Xiao-Qin Mu

The significant economic burden of colorectal cancer (CRC) necessitates the development of innovative therapeutic approaches. Interest in the gut microbiota’s role in CRC has increased. Capecitabine, as a chemotherapy, may disrupt the balance of the intestinal microbiota. This study investigated the anticancer effects of capecitabine combined with fecal microbiota transplantation (FMT) in a CRC mouse model caused by azoxymethane and dextran sodium sulfate. FMT was achieved with fecal microbiota from healthy mice through enema. Capecitabine decreased the number and diameter of cancer foci in CRC mice, while FMT supplementation had a more noticeable impact, indicated by increased body weight and survival rate. Capecitabine significantly reduced the abundance of pathogenic bacteria in mice with CRC, such as Bacteroides, Enterorhabdus, Monoglobus, Rodentibacter, uncultured_rumen_bacterium, Turicibacter, and Streptococcus. The supplementation of FMT more effectively reversed the gut microbiota dysbiosis in CRC mice, as demonstrated by the ACE and Chao 1 indices, PCoA analysis, and enhanced normal biological pathways. Microbial dysbiosis induced immunological dysfunction in CRC mice, indicated by abnormal immune cell recruitment and excessive cytokine production. Capecitabine treatment reduced immune cell infiltration, including CD3⁺ T cells, CD4⁺ T cells, and CD49b⁺ NK cells, as chemotherapy often suppresses the immune system. The supplement of FMT increased the proportion of CD4⁺ T cells, CD49b⁺ NK cells, CD8⁺ T cells, and LY6G⁺ neutrophils, indicating improved immune responses against CRC. Moreover, capecitabine therapy alone reduced the overexpression of IL1a, IL6, IL12a, IL12b, IL17, IL22, FOXP3, STAT3, IFN-γ, TNF-α, TGF-β, GZMA, CXCR4, OPN, PD-1 and PD-L1. FMT supplementation resulted in a higher immune response to CRC, as it had a greater inhibitory effect on the overexpression of inflammatory cytokines and enhanced the production of IL10, IFN-γ, and CXCR4. These cytokines were positively correlated with Azospirillum_sp._47_25, Romboutsia, Lactococcus, Rikenella_sp._Marseille_P3215 and Turicibacter and negatively correlated with Parabacteroids, unclassified_Oscillospiraceae, Marvinbryantia, unclassified_Clostridia_vadinBB60_group, unclassified_Erysipelatoclostridiaceae, A2, Roseburia, Rikenellaceae_RC9_gut_group, Acetatifactor and unclassified_Clostridia. The combination of capecitabine and FMT is more effective at preventing CRC than capecitabine alone, as it reverses gut microbial abnormalities and boosts immune responses to CRC.

Several studies have indicated that the dysregulation of microbial metabolites and the inflammatory environment resulting from microbial dysbiosis may contribute to the occurrence and progression of cardiovascular diseases. Therefore, restoring the disordered gut microbiota in patients with colorectal cancer by fecal microbiota transplantation (FMT) has the potential to reduce the incidence of cardiac disease. In this study, we identified cardiac dysfunction in azomethane and dextran sodium sulfate-induced colorectal cancer mice. Intestinal microbes from healthy mice were transferred to colorectal cancer mice, which vastly reversed the disorder of the gut microbiota and effectively alleviated cardiac dysfunction. Moreover, FMT regulated the expression of serum metabolites such as uridine triphosphate (UTP), tiamulin, andrographolide, and N-Acetyl-D-glucosamine, as well as cytokines like TGF-β, IRF5, and β-MHC in the heart. These findings uncover that the disturbed gut microbiota causes cardiac dysfunction in colorectal cancer mice by modulating the expression of serum metabolites and cytokines, which could be alleviated by treatment with FMT.

Dysbiosis of the intestinal microbiota is prevalent among patients with colorectal cancer (CRC). This study aims to explore the anticancer roles of the fecal microbiota in inhibiting the progression of colorectal cancer and possible mechanisms. The intestinal microbial dysbiosis in CRC mice was significantly ameliorated by fecal microbiota transplantation (FMT), as indicated by the restored ACE index and Shannon index. The diameter and number of cancerous foci were significantly decreased in CRC mice treated with FMT, along with the restoration of the intestinal mucosal structure and the lessening of the gland arrangement disorder. Key factors in oxidative stress (TXN1, TXNRD1, and HIF-1α); cell cycle regulators (IGF-1, BIRC5, CDK8, HDAC2, EGFR, and CTSL); and a critical transcription factor of the innate immune signal pathway (IRF5) were among the repressed oncogenic targets engaged in the FMT treatment of CRC. Correlation analysis revealed that their expressions were positively correlated with uncultured_bacterium_o_Mollicutes_RF39, Rikenellaceae_RC9_gut_group, and negatively correlated with Bacillus, Marvinbryantia, Roseburia, Angelakisella, Enterorhabdus, Bacteroides, Muribaculum, and genera of uncultured_bacterium_f_Eggerthellaceae, uncultured_bacterium_f_Xanthobacteraceae, Prevotellaceae_UCG-001, uncultured_bacterium_f_Erysipelotrichaceae, uncul-tured_bacterium_f_Lachnospiraceae, uncultured_bacterium_f_Ruminococcaceae, Eubacterium_coprostanoligenes_group, Ruminococcaceae_UCG-005, and uncultured_bacterium_f_Peptococcaceae. This study provides more evidence for the application of FMT in the clinical treatment of CRC.

