Background. Although immunotherapy has recently achieved clinical successes in a variety of cancers, thus far there is no immunotherapeutic strategy for breast cancer (BC). Thus, it is important to discover biomarkers for identifying BC patients responsive to immunotherapy. TP53 mutations were often associated with worse clinical outcomes in BC whose triple-negative subtype has a high TP53 mutation rate (approximately 80%). To explore a potentially promising therapeutic option for the TP53-mutated BC subtype, we studied the association between TP53 mutations and immunogenic activity in BC. Methods. We compared the enrichment levels of 26 immune signatures that indicated activities of diverse immune cells, functions, and pathways between TP53-mutated and TP53-wildtype BCs based on two large-scale BC multiomics datasets. Moreover, we explored the molecular cues associated with the differences in immunogenic activity between TP53-mutated and TP53-wildtype BCs. Furthermore, we performed experimental validation of the findings from bioinformatics analysis. Results. Bioinformatics analysis showed that almost all analyzed immune signatures showed significantly higher enrichment levels in TP53-mutated BCs than in TP53-wildtype BCs. Moreover, in vitro experiments confirmed that mutant p53 could increase BC immunogenicity. Both computational and experimental results demonstrated that TP53 mutations could promote BC immunogenicity via regulation of the p53-mediated pathways including cell cycle, apoptosis, Wnt, Jak-STAT, NOD-like receptor, and glycolysis. Furthermore, we found that elevated immune activity was likely associated with a better survival prognosis in TP53-mutated BCs, but not necessarily in TP53-wildtype BCs. Conclusions. TP53 mutations may promote immunogenic activity in BC, suggesting that the TP53 mutation status could be a useful biomarker for stratifying BC patients responsive to immunotherapy.

Herein, we identified that Ahr deficiency in intestinal epithelial cells enriched Helicobacter hepaticus and Helicobacter ganmani in the gut, promoted their translocation to liver, and aggravated alcohol-related liver disease (ALD) development. Dietary supplementation with AHR agonists effectively ameliorated ALD in mice, providing a new strategy for ALD treatment.

Nonalcoholic fatty liver disease (NAFLD) is a global epidemic, and there is no standard and efficient therapy for it. Chitosan oligosaccharide (COS) is widely known to have various biological effects, and in this study we aimed to evaluate the liver-protective effect in diet-induced obese mice for an enzymatically digested product of COS called COS23 which is mainly composed of dimers and trimers. An integrated analysis of the lipidome and gut microbiome were performed to assess the effects of COS23 on lipids in plasma and the liver as well as on intestinal microbiota. Our results revealed that COS23 obviously attenuated hepatic steatosis and ameliorated liver injury in diet-induced obese mice. The hepatic toxic lipids—especially triglycerides (TGs) and free fatty acids (FFAs)—were decreased dramatically after COS23 treatment. COS23 regulated lipid-related pathways, especially inhibiting the expressions of FFA-synthesis-related genes and inflammation-related genes. Furthermore, COS23 could alter lipid profiles in plasma. More importantly, COS23 also decreased the abundance of Mucispirillum and increased the abundance of Coprococcus in gut microbiota and protected the intestinal barrier by up-regulating the expression of tight-junction-related genes. In conclusion, COS23, an enzymatically digested product of COS, might serve as a promising candidate in the clinical treatment of NAFLD.

Background & Aims Nonalcoholic fatty liver disease encompasses isolated steatosis or nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH). NASH develops from isolated steatosis with obscure driving forces. We aim to identify key factors promoting this transition. Methods Following 21‐week of high‐fat diet feeding, obese mice were classified into two groups termed as isolated steatosis and NASH based on hematoxylin‐eosin staining of liver histology. The integrated multi‐omics analysis of lipidome, transcriptome and gut microbiome were performed in mice with isolated steatosis and NASH, and confirmed in human samples. Results Livers in mice with NASH lost most lipids, and the transcriptional landscape was also changed dramatically in mice with NASH in relative to mice with isolated steatosis. Plasma lipidome analysis demonstrated a very clear difference between these two groups of mice, which was partially recapitulated in serum of patients with isolated steatosis and NASH. The microbiota composition revealed that Bacteroides genus and Bacteroides uniformis species decreased while Mucispirillum genus and Mucispirillum schaedleri species increased largely in mice with NASH. More importantly, we found that Bacteroides uniformis correlated positively with triglycerides (TGs) and negatively with free fatty acids (FFAs) and PE(18:1/20:4), while Mucispirillum schaedleri correlated positively with FFAs, LysoPC(20:3), LysoPC(20:4) and DG(16:1/18:2). Mechanically, administration of Bacteroides uniformis increased specific TGs, and decreased hepatic injury and inflammation in diet‐induced mice. Conclusions Overall, through multi‐omics integration, we identified a microbiota‐lipid axis promoting the initiation of NASH from isolated steatosis, which might provide a novel perspective on NASH pathogenesis and treatment.