This review delves into the complex and multi-layered mechanisms that govern the interaction between gut microbiota and T cells in the context of colorectal cancer (CRC), revealing a novel "microbiota-immune regulatory landscape" within the tumor microenvironment. As CRC progresses, the gut microbiota experiences a significant transformation in both its composition and metabolic patterns. On one hand, specific microbial entities within the gut microbiota can directly engage with T cells, functioning as "immunological triggers" that shape T-cell behavior. Simultaneously, microbial metabolites, such as short-chain fatty acids and bile acids, serve as "molecular regulators" that intricately govern T-cell function and differentiation, fine-tuning the immune response. On the other hand, the quorum-sensing mechanism, a recently recognized communication network among bacteria, also plays a pivotal role in orchestrating T-cell immunity. Additionally, the gut microbiota forms an intriguing connection with the neuro-immune regulatory axis, a largely unexplored "territory" in CRC research. Regarding treatment strategies, a diverse array of intervention approaches-including dietary modifications, the utilization of probiotics, bacteriophages, and targeted antibiotic therapies-offer promising prospects for restoring the equilibrium of the gut microbiota, thereby acting as "ecosystem renovators" that impede tumor initiation and progression. Nevertheless, the current research landscape in this field is fraught with challenges. These include significant variations in microbial composition, dietary preferences, and tumor microenvironments among individuals, a lack of large-scale cohort studies, and insufficient research that integrates tumor mutation analysis, gut microbiota investigations, and immune microenvironment evaluations. This review emphasizes the necessity for future research efforts to seamlessly incorporate multiple factors and utilize bioinformatics analysis to construct a more comprehensive "interactive map" of the gut microbiota-T cell relationship in CRC. The aim is to establish a solid theoretical basis for the development of highly effective and personalized treatment regimens, ultimately transforming the therapeutic approach to CRC.

Silicosis, a chronic lung disease caused by inhalation of silica (SiO2) particles from environmental contamination or industrial exposure, is characterized by persistent inflammation and fibrosis. This study elucidates a novel mechanism where SiO2 exposure triggers ferroptosis, a lipid peroxidation-dependent form of cell death, in dendritic cells (DCs), thereby activating retinoic acid (RA) signaling. The RA response amplifies inflammatory pathways, including cGAS-STING-IFN-I and IL-1β signaling, exacerbating lung inflammation and fibrosis. The study uses murine models to demonstrate that ferroptosis inhibitors, such as ferrostatin-1, mitigate SiO2-induced inflammation and collagen deposition. Furthermore, systemic administration of the synthetic retinoid AM80 reduces pulmonary damage by modulating immune cell distribution and promoting lymphocyte homing. These findings reveal the interplay between ferroptosis and RA signaling as a pivotal driver of silicosis pathology and suggest therapeutic avenues targeting ferroptosis and RA modulation for disease management.

To determine whether transthyretin (TTR) influences the prognosis of patients with colorectal cancers and establish a predictive model based on TTR.

Between January 2013 and February 2019, the clinical data of 1322 CRC patients aged from 18 years to 80 years who underwent surgical treatment were retrospectively analyzed. The preoperative TTR level, clinicopathological data, and follow-up data were recorded. The X-tile program was used to determine the optimal cut-off value. Cox proportional hazard regression analysis was conducted to evaluate the correlation between the TTR and the cumulative incidence of cancer-specific survival (CSS). Nomograms were then developed to predict CSS. Furthermore, an additional cohort of 377 CRC patients enrolled between January 2014 and December 2015 was included as an external validation.

Based on the optimal cut-off value of 121.3 mg/L, we divided the patients into the TTR-lower group (<121.3 mg/L) and the TTR-higher group (≥121.3 mg/L). Comparative analysis revealed that the TTR-higher group exhibited a younger demographic, a higher prevalence of low colorectal cancers, an elevated R0 resection rate, superior differentiation, earlier stage and lower levels of carcinoembryonic antigen (CEA) in contrast to the TTR-lower group. The Cox multivariable analysis underscored the significance of TTR and various clinicopathological factors, encompassing age, tumor location, R0 resection status, differentiation grade, disease stage, postoperative chemoradiotherapy, and preoperative CEA levels, as substantial prognostic indicators. The postoperative survival nomogram, when internally and externally assessed, demonstrated commendable performance across multiple metrics, including the area under the receiver operating characteristic curve (AUC), calibration plots, and decision curve analysis (DCA). Compared with other models, the proportional hazards model combined with TTR demonstrates superior performance in terms of C-index, AUC, calibration chart, and DCA within the prognostic column chart.

The preoperative TTR was identified as a prognostic factor for predicting the long-term prognosis of CRC patients who underwent surgical treatment, supporting its role as a prognostic biomarker in clinical practice.

Intestinal stem cells differentiate into absorptive enterocytes, characterised by increased brush border enzymes such as intestinal alkaline phosphatase (IAP), making up the majority (95%) of the terminally differentiated cells in the villus. Loss of integrity of the intestinal epithelium plays a key role in inflammatory diseases and gastrointestinal infection. Here, we show that the intestinal microRNA (miR)-27a-3p is an important regulator of intestinal epithelial cell proliferation and enterocyte differentiation. Repression of endogenous miR-27a-3p leads to increased enterocyte differentiation and decreased intestinal epithelial cell proliferation in mouse and human small intestinal organoids. Mechanistically, miR-27a-3p regulates intestinal cell differentiation and proliferation at least in part through the regulation of retinoic acid receptor α (RXRα), a modulator of Wnt/β-catenin signalling. Repression of miR-27a-3p increases the expression of RXRα and concomitantly, decreases the expression of active β-catenin and cyclin D1. In contrast, overexpression of miR-27a-3p mimic decreases the expression of RXRα and increases the expression of active β-catenin and cyclin D1. Moreover, overexpression of the miR-27a-3p mimic results in impaired enterocyte differentiation and increases intestinal epithelial cell proliferation. These alterations were attenuated or blocked by Wnt inhibition. Our study demonstrates an miR-27a-3p/RXRα/Wnt/β-catenin pathway that is important for the maintenance of enterocyte homeostasis in the small intestine.

