass, reduced energy expenditure, and blunted browning of white adipose tissue in mice, with decreases of thyrotropin-releasing hormone (TRH) expression in the paraventricular nucleus (PVN) and hypothalamic-pituitary-thyroid (HPT) axis activity. Mice with adeno-associated virus-mediated deletion of BCKDHA in the PVNTRH neurons displays a similar metabolic phenotype to Bckdhaf/f;RIP-Cre mice. TRH supplementation ameliorates the abnormal phenotypes of Bckdhaf/f;RIP-Cre mice. Defective BCAA catabolism in the hypothalamus results in hypoacetylation of histone H3 lysine 27 (H3K27) due to decreased acetyl-CoA content, reducing its binding to the Trh promoter. Our study highlights the crucial role of hypothalamic BCAA catabolism in maintaining energy homeostasis through HPT axis.

Transfer RNA modifications have emerged as critical regulators of translational reprogramming, yet their roles in colorectal cancer (CRC) remain largely elusive. Here, we find that tRNA N1-methyladenosine (m1A) methyltransferase TRMT6 is upregulated in human CRC tissues and high TRMT6 expression correlates with poor survival in patients with CRC. Using orthotopic, metastatic and conditional knockout mouse models, we establish the oncogenic role of TRMT6 in CRC. Mechanistically, TRMT6 increases tRNA m1A levels by maintaining the stability of the TRMT6–TRMT61A complex. Targeting TRMT6-mediated tRNA m1A modification in CRC cells destabilizes tRNA-Lys-TTT-1-1 and impairs histone mRNA translation in a codon-biased manner, thereby restricting histone synthesis and hindering cell cycle progression. Our study provides evidence that TRMT6 functions as a translational checkpoint in the accelerated histone synthesis of CRC cells, highlighting TRMT6 as a promising target for potential anti-CRC therapies. Tao et al. study the role of TRMT6 in colorectal cancer, where it is upregulated and show that TRMT6 supports histone biosynthesis by stabilizing tRNA-Lys-TTT-1-1. Targeting TRMT6 reduced histone mRNA translation in a codon-biased manner.