The gut and the liver are anatomically and physiologically connected, and this connection is called the “gut-liver axis,” which exerts various influences on liver physiology and pathology. The gut microbiota has been recognized to trigger innate immunity and modulate the liver immune microenvironment. Gut microbiota influences the physiological processes in the host, such as metabolism, by acting on various signaling receptors and transcription factors through their metabolites and related molecules. The gut microbiota has also been increasingly recognized to modulate the efficacy of immune checkpoint inhibitors. In this review, we discuss recent updates on gut microbiota-associated mechanisms in the pathogenesis of chronic liver diseases such as NAFLD and NASH, as well as liver cancer, in light of the gut-liver axis. We particularly focus on gut microbial metabolites and components that are associated with these liver diseases. We also discuss the role of gut microbiota in modulating the response to immunotherapy in liver diseases.

Preterm birth (PTB) and threatened preterm labor (TPL), an important pre-PTB state, are major obstetric complications during pregnancy. However, their triggers have not been fully elucidated. The vagina is dominated by Lactobacillus species (categorized as community state types; CSTs I, II, III, and V) or by mixed anaerobes (CST IV). An abundance of the latter is associated with bacterial vaginosis (BV) and BV-triggered PTB/TPL. To identify factors that influence the diversity of vaginal microbiota associated with BV and CST IV (BV-type) bacterial profile, we performed a bioinformatic analysis of the microbial taxa using 16S rRNA amplicon sequencing data of bacterial genome in oral, vaginal, and rectal samples collected from 58 pregnant Japanese women. Interestingly, common residence of BV-associated bacteria in the vagina and rectum was individually detected in the CST IV (non-Lactobacillus dominated) group by species-level Spearman correlation coefficient analysis, suggesting that the rectum acts as a reservoir of BV-associated bacterial species in the CST IV group. The current study provides evidence of bacterial co-residence in vagina and rectum in the non-Lactobacillus dominated group, which could be targeted to reduce the risk of preterm incidence in pregnancy.

The incidence of oral cancer has recently been increasing worldwide, particularly among young individuals and women. The primary risk factors for head and neck cancers, including oral and pharyngeal cancers, are smoking, alcohol consumption, poor oral hygiene, and repeated exposure to mechanical stimuli. However, approximately one-third of the patients with oral and pharyngeal cancers are neither smokers nor drinkers, which points to the existence of other mechanisms. Recently, human microbes have been linked to various diseases, including cancer. Oral pathogens, especially periodontal pathobionts, are reported to play a role in the development of colon and other types of cancer. In this study, we employed a series of bioinformatics analyses to pinpoint Fusobacterium nucleatum as the predominant oral bacterial species in oral and pharyngeal cancer tissue samples. We successfully isolated Fn. polymorphum from the saliva of patients with oral cancer and demonstrated that Fn. polymorphum indeed promoted oral squamous cell carcinoma development by activating YAP in a mouse tongue cancer model. Our research offers scientific evidence for the role of the oral microbiome in oral cancer progression and provides insights that would help in devising preventative strategies against oral cancer, potentially by altering oral bacterial profiles.

While topical corticosteroid (TCS) treatment is widely used for many skin diseases, it can trigger adverse side effects, and some of such effects can last for a long time after stopping the treatment. However, molecular changes induced by TCS treatment remain largely unexplored, although transient changes in histology and some major ECM components have been documented. Here, we investigated transcriptomic and proteomic changes induced by fluocinolone acetonide (FA) treatment in the mouse skin by conducting RNA-Seq and quantitative proteomics. Chronic FA treatment affected the expression of 4229 genes, where downregulated genes were involved in cell-cycle progression and ECM organization, and upregulated genes were involved in lipid metabolism. The effects of FA on transcriptome and histology of the skin largely returned to normal by two weeks after the treatment. Only a fraction of transcriptomic changes were reflected by proteomic changes, and the expression of 46 proteins was affected one day after chronic FA treatment. A comparable number of proteins were differentially expressed between control and FA-treated skin samples even at 15 and 30 days after stopping chronic FA treatment. Interestingly, proteins affected during and after chronic FA treatment were largely different. Our results provide fundamental information of molecular changes induced by FA treatment in the skin.

Oral squamous cell carcinoma (OSCC) develops through multiple pathogenic and environmental factors. Increasing evidence suggests that the oral microbiota, particularly intratumoral bacteria, is also associated with OSCC progression; however, the relationship between individual bacterial subspecies and the tumor immune microenvironment remains poorly understood. We previously demonstrated that Fusobacterium nucleatum is enriched in OSCC tissues. In this study, we investigated the biological and immunological properties of F. nucleatum subspecies, with a particular focus on regulatory T-cell (Treg) induction. We reanalyzed our 16S rRNA gene sequencing dataset from 12 oral and pharyngeal squamous cell carcinoma specimens at the amplicon sequence variant (ASV) level and examined archived human OSCC tissues by immunofluorescence and fluorescence in situ hybridization (FISH). Treg differentiation and bacterial metabolite production were examined in vitro, and selected F. nucleatum subspecies were evaluated in a mouse tongue carcinogenesis model (n = 6/group). ASVs most closely matching F. nucleatum subsp. animalis were the most abundant among the detected F. nucleatum-associated ASVs. In three human OSCC specimens with detectable F. nucleatum, FOXP3-positive cells preferentially accumulated in the peritumoral stroma. In vitro, culture supernatants from F. nucleatum subsp. animalis, but not subsp. polymorphum, promoted Treg differentiation in two independent experiments, and butyrate production may be associated with the Treg-promoting strains. In vivo, subsp. animalis significantly increased Ki67-positive, nuclear YAP1-positive, and Foxp3-positive cell numbers, whereas subsp. polymorphum significantly increased only nuclear YAP1-positive cell numbers. Furthermore, FISH demonstrated spatial proximity between F. nucleatum and FOXP3-positive cells in a human OSCC case. These findings indicate functional heterogeneity among F. nucleatum subspecies and suggest that their effects on epithelial and immune parameters differ among subspecies. Our findings support possible subspecies-specific immunomodulatory effects of F. nucleatum in OSCC and highlight the importance of subspecies- and strain-level analyses for understanding the biological significance of the intratumoral microbiota.