Oxapliplatin-induced peripheral neuropathy (OIPN) is a significant adverse effect encountered in patients with colorectal cancer undergoing oxaliplatin therapy. However, the pathogenesis of OIPN remains unclear. This study aimed to identify potential diagnostic biomarkers for OIPN and discover the metabolic pathways associated with the disease. Serum samples were collected from 218 subjects, including patients with OIPN and control (CONT). The metabolite profiles were analyzed using nontargeted liquid chromatography-mass spectrometry (LC-MS) serum metabolomics method. Subsequently, differentially altered metabolites were identified and evaluated through multivariate statistical analyses. In this study, patients with OIPN and CONT were distinguished by ten significant metabolites. The levels of racemethionine, O-acetylcarnitine, stearolic acid, aminoadipic acid, iminoarginine, galactaric acid, and all-trans-retinoic acid were increased, whereas the levels of 3-methyl-L-tyrosine, 5-aminopentanoic acid, and erythritol compared were found to be diminished in patients with OIPN when compared to the CONT. Through receiver operating characteristic (ROC) curve analysis, racemethionine, stearolic acid, 5-aminopentanoic acid, erythritol, aminoadipic acid, and all-trans-retinoic acid were pinpointed as promising biomarkers for OIPN. Significantly altered pathways included amino acids (arginine biosynthesis, beta-alanine metabolism, arginine and proline metabolism, alanine, aspartate and glutamate metabolism, lysine degradation, and phenylalanine, tyrosine and tryptophan biosynthesis), lipid (linoleic acid metabolism and the biosynthesis of unsaturated fatty acids), and energy metabolism. This study, by identifying serum biomarkers and dissecting metabolic pathways, offers a groundbreaking perspective on the susceptibility mechanisms underlying OIPN. It stands as an invaluable resource for the adjunctive diagnosis of OIPN, with the potential to diminish the incidence of adverse reactions and to enhance the objectivity and reliability of clinical diagnoses of OIPN.

The interplay between gut microbiota and immune responses is crucial in ulcerative colitis (UC). Though Akkermansia muciniphila (Akk) shows therapeutic potential, the mechanisms remain unclear. This study sought to investigate differences in therapeutic efficacy among different forms or strains of Akk and elucidate the underlying mechanisms.

Employing a dextran sulfate sodium (DSS)-induced colitis mouse model, we assessed Akk's impact on colitis using cellular cytokine analysis, immune phenotyping, proteomics, and biochemical methods. Our results suggest that treatment with live Akk effectively reduced colitis in the DSS-induced model, whereas heat-inactivated Akk did not yield the same results. Notably, Akk exhibited protective properties by promoting the secretion of IL-22 by Group 3 innate lymphoid cells (ILC3s), as evidenced by the absence of protection in IL-22 knockout mice. Additionally, Akk augmented the population of CD103+CD11b- dendritic cells (DCs) and enhanced their retinoic acid (RA) synthesis through the modulation of RALDH2, a crucial enzyme in RA metabolism. The depletion of RALDH2 in DCs diminished Akk's protective properties and impaired IL-22-mediated mucosal healing. Mechanistically, Akk activated RA production in DCs by enhancing the JAK2-STAT3 signaling pathway. Additionally, various strains of Akk may exhibit differing abilities to alleviate colitis, with the novel strain Am06 derived from breast milk showing consistent efficacy similar to the reference strain.

In summary, our findings indicate that certain strains of Akk may mitigate colitis through the promotion of RA synthesis and IL-22 secretion, underscoring the potential efficacy of Akk as a therapeutic intervention for the management of UC. Video Abstract.

Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection is associated with significant gut damage, similar to that observed in patients with inflammatory bowel disease (IBD). This pathology includes loss of epithelial integrity, microbial translocation, dysbiosis, and resultant chronic immune activation. Additionally, the levels of all-trans-retinoic acid (atRA) are dramatically attenuated. Data on the therapeutic use of anti-α4β7 antibodies has shown promise in patients with ulcerative colitis and Crohn's disease. Recent evidence has suggested that the microbiome and short-chain fatty acid (SCFA) metabolites it generates may be critical for anti-α4β7 efficacy and maintaining intestinal homeostasis.

To determine whether the microbiome contributes to gut homeostasis after anti-α4β7 antibody administered to SIV-infected rhesus macaques, faecal SCFA concentrations were determined, 16S rRNA sequencing was performed, plasma viral loads were determined, plasma retinoids were measured longitudinally, and gut retinoid synthesis/response gene expression was quantified.

Our results suggest that anti-α4β7 antibody facilitates the return of retinoid metabolism to baseline levels after SIV infection. Furthermore, faecal SCFAs were shown to be associated with retinoid synthesis gene expression and rebound viral loads after therapy interruption.

Taken together, these data demonstrate the therapeutic advantages of anti-α4β7 antibody administration during HIV/SIV infection and that the efficacy of anti-α4β7 antibody may depend on microbiome composition and SCFA generation.

Cancer is a biological process that emerged at the end of the Precambrian era with the rise of multicellular organisms. Traditionally, cancer has been viewed primarily as a disease relevant to human and domesticated animal health, attracting attention mainly from oncologists. In recent years, however, the community of ecologists and evolutionary biologists has recognized the pivotal role of cancer-related issues in the evolutionary paths of various species, influencing multiple facets of their biology. It has become evident that overlooking these issues is untenable for a comprehensive understanding of species evolution and ecosystem functioning. In this article, we highlight some significant advancements in this field, also underscoring the pressing need to consider reciprocal interactions not only between cancer cells and their hosts but also with all entities comprising the holobiont. This reflection gains particular relevance as ecosystems face increasing pollution from mutagenic substances, resulting in a resurgence of cancer cases in wildlife.

