Yang Mi

Background: Mitochondrial function is essential for biology, particularly in cancer. However, cell-type-specific expression patterns of conserved mitochondrial genes in gastric cancer (GC) remain unclear. We herein raised and tested a novel hypothesis of “mitochondrial conserved gene expression homeostasis imbalance” in GC cohorts with single-cell resolution. Methods: This work analyzed an open-accessed scRNA-seq dataset (GSE206785, 24 GC patients, 48 samples) with Seurat and defined 43 clusters grouped into 15 cell subtypes. In parallel, Pseudobulk profiles were generated to simulate bulk RNA-seq. A mitochondrial conserved gene score was computed by Seurat AddModuleScore, GSVA, and AUCell. Mitochondria-related biomarkers were also screened, validated, and incorporated into a mitochondria-dependent prognostic model that was further evaluated. Results: Without considering cell-type-specific expression patterns, Pseudobulk analysis showed no significant differences in mitochondrial conserved gene expression between GC and control samples. In contracst, single-cell analysis found a cell-type-specific imbalance, under which tumor-associated epithelial cells displayed relatively elevated mitochondrial conserved gene expression, while non-epithelial cells showed reduced. Notably, survival analyses identified gene KRT7 and KLRC1 as robust prognostic biomarkers for early GC. Conclusion: Our findings support a mitochondrial conserved gene expression homeostasis imbalance in GC, which is characterized by compartment-specific mtGene expression imbalance. Also, KRT7 and KLRC1 emerge as prognostic markers for therapies aimed at restoring mitochondrial homeostasis in GC.

BACKGROUND Gastric intestinal metaplasia (GIM) represents a critical precancerous condition in the progression from chronic gastritis to gastric cancer, with limited therapeutic options. Emerging evidence suggests that taurine, a cytoprotective amino acid, may modulate gastric epithelial dysfunction. However, its application and efficiency in the context of GIM remain poorly understood. AIM To investigate the therapeutic effects of taurine on GIM using patient-derived organoids and Atp4a -/- mouse models. METHODS Patient-derived GIM organoids (n = 3) and Atp4a -/- mice, which spontaneously develop GIM, were used as experimental models. Morphological changes were assessed via Alcian blue-periodic acid Schiff staining. The expression levels of the gastric epithelial marker mucin 5AC (MUC5AC ) and GIM-associated markers (caudal type homeobox 2 [CDX2 ], MUC2 , Trefoil factor family 3 [TFF3 ]) were quantified via quantitative PCR, Western blotting, and immunohistochemistry. RESULTS We confirmed that taurine treatment significantly attenuated pathological changes, including glandular hypertrophy and vacuolar dilation, in Atp4a -/- mice. It also reduced GIM severity compared with that in the untreated model group. Under taurine treatment, MUC5AC expression was significantly increased, whereas the intestinal-specific markers CDX2 , MUC2 , and TFF3 were reduced (P < 0.05). In parallel, in patient-derived GIM organoids, taurine treatment significantly ameliorated GIM features, as evidenced by increased MUC5AC expression and decreased CDX2 , MUC2 , and TFF3 expression. CONCLUSION This study highlights the potential application of taurine as a therapeutic agent for treating GIM, offering a promising strategy for its clinical management.

Background: The gut microbiome has emerged as a critical modulator of cancer immunotherapy response. However, the mechanisms by which gut-associated metabolites influence checkpoint blockade efficacy in prostate cancer (PC) remain not fully explored. The study aimed to explore how gut metabolites regulate death-ligand 1 (PD-L1) blockade via exosomes and boost immune checkpoint inhibitors (ICIs) in PC. Methods: We recruited 70 PC patients to set up into five subgroups. The integrated multi-omics analysis was performed. In parallel, we validated the function of gut microbiome-associated metabolites on PD-L1 production and immunotherapy treatment efficacy in PC cell lines and transgenic adenocarcinoma of the mouse prostate (TRAMP) models. Results: We identified two metabolites, 16(R)-Hydroxyeicosatetraenoic acid (16(R)-HETE) and 6-Keto-Prostaglandin E1 (6-Keto-PGE1), that positively correlated with the plasma exosomal PD-L1 levels. The in vitro experiments found that both 16(R)-HETE and 6-Keto-PGE1 can enhance PD-L1 expression at the mRNA, protein, and exosome levels in both human and mouse PC cell lines, which were also validated in vivo based on subcutaneous mouse models. Both metabolites significantly promoted the anti-PD-L1 efficacy against PC in situ on a TRAMP mouse model. Conclusions: Targeting the “gut-tumor metabolic axis” is a promising strategy to improve the efficacy of immune checkpoint inhibitors in tumors.

The occurrence and progression of gastric cancer (GC) are closely associated with dysbiosis of the gastric microbiota and alteration in host microenvironments. However, the interaction between intratumoral bacteria and gastric microenvironments remains incompletely understood. In this study, we characterized the biological profiles of intratumoral bacteria, metabolome, and proteome in 20 GC tumors and paired non-tumor tissues, in combination with 6 independent datasets (comprising 477 gastric tissue biopsies and 534 normal tissues), as well as mucosal tissues from 10 individuals without GC. We found that the diversity and richness of gastric microbiota were significantly higher in tumor tissues than in non-tumor tissues. In contrast, the lowest biodiversity, at both the genus and species levels, was found in the microbiota of individuals without GC. Specifically, tumors were enriched with Bacteroides thetaiotaomicron, Lactobacillus parabrevis, Brevundimonas nasdae, and Brevundimonas vesicularis. We also identified 39 human immunity-related proteins, particularly in the tryptophan metabolic pathway, which were differentially expressed across various microenvironments (tumor and non-tumor). Furthermore, we found that several pathways involved in the human immune system and associated with the gastric microbiota, such as thiazole biosynthesis II, pyrimidine deoxyribonucleoside salvage, superpathway of pyrimidine deoxyribonucleoside salvage, and superpathway of heme biosynthesis from uroporphyrinogen-III, hold potential as biomarkers for early detection of GC. Our results provide a comprehensive framework for investigating the complex interactions between the tumor immune microenvironment and intratumoral bacterial community.

Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and the presence of restricted, repetitive behaviors or interests. Studies have revealed that gut microbiota and their metabolism play important roles in ASD, and become the underlying mechanisms of ASD. Methods: In this study, we performed long-read 16S rRNA sequencing and untargeted metabolomics to comprehensively characterize the profiles of gut microbiota and fecal metabolites in 34 ASD patients and 18 healthy controls. The associations between gut microbiota, fecal metabolites and clinical symptoms were analyzed to screen related biomarkers for ASD. Results: The results showed the similarity of the overall microbial richness and diversity between ASD patients and controls, however, some specific bacterial taxa exhibited significant differences, including Klebsiella and Escherichia-Shigella at genera level, and Clostridium-sporogenes , Escherichia-coli-O157H7 and Bacteroides-ovatus at species level. The fecal metabolomics validated that a lot of metabolites had significantly differential levels, including a series of organic acids, amino acids and dopamine. Discussion: The associations of gut microbiota and fecal metabolites might shed new light on the pathogenesis of ASD and help us to understand the importance of gut microbiota as potential biomarkers and therapeutic targets in the development of ASD.