Stroke, as a serious cerebral vascular disease with high incidence and high rates of disability and mortality, has limited therapeutic options due to the narrow time window. Compelling evidence has highlighted the significance of the gut microbiota and gut–brain axis as critical regulatory factors affecting stroke. Along the microbiota–gut–brain axis, tryptophan metabolism further acquires increasing attention for its intimate association with central nervous system diseases. For the purpose of exploring the potential role of tryptophan metabolism in stroke and providing systematic insights into the intricate connection of the microbiota–gut–brain axis with the pathological procedure of stroke, this review first summarized the practical relationship between microbiota and stroke by compiling the latest case-control research. Then, the microbiota–gut–brain axis, as well as its interaction with stroke, were comprehensively elucidated on the basis of the basic anatomical structure and physiological function. Based on the crosstalk of microbiota–gut–brain, we further focused on the tryptophan metabolism from the three major metabolic pathways, namely, the kynurenine pathway, serotonin pathway, and microbial pathway, within the axis. Moreover, the effects of tryptophan metabolism on stroke were appreciated and elaborated here, which is scarcely found in other reviews. Hopefully, the systematic illustration of the mechanisms and pathways along the microbiota–gut–brain axis will inspire more translational research from metabolic perspectives, along with more attention paid to tryptophan metabolism as a promising pharmaceutical target in order to reduce the risk of stroke, mitigate the stroke progression, and ameliorate the stroke prognosis.

Many lines of evidence demonstrate the associations of colorectal cancer (CRC) with intestinal microbial dysbiosis. Recent reports have suggested that maintaining the homeostasis of microbiota and host might be beneficial to CRC patients, but the underlying mechanisms remain unclear. In this study, we established a CRC mouse model of microbial dysbiosis and evaluated the effects of fecal microbiota transplantation (FMT) on CRC progression. Azomethane and dextran sodium sulfate were used to induce CRC and microbial dysbiosis in mice. Intestinal microbes from healthy mice were transferred to CRC mice by enema. The vastly disordered gut microbiota of CRC mice was largely reversed by FMT. Intestinal microbiota from normal mice effectively suppressed cancer progression as assessed by measuring the diameter and number of cancerous foci and significantly prolonged survival of the CRC mice. In the intestine of mice that had received FMT, there were massive infiltration of immune cells, including CD8⁺ T and CD49b⁺ NK, which is able to directly kill cancer cells. Moreover, the accumulation of immunosuppressive cells, Foxp3⁺ Treg cells, seen in the CRC mice was much reduced after FMT. Additionally, FMT regulated the expressions of inflammatory cytokines in CRC mice, including down-regulation of IL1a, IL6, IL12a, IL12b, IL17a, and elevation of IL10. These cytokines were positively correlated with Azospirillum_sp._47_25, Clostridium_sensu_stricto_1, the E. coli complex, Akkermansia, Turicibacter, and negatively correlated with Muribaculum, Anaeroplasma, Candidatus_Arthromitus, and Candidatus Saccharimonas. Furthermore, the repressed expressions of TGFb, STAT3 and elevated expressions of TNFa, IFNg, CXCR4 together promoted the anti-cancer efficacy. Their expressions were positively correlated with Odoribacter, Lachnospiraceae-UCG-006, Desulfovibrio, and negatively correlated with Alloprevotella, Ruminococcaceae UCG-014, Ruminiclostridium, Prevotellaceae UCG-001 and Oscillibacter. Our studies indicate that FMT inhibits the development of CRC by reversing gut microbial disorder, ameliorating excessive intestinal inflammation and cooperating with anti-cancer immune responses.

Sterol-regulatory element binding protein 1 (SREBP1), an intracellular cholesterol sensor located in the endoplasmic reticulum, regulates the intracellular cholesterol by the Insig-Srebp-Scap pathway. Over-expression of SREBP1 can cause dyslipidemia. SREBP1 can regulate the metabolic pathway, and then promote the proliferation of tumor cells. However, there is no relevant research of metastasis and invasion in the field of colorectal cancer (CRC). Expression of SREBP1 was manipulated in CRC cell lines with low and high level SREBP1 expression by transfectiong with plasmids containing the SREBP1 gene, or by shRNA. The effect of SREBP1 on cell migration was assayed. The expression of SREBP1, p65 and MMP7 were detected by western blot. Human umbilical vein endothelial cell was used for detection of angiogenesis by adding the culture supernatant from HT29 and SW620. The level of reactive oxygen species (ROS) was detected by Dihydroethidium (DHE) staining. NF-κB inhibitor SN50 was used to test the relationship of SREBP1, NF-κB pathway and MMP7. We found that the expression of SREBP1 in colon adenocarcinoma was significantly higher than that in noncancerous tissues, especially in the invasive tumor front including tumor budding. In vitro, SREBP1 over-expressed in colon cancer cell lines HT29 promoted angiogenesis in endothelial cells, increased ROS levels, phosphorylation of NF-κB-p65 and increases MMP7 expression. The effect of SREBP1 on expression of MMP7 was lost following treatment with the NF-κB inhibitor SN50. Our results suggest that SREBP1 can promote the invasion and metastasis of CRC cells by means of promoting the expression of MMP7 related to phosphorylation of p65.