The correlation between liver disease and the progression of ulcerative colitis (UC) has remained elusive. In this study, it demonstrates that liver injury is intricately linked to the heightened severity of UC in patients, and causes more profound intestinal damage during DSS-induced colitis in mice. Metabolomics analysis of plasma from liver cirrhosis patients shows liver injury compromising nicotinamide supply for NAD+ biosynthesis in the intestine. Subsequent investigation identifies intestinal group 2 innate lymphoid cells (ILC2s) are responsible for liver injury-exacerbated colitis. Reconstitution of ILC2s or the restoration of NAD+ metabolism proves effective in relieving liver injury-aggravated experimental colitis. Mechanistically, the NAD+ salvage pathway regulates gut ILC2s in a cell-intrinsic manner by supporting the generation of succinate, which fuels the electron transport chain to sustaining ILC2s function. This research deepens the understanding of cellular and molecular mechanisms in liver disease-UC interplay, identifying a metabolic target for innovative treatments in liver injury-complicated colitis.

Gut Akkermansia muciniphila (Akk) has been implicated in impacting immunotherapy or oncogenesis. This study aims to dissect the Akk-associated tumor immune ecosystem (TIME) by single-cell profiling coupled with T cell receptor (TCR) sequencing. We adopted mouse cancer models under anti-PD-1 immunotherapy, combined with oral administration of three forms of Akk, including live Akk, pasteurized Akk (Akk-past), or its membrane protein Amuc_1100 (Amuc). We show that live Akk is most effective in activation of CD8 T cells by rescuing the exhausted type into cytotoxic subpopulations. Remarkably, only live Akk activates MHC-II-pDC pathways, downregulates CXCL3 in Bgn(+)Dcn(+) cancer-associated fibroblasts (CAFs), blunts crosstalk between Bgn(+)Dcn(+) CAFs and PD-L1(+) neutrophils by a CXCL3-PD-L1 axis, and further suppresses the crosstalk between PD-L1(+) neutrophils and CD8 T cells, leading to the rescue of exhausted CD8 T cells. Together, this comprehensive picture of the tumor ecosystem provides deeper insights into immune mechanisms associated with gut Akk-dependent anti-PD-1 immunotherapy.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder with no effective interventions for curing or modifying its progression. However, emerging research suggests that vitamin A in the diet may play a role in both the prevention and treatment of AD, although the exact mechanisms are not fully understood.

This study aims to investigate the dietary vitamin A modifies the gut microbiota and intestinal tissue transcriptome, impacting intestinal permeability and the release of inflammatory factors, thereby influencing Aβ pathology shedding light on its potential as a dietary intervention for AD prevention and treatment.

The APP/PS1-AD mouse model was employed and divided into three dietary groups: vitamin A-deficient (VAD), normal vitamin A (VAN), and vitamin A-supplemented (VAS) for a 12-week study. Neurobehavioral functions were assessed using the Morris Water Maze Test (MWM). Enzyme-linked immunosorbent assay (ELISA) was used to quantify levels of Diamine Oxidase (DAO), D-lactate, IL-6, IL-1β, and TNF-a cytokines. Serum vitamin A levels were analyzed via LC-MS/MS analysis. Immunohistochemical analysis and morphometry were performed to evaluate the deposition of Aβ in brain tissue. The gut microbiota of APP/PS1 mice was analyzed using 16S rRNA sequencing analysis. Additionally, transcriptomic analysis was conducted on intestinal tissue from APP/PS1 mice.

No significant changes in food intake and body weight were observed among the groups. However, the VAD and VAS groups showed reduced food intake compared to the VAN group at various time points. In terms of cognitive function, the VAN group performed better in the Morris Water Maze Test, indicating superior learning and memory abilities. The VAD and VAS groups exhibited impaired performance, with the VAS group performing relatively better than the VAD group. Serum vitamin A concentrations differed significantly among the groups, with the VAS group having the highest concentration. Aβ levels were significantly higher in the VAD group compared to both the VAN and VAS groups. Microbial analysis revealed that the VAS and VAN groups had higher microbial diversity than the VAD group, with specific taxa characterizing each group. The VAN group was characterized by taxa such as Actinohacteriota and Desulfovibrionaceae, while the VAD group was characterized by Parabacteroides and Tannerellaceae. The VAS group showed similarities with both VAN and VAD groups, with taxa like Desulfobacterota and Desulfovibrionaceae being present. The VAD vs. VAS, VAD vs. VAN, and VAS vs. VAN comparisons identified 571, 313, and 243 differentially expressed genes, respectively, which associated with cellular and metabolic processes, and pathway analysis revealed enrichment in pathways related to chemical carcinogenesis, drug metabolism, glutathione metabolism, and immune-related processes. The VAD group exhibited higher levels of D-lactate, diamine oxidase, and inflammatory cytokines (TNF-a, IL-1β, IL-6) compared to the VAN and VAS groups.

Dietary vitamin A supplementation modulates the gut microbiota, intestinal permeability, inflammatory factors, and Aβ protein formation, offering insights into the pathogenesis of AD and potential therapeutic avenues for further exploration. This research highlights the intricate interplay between diet, gut microbiota, and neurodegenerative processes, emphasizing the importance of dietary interventions in managing AD-related pathologies.

All-trans retinoic acid (ATRA) is the most relevant and functionally active metabolite of Vitamin-A. From a therapeutic standpoint, ATRA is the first example of pharmacological agent exerting its anti-tumor activity via a cell differentiating action. In the clinics, ATRA is used in the treatment of Acute Promyelocytic Leukemia, a rare form of myeloid leukemia with unprecedented therapeutic results. The extraordinary effectiveness of ATRA in the treatment of Acute Promyelocytic Leukemia patients has raised interest in evaluating the potential of this natural retinoid in the treatment of other types of neoplasias, with particular reference to solid tumors.The present article provides an overview of the available pre-clinical and clinical studies focussing on ATRA as a therapeutic agent in the context of breast cancer from a holistic point of view. In detail, we focus on the direct effects of ATRA in breast cancer cells as well as the underlying molecular mechanisms of action. In addition, we summarize the available information on the action exerted by ATRA on the breast cancer micro-environment, an emerging determinant of the progression and invasive behaviour of solid tumors. In particular we discuss the recent evidences of ATRA activity on the immune system. Finally, we analyse and discuss the results obtained with the few ATRA-based clinical trials conducted in the context of breast cancer.

Chemotherapy is included in treatment regimens for many solid cancers, but when administered as a single agent it is rarely curative. The addition of immune checkpoint therapy to standard chemotherapy regimens has improved response rates and increased survival in some cancers. However, most patients do not respond to treatment and immune checkpoint therapy can cause severe side effects. Therefore, there is a need for alternative immunomodulatory drugs that enhance chemotherapy.

We used gene expression data from cyclophosphamide (CY) responders and non-responders to identify existing clinically approved drugs that could phenocopy a chemosensitive tumor microenvironment (TME), and tested combination treatments in multiple murine cancer models.

The vitamin A derivative tretinoin was the top predicted upstream regulator of response to CY. Tretinoin pre-treatment induced an inflammatory, interferon-associated TME, with increased infiltration of CD8 + T cells, sensitizing the tumor to subsequent chemotherapy. However, while combination treatment significantly improved survival and cure rate in a CD4+ and CD8+ T cell dependent manner in AB1-HA murine mesothelioma, this effect was model-selective, and could not be replicated using other cell lines.

Despite the promising data in one model, the inability to validate the efficacy of combination treatment in multiple cancer models deprioritizes tretinoin/cyclophosphamide combination therapy for clinical translation.

The gut microbiota is a critical factor in the regulation of host health, but the relationship between the differential resistance of hosts to pathogens and the interaction of gut microbes is not yet clear. Herein, we investigated the potential correlation between the gut microbiota of piglets and their disease resistance using single-cell transcriptomics, 16S amplicon sequencing, metagenomics, and untargeted metabolomics.

Porcine epidemic diarrhea virus (PEDV) infection leads to significant changes in the gut microbiota of piglets. Notably, Landrace pigs lose their resistance quickly after being infected with PEDV, but transplanting the fecal microbiota of Min pigs to Landrace pigs alleviated the infection status. Macrogenomic and animal protection models identified Lactobacillus reuteri and Lactobacillus amylovorus in the gut microbiota as playing an anti-infective role. Moreover, metabolomic screening of the secondary bile acids' deoxycholic acid (DCA) and lithocholic acid (LCA) correlated significantly with Lactobacillus reuteri and Lactobacillus amylovorus, but only LCA exerted a protective function in the animal model. In addition, LCA supplementation altered the distribution of intestinal T-cell populations and resulted in significantly enriched CD8+ CTLs, and in vivo and in vitro experiments showed that LCA increased SLA-I expression in porcine intestinal epithelial cells via FXR receptors, thereby recruiting CD8+ CTLs to exert antiviral effects.

Overall, our findings indicate that the diversity of gut microbiota influences the development of the disease, and manipulating Lactobacillus reuteri and Lactobacillus amylovorus, as well as LCA, represents a promising strategy to improve PEDV infection in piglets. Video Abstract.

Retinoic acid (RA), the derivative of vitamin A/retinol, is a signaling molecule with important implications in health and disease. It is a well-known developmental morphogen that functions mainly through the transcriptional activity of nuclear RA receptors (RARs) and, uncommonly, through other nuclear receptors, including peroxisome proliferator-activated receptors. Intracellular RA is under spatiotemporally fine-tuned regulation by synthesis and degradation processes catalyzed by retinaldehyde dehydrogenases and P450 family enzymes, respectively. In addition to dictating the transcription architecture, RA also impinges on cell functioning through non-genomic mechanisms independent of RAR transcriptional activity. Although RA-based differentiation therapy has achieved impressive success in the treatment of hematologic malignancies, RA also has pro-tumor activity. Here, we highlight the relevance of RA signaling in cell-fate determination, neurogenesis, visual function, inflammatory responses and gametogenesis commitment. Genetic and post-translational modifications of RAR are also discussed. A better understanding of RA signaling will foster the development of precision medicine to improve the defects caused by deregulated RA signaling.

The diverse bacterial populations within the symbiotic microbiota play a pivotal role in both health and disease. Microbiota modulates critical aspects of tumor biology including cell proliferation, invasion, and metastasis. This regulation occurs through mechanisms like enhancing genomic damage, hindering gene repair, activating aberrant cell signaling pathways, influencing tumor cell metabolism, promoting revascularization, and remodeling the tumor immune microenvironment. These microbiota-mediated effects significantly impact overall survival and the recurrence of tumors after surgery by affecting the efficacy of chemoradiotherapy. Moreover, leveraging the microbiota for the development of biovectors, probiotics, prebiotics, and synbiotics, in addition to utilizing antibiotics, dietary adjustments, defensins, oncolytic virotherapy, and fecal microbiota transplantation, offers promising alternatives for cancer treatment. Nonetheless, due to the extensive and diverse nature of the microbiota, along with tumor heterogeneity, the molecular mechanisms underlying the role of microbiota in cancer remain a subject of intense debate. In this context, we refocus on various cancers, delving into the molecular signaling pathways associated with the microbiota and its derivatives, the reshaping of the tumor microenvironmental matrix, and the impact on tolerance to tumor treatments such as chemotherapy and radiotherapy. This exploration aims to shed light on novel perspectives and potential applications in the field.

Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer with major challenges in both prevention and therapy. Metformin, adenosine monophosphate-activated protein kinase (AMPK) activator, has been suggested to reduce the incidence of HCC when used for patients with diabetes in preclinical and clinical studies. However, the possible effects of metformin and their mechanisms of action in non-diabetic HCC have not been adequately investigated.

Fah-/-  mice were used to construct a liver-injury-induced non-diabetic HCC model for exploring hepatocarcinogenesis and therapeutic potential of metformin. Changes in relevant tumour and biochemical indicators were measured. Bulk and single-cell RNA-sequencing analyses were performed to validate the crucial role of proinflammatory/pro-tumour CD8+ T cells. In vitro and in vivo experiments were performed to confirm Cyp26a1-related antitumour mechanisms of metformin.

RNA-sequencing analysis showed that chronic liver injury led to significant changes in AMPK-, glucose- and retinol metabolism-related pathways in Fah-/- mice. Metformin prevented the formation of non-diabetic HCC in Fah-/- mice with chronic liver injury. Cyp26a1 ddexpression in hepatocytes was significantly suppressed after metformin treatment. Moreover, downregulation of Cyp26a1 occurred in conjunction with increased levels of all-trans-retinoic acid (atRA), which is involved in the activation of metformin-suppressed hepatocarcinogenesis in Fah-/- mice. In contrast, both CD8+  T-cell infiltration and proinflammatory/pro-tumour cytokines in the liver were significantly upregulated in Fah-/- mice during chronic liver injury, which was notably reversed by either metformin or atRA treatment. Regarding mechanisms, metformin regulated the decrease in Cyp26a1 enzyme expression and increased atRA expression via the AMPK/STAT3/Gadd45β/JNK/c-Jun pathway.

Metformin inhibits non-diabetic HCC by upregulating atRA levels and downregulating CD8+ T cells. This is the first reporting that the traditional drug metformin regulates the metabolite atRA via the Cyp26a1-involved pathway. The present study provides a potential application of metformin and atRA in non-diabetic HCC.

Colorectal cancer (CRC) is the third most common cancer worldwide. One of the main causes of colorectal cancer is inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). Intestinal epithelial cells (IECs), intestinal mesenchymal cells (IMCs), immune cells, and gut microbiota construct the main body of the colon and maintain colon homeostasis. In the development of colitis and colitis-associated carcinogenesis, the damage, disorder or excessive recruitment of different cells such as IECs, IMCs, immune cells and intestinal microbiota play different roles during these processes. This review aims to discuss the various roles of different cells and the crosstalk of these cells in transforming intestinal inflammation to cancer, which provides new therapeutic methods for chemotherapy, targeted therapy, immunotherapy and microbial therapy.

Accumulating researchers have recognized mitophagy as a key player in tumors, but few studies have investigated its role in the tumor microenvironment (TME). Advances in the technology of single-cell RNA sequencing (scRNA-seq) have allowed unveiling the concealed features of the TME at cellular resolution. This study aimed to elucidate the role of mitophagy within the TME of colorectal cancer (CRC) and to establish a mitophagy-mediated risk model.

We assessed mitophagy-related pathway activities at both single-cell and tissue levels. Subsequently, an unsupervised clustering algorithm was employed to identify mitophagy-mediated subtypes. Furthermore, we developed a mitophagy-mediated risk signature (MMRS) using least absolute shrinkage and selection operator (LASSO) Cox analysis and constructed a MMRS model incorporating the risk score and clinical variables. Subsequently, we used quantitative reverse transcription polymerase chain reaction analysis to verify the expression of the screened genes.

We retrieved and annotated a total of 14,719 cells from eight samples in the scRNA-seq GSE132465 data set. The activities of mitophagy-related pathways were uniformly upregulated in cancer cells. Integrating with bulk RNA-seq data, we identified two mitophagy-mediated clusters (C1 and C2) with distinct characteristics and prognoses. C2 was identified as a mitophagy-high cluster. Then, we developed a five-gene MMRS via LASSO Cox analysis in The Cancer Genome Atlas (TCGA) cohort. We utilized the GSE39582 cohort to validate the efficacy of our model. The expression of CX3CL1 and INHBB was upregulated in CRC tissues.

The present study identified two mitophagy-mediated CRC subtypes with distinct features. Our MMRS may provide potential therapeutic strategies for CRC. The findings of our work offer novel insights into the involvement of mitophagy in CRC.

Corpus luteum cysts are a serious reproductive disorder that affects the reproductive performance of sows. In this study, transcriptome and metabolome datasets of porcine normal and cyst luteal granulosa cells were generated to explore the molecular mechanism of luteal cyst formation. We obtained 28.9 Gb of high-quality transcriptome data from luteum tissue samples and identified 1048 significantly differentially expressed genes between the cyst and normal corpus luteum samples. Most of the differentially expressed genes were involved in cancer and immune signaling pathways. Furthermore, 22,622 information-containing positive and negative ions were obtained through gas chromatography-mass spectrometry, and 1106 metabolites were successfully annotated. Important differentially abundant metabolites and pathways were identified, among which abnormal lipid and choline metabolism were involved in the formation of luteal cysts. The relationships between granulosa cells of luteal cysts and cancer, immune-related signaling pathways, and abnormalities of lipid and choline metabolism were elaborated, providing new entry points for studying the pathogenesis of porcine luteal cysts.

Vitamin A has long been associated with bladder cancer, and many exogenous vitamin A supplements, vitamin A derivatives, and synthetic drugs have been investigated over the years. However, the effectiveness of these strategies in clinical practice has not met expectations, and they have not been widely adopted. Recent medical research on intestinal flora has revealed that bladder cancer patients exhibit reduced serum vitamin A levels and an imbalance of gut microbiota. In light of the close relationship between gut microbiota and vitamin A, one can speculate that a complex regulatory mechanism exists between the two in the development and occurrence of bladder cancer. As such, further exploration of their interaction in bladder cancer may help guide the use of vitamin A for preventive purposes. During the course of this review, attention is paid to the influence of intestinal microbiota on the vitamin A metabolism and the RA signaling pathway, as well as the mutual promotion relationships between them in the prevention of bladder cancer, In addition, it emphasizes the importance of intestinal microbiota for bladder cancer prevention and treatment.

Accumulating evidence has indicated the role of gut microbiota in remodeling host immune signatures, but various interplays underlying colorectal cancers (CRC) with deficient DNA mismatch repair (dMMR) and proficient DNA mismatch repair (pMMR) remain poorly understood. This study aims to decipher the gut microbiome-host immune interactions between dMMR and pMMR CRC.

We performed metagenomic sequencing and metabolomic analysis of fecal samples from a cohort encompassing 455 participants, including 21 dMMR CRC, 207 pMMR CRC, and 227 healthy controls. Among them, 50 tumor samples collected from 5 dMMR CRC and 45 pMMR CRC were conducted bulk RNA sequencing.

Pronounced microbiota and metabolic heterogeneity were identified with 211 dMMR-enriched species, such as Fusobacterium nucleatum and Akkermansia muciniphila, 2 dMMR-depleted species, such as Flavonifractor plautii, 13 dMMR-enriched metabolites, such as retinoic acid, and 77 dMMR-depleted metabolites, such as lactic acid, succinic acid, and 2,3-dihydroxyvaleric acid. F. plautii was enriched in pMMR CRC and it was positively associated with fatty acid degradation, which might account for the accumulation of dMMR-depleted metabolites classified as short chain organic acid (lactic acid, succinic acid, and 2,3-dihydroxyvaleric acid) in pMMR CRC. The microbial-metabolic association analysis revealed the characterization of pMMR CRC as the accumulation of lactate induced by the depletion of specific gut microbiota which was negatively associated with antitumor immune, whereas the nucleotide metabolism and peptide degradation mediated by dMMR-enriched species characterized dMMR CRC. MMR-specific metabolic landscapes were related to distinctive immune features, such as CD8+ T cells, dendritic cells and M2-like macrophages.

Our mutiomics results delineate a heterogeneous landscape of microbiome-host immune interactions within dMMR and pMMR CRC from aspects of bacterial communities, metabolic features, and correlation with immunocyte compartment, which infers the underlying mechanism of heterogeneous immune responses.

Dietary plant polysaccharides, one of the main sources of natural polysaccharides, possess significant cancer prevention activity and potential development value in the food and medicine fields. The anti-tumor mechanisms of plant polysaccharides are mainly elaborated from three perspectives: enhancing immunoregulation, inhibiting tumor cell growth and inhibiting tumor cell invasion and metastasis. The immune system plays a key role in cancer progression, and immunomodulation is considered a significant pathway for cancer prevention or treatment. Although much progress has been made in revealing the relationship between the cancer prevention activity of polysaccharides and immunoregulation, huge challenges are still met in the research and development of polysaccharides. Results suggest that certain polysaccharide types and glycosidic linkage forms significantly affect the biological activity of polysaccharides in immunoregulation. At present, the in vitro anti-tumor effects and immunoregulation of dietary polysaccharides are widely reported in articles; however, the anti-tumor effects and in vivo immunoregulation of dietary polysaccharides are still deserving of further investigation. In this paper, aspects of the mechanisms behind dietary polysaccharides' cancer prevention activity achieved through immunoregulation, the role of immune cells in cancer progression, the role of the mediatory relationship between the gut microbiota and dietary polysaccharides in immunoregulation and cancer prevention are systematically summarized, with the aim of encouraging future research on the use of dietary polysaccharides for cancer prevention.

Colo-rectal cancer (CRC) is undoubtedly one of the most severe complications of inflammatory bowel diseases (IBD). While sporadic CRC develops from a typical adenoma-carcinoma sequence, IBD-related CRC follows different and less understood pathways and its pathophysiological mechanisms were not completely elucidated. In contrast to chronic inflammation, which is nowadays a well-recognised drive towards neoplastic transformation in IBD, only recently was gut microbiota demonstrated to interfere with both inflammation processes and immune-mediated anticancer surveillance. Moreover, the role of microbiota appears particularly complex and intriguing when also considering its multifaceted interactions with multiple environmental stimuli, notably chronic pathologies such as diabetes and obesity, lifestyle (diet, smoking) and vitamin intake. In this review, we presented a comprehensive overview on current evidence of the influence of gut microbiota on IBD-related CRC, in particular its mutual interconnections with the environment.

Atractylodes macrocephala Koidz. (AM) is a functional food with strong ant-colitis activity. AM volatile oil (AVO) is the main active ingredient of AM. However, no study has investigated the improvement effect of AVO on ulcerative colitis (UC) and the bioactivity mechanism also remains unknown. Here, we investigated whether AVO has ameliorative activity on acute colitis mice and its mechanism from the perspective of gut microbiota.

Acute UC was induced in C57BL/6 mice by dextran sulfate sodium and treated with the AVO. Body weight, colon length, colon tissue pathology, and so on were assessed. The gut microbiota composition was profiled using 16s rRNA sequencing and global metabolomic profiling of the feces was performed. The results showed that AVO can alleviate bloody diarrhea, colon damage, and colon inflammation in colitis mice. In addition, AVO decreased potentially harmful bacteria (Turicibacter, Parasutterella, and Erysipelatoclostridium) and enriched potentially beneficial bacteria (Enterorhabdus, Parvibacter, and Akkermansia). Metabolomics disclosed that AVO altered gut microbiota metabolism by regulating 56 gut microbiota metabolites involved in 102 KEGG pathways. Among these KEGG pathways, many metabolism pathways play an important role in maintaining intestine homeostasis, such as amino acid metabolism (especially tryptophan metabolism), bile acids metabolism, and retinol metabolism.

In conclusion, our study indicated that AVO can be expected as novel prebiotics to treat ulcerative colitis, and modulating the composition and metabolism of gut microbiota may be its pharmacological mechanism.

Stromal myo-/fibroblasts (MFs) account for up to 30% of lamina propria cells in the normal human colon and their number is dramatically increased in colon cancer (CRC). Fibroblasts from cancers, also known as cancer-associated fibroblasts (CAFs), differ from normal colonic MF (N-MFs) and support tumor-promoting inflammation, in part due to increased IL-6 secretion. In this editorial, we highlight recent data obtained regarding IL-6 regulation in colorectal cancer CAFs through vitamin A (retinol) metabolism, discuss current limitations in our understanding of the mechanisms leading to the CAF pro-inflammatory phenotype, and discuss potential approaches to target CAF retinoid metabolism during CRC treatment.

Gene expression altering epigenomic modifications such as DNA methylation, histone modification, and chromosome remodeling is crucial to regulating many biological processes. Several lifestyle factors, such as diet and natural, bioactive food compounds, such as vitamins, modify epigenetic patterns. However, epigenetic dysregulation can increase the risk of many diseases, including cancer. Various studies have provided supporting and contrasting evidence on the relationship between vitamins and cancer risk. Though there is a gap in knowledge about whether dietary vitamins can induce epigenetic modifications in the context of colorectal cancer (CRC), the possibility of using them as epidrugs for CRC treatment is being explored. This is promising because such studies might be informative about the most effective way to use vitamins in combination with DNA methyltransferase inhibitors and other approved therapies to prevent and treat CRC. This review summarizes the available epidemiological and observational studies involving dietary, circulating levels, and supplementation of vitamins and their relationship with CRC risk. Additionally, using available in vitro, in vivo, and human observational studies, the role of vitamins as potential epigenetic modifiers in CRC is discussed. This review is focused on the action of vitamins as modifiers of DNA methylation because aberrant DNA methylation, together with genetic alterations, can induce the initiation and progression of CRC. Although this review presents some studies with promising results, studies with better study designs are necessary. A thorough understanding of the underlying molecular mechanisms of vitamin-mediated epigenetic regulation of CRC genes can help identify effective therapeutic targets for CRC prevention and treatment.

The pathogenesis of gut microbiota and their metabolites in the development of metabolic syndrome (MS) remains unclear. This study aimed to evaluate the signatures of gut microbiota and metabolites as well as their functions in obese children with MS. A case-control study was conducted based on 23 MS children and 31 obese controls. The gut microbiome and metabolome were measured using 16S rRNA gene amplicon sequencing and liquid chromatography-mass spectrometry. An integrative analysis was conducted, combining the results of the gut microbiome and metabolome with extensive clinical indicators. The biological functions of the candidate microbial metabolites were validated in vitro. We identified 9 microbiota and 26 metabolites that were significantly different from the MS and the control group. The clinical indicators of MS were correlated with the altered microbiota Lachnoclostridium, Dialister, and Bacteroides, as well as with the altered metabolites all-trans-13,14-dihydroretinol, DL-dipalmitoylphosphatidylcholine (DPPC), LPC 24: 1, PC (14:1e/10:0), and 4-phenyl-3-buten-2-one, etc. The association network analysis further identified three MS-linked metabolites, including all-trans-13,14-dihydroretinol, DPPC, and 4-phenyl-3-buten-2-one, that were significantly correlated with the altered microbiota. Bio-functional validation showed that all-trans-13, 14-dihydroretinol could significantly upregulate the expression of lipid synthesis genes and inflammatory genes. This study identified a new biomarker that may contribute to MS development. These findings provided new insights regarding the development of efficient therapeutic strategies for MS. IMPORTANCE Metabolic syndrome (MS) has become a health concern worldwide. Gut microbiota and metabolites play an important role in human health. We first endeavored to comprehensively analyze the microbiome and metabolome signatures in obese children and found the novel microbial metabolites in MS. We further validated the biological functions of the metabolites in vitro and illustrated the effects of the microbial metabolites on lipid synthesis and inflammation. The microbial metabolite all-trans-13, 14-dihydroretinol may be a new biomarker in the pathogenesis of MS, especially in obese children. These findings were not available in previous studies, and they provide new insights regarding the management of metabolic syndrome.

Abnormal proline-rich protein 11 (PRR11) expression is associated with various tumors. However, there are few reports concerning PRR11 with prognostic risk, immune infiltration, or immunotherapy of bladder urothelial carcinoma (BLCA). This study is based on online databases, such as Oncomine, GEPIA, HPA, LinkedOmics, TIMER, ESTIMATE and TISIDB, and BLCA data downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus, we employed an array of bioinformatics methods to explore the potential oncogenic roles of PRR11, including analyzing the relationship between PRR11 and prognosis, tumor mutational burden (TMB), microsatellite instability, and immune cell infiltration in BLCA. The results depict that PRR11 is highly expressed in BLCA, and BLCA patients with higher PRR11 expression have worse outcomes. In addition, there was a significant correlation between PRR11 expression and TMB and tumor immune infiltration. These findings suggest that PRR11 can be used as a potential marker for BLCA patient assessment and risk stratification to improve clinical prognosis, and its potential regulatory mechanism in the BLCA tumor microenvironment and targeted therapy is worthy of further investigation.

Increases in IL-6 by cancer-associated fibroblasts (CAFs) contribute to colon cancer progression, but the mechanisms involved in the increase of this tumor-promoting cytokine are unknown. The aim of this study was to identify novel targets involved in the dysregulation of IL-6 expression by CAFs in colon cancer.

Colonic normal (N), hyperplastic, tubular adenoma, adenocarcinoma tissues, and tissue-derived myo-/fibroblasts (MFs) were used in these studies.

Transcriptomic analysis demonstrated a striking decrease in alcohol dehydrogenase 1B (ADH1B) expression, a gene potentially involved in IL-6 dysregulation in CAFs. ADH1B expression was downregulated in approximately 50% of studied tubular adenomas and all T1-4 colon tumors, but not in hyperplastic polyps. ADH1B metabolizes alcohols, including retinol (RO), and is involved in the generation of all-trans retinoic acid (atRA). LPS-induced IL-6 production was inhibited by either RO or its byproduct atRA in N-MFs, but only atRA was effective in CAFs. Silencing ADH1B in N-MFs significantly upregulated LPS-induced IL-6 similar to those observed in CAFs and lead to the loss of RO inhibitory effect on inducible IL-6 expression.

Our data identify ADH1B as a novel potential mesenchymal tumor suppressor, which plays a critical role in ADH1B/retinoid-mediated regulation of tumor-promoting IL-6.

Immune cell trafficking is a complex and tightly regulated process that is indispensable for the body's fight against pathogens. However, it is also increasingly acknowledged that dysregulation of cell trafficking contributes to the pathogenesis of immune-mediated inflammatory diseases (IMIDs) in gastroenterology and hepatology, such as inflammatory bowel disease and primary sclerosing cholangitis. Moreover, altered cell trafficking has also been implicated as a crucial step in the immunopathogenesis of other IMIDs, such as rheumatoid arthritis and multiple sclerosis. Over the past few years, a central role of the gut in mediating these disorders has progressively emerged, and the partly microbiota-driven imprinting of particular cell trafficking phenotypes in the intestine seems to be crucially involved. Therefore, this Review highlights achievements in understanding immune cell trafficking to, within and from the intestine and delineates its consequences for immune-mediated pathology along the gut-liver, gut-joint and gut-brain axes. We also discuss implications for current and future therapeutic approaches that specifically interfere with homing, retention, egress and recirculation of immune cells.

Clear cell renal cell carcinoma's (ccRCC) occurrence and development are strongly linked to the metabolic reprogramming of tumors, and thus far, neither its prognosis nor treatment has achieved satisfying clinical outcomes.

The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, respectively, provided us with information on the RNA expression of ccRCC patients and their clinical data. Cuproptosis-related genes (CRGS) were discovered in recent massive research. With the help of log-rank testing and univariate Cox analysis, the prognostic significance of CRGS was examined. Different cuproptosis subtypes were identified using consensus clustering analysis, and GSVA was used to further investigate the likely signaling pathways between various subtypes. Univariate Cox, least absolute shrinkage and selection operator (Lasso), random forest (RF), and multivariate stepwise Cox regression analysis were used to build prognostic models. After that, the models were verified by means of the C index, Kaplan-Meier (K-M) survival curves, and time-dependent receiver operating characteristic (ROC) curves. The association between prognostic models and the tumor immune microenvironment as well as the relationship between prognostic models and immunotherapy were next examined using ssGSEA and TIDE analysis. Four online prediction websites-Mircode, MiRDB, MiRTarBase, and TargetScan-were used to build a lncRNA-miRNA-mRNA ceRNA network.

By consensus clustering, two subgroups of cuproptosis were identified that represented distinct prognostic and immunological microenvironments.

A prognostic risk model with 13 CR-lncRNAs was developed. The immune microenvironment and responsiveness to immunotherapy are substantially connected with the model, which may reliably predict the prognosis of patients with ccRCC.

The role of microbiota:immune system dysregulation in the etiology of colorectal cancer (CRC) is poorly understood. CRC develops in gut epithelium, accompanied by low level inflammatory signaling, intestinal microbial dysbiosis and immune dysfunction. We examined populations of intraepithelial lymphocytes in non-affected colonic mucosa of CRC and healthy donors and circulating immune memory to commensal bacterial species and yeasts. γδ T cells and resident memory T cells, populations with a regulatory CD39-expressing phenotype, were found at lower frequencies in the colonic tissue of CRC donors compared to healthy controls. Patterns of T cell proliferative responses to a panel of commensal bacteria were distinct in CRC, while B cell memory responses to several bacteria/yeast were significantly increased, accompanied by increased proportions of effector memory B cells, transitional B cells and plasmablasts in blood. IgA responses to mucosal microbes were unchanged. Our data describe a novel immune signature with similarities to and differences from that of inflammatory bowel disease. They implicate B cell dysregulation as a potential contributor to parainflammation and identify pathways of weakened barrier function and tumor surveillance in CRC-susceptible individuals.

The role of microbiota:immune system dysregulation in the etiology of colorectal cancer (CRC) is poorly understood. CRC develops in gut epithelium, accompanied by low level inflammatory signaling, intestinal microbial dysbiosis and immune dysfunction. We examined populations of intraepithelial lymphocytes in non-affected colonic mucosa of CRC and healthy donors and circulating immune memory to commensal bacterial species and yeasts. γδ T cells and resident memory T cells, populations with a regulatory CD39-expressing phenotype, were found at lower frequencies in the colonic tissue of CRC donors compared to healthy controls. Patterns of T cell proliferative responses to a panel of commensal bacteria were distinct in CRC, while B cell memory responses to several bacteria/yeast were significantly increased, accompanied by increased proportions of effector memory B cells, transitional B cells and plasmablasts in blood. IgA responses to mucosal microbes were unchanged. Our data describe a novel immune signature with similarities to and differences from that of inflammatory bowel disease. They implicate B cell dysregulation as a potential contributor to parainflammation and identify pathways of weakened barrier function and tumor surveillance in CRC-susceptible individuals.

The intestinal epithelium plays critical roles in sensing and integrating dietary and microbial signals. How microbiota and intestinal epithelial cell (IEC) interactions regulate host physiology in the proximal small intestine, particularly the duodenum, is unclear. Using single-cell RNA sequencing of duodenal IECs under germ-free (GF) and different conventional microbiota compositions, we show that specific microbiota members alter epithelial homeostasis by increasing epithelial turnover rate, crypt proliferation, and major histocompatibility complex class II (MHCII) expression. Microbiome profiling identified Faecalibaculum rodentium as a key species involved in this regulation. F. rodentium decreases enterocyte expression of retinoic-acid-producing enzymes Adh1, Aldh1a1, and Rdh7, reducing retinoic acid signaling required to maintain certain intestinal eosinophil populations. Eosinophils suppress intraepithelial-lymphocyte-mediated production of interferon-γ that regulates epithelial cell function. Thus, we identify a retinoic acid-eosinophil-interferon-γ-dependent circuit by which the microbiota modulates duodenal epithelial homeostasis.