Inflammatory bowel disease (IBD) is defined as an immune dysregulation disease with poor prognosis. Various therapies based on gut microbe modulation have been proposed. In this study, we aim to explore the therapeutic effect of B. adolescentis on IBD, as well as the immune and microecology mechanism of B. adolescentis in IBD. The fecal level of B. adolescentis was decreased in the IBD patients compared with the normal people in our cohort and the GMrepo database. To further clarify the role of B. adolescentis in IBD, we induced chronic colitis with three cycles of dextran sulfate sodium (DSS). We found B. adolescentis gavage exhibited protective effects as evidenced by the significantly decreased diarrhea score, spleen weight, and increased colon length. Accordingly, the cumulative histological grading was decreased in the B. adolescentis administration group. In addition, tight junction protein and mucin family were enhanced after B. adolescentis treatment. Furthermore, distinct effects were found with decreased pro-inflammatory cytokines such as TNF-α, IL-6, IL-1β, IL-18, IL-22, IL-9 and increased anti-inflammatory cytokines IL-10, IL-4, IL-5. Importantly, the colon lamina propria in the B. adolescentis group consisted of more Treg and Th2 cells, which inhibited extreme gut inflammation. Additionally, 16srRNA sequencing showed an evident increase in the B:F ratio in the B. adolescentis group. In particular, B. adolescentis application inhibited the excessive growth of Akkermansia and Escherichia-Shigella in genus level. In conclusion, B. adolescentis refined the DSS-induced chronic colitis by stimulating protective Treg/Th2 response and gut microbiota remodeling. B. adolescentis regularly treatment might improve the therapeutic effects for inflammatory bowel disease.
The gut microbiota and host immune response interaction influences the progression of intestinal inflammatory disease. As a well-recognized next-generation probiotic, Akkermansia muciniphila has been proved to play a crucial role in the progression of colitis, but its underlying mechanism remains inconclusive.
Colorectal cancer (CRC) is one of the most common malignant tumors and is associated with Fusobacterium nucleatum ( F. nucleatum, Fn ) infection. In this study, we explored the role of F. nucleatum in the CRC metastasis. Our results showed that the abundance of F. nucleatum was enriched in the feces and tumors of patients with CRC and tended to increase in stage IV compared to stage I in patients with metastatic CRC. Tumor-derived CCL20 activated by F. nucleatum not only increases CRC metastasis, but also participates in the reprograming of the tumor microenvironment. F. nucleatum promoted macrophage infiltration through CCL20 activation and simultaneously induced M2 macrophage polarization, enhancing the metastasis of CRC. In addition, we identified using database prediction and luciferase activity hat miR-1322, a candidate regulatory micro-RNA, could bind to CCL20 directly. F. nucleatum infection decreased the expression of miR-1322 by activating the NF-κB signaling pathway in CRC cells. In conclusion, F. nucleatum promotes CRC metastasis through the miR-1322/CCL20 axis and M2 polarization.
Type 2 resistant starch (RS2) is a fermentable dietary fiber conferring health benefits. We investigated the effects of RS2 on host, gut microbiota, and metabolites in aged mice on high-fat diet. In eighteen-month old mice randomly assigned to control, high-fat (HF), or high-fat+20% RS2 (HFRS) diet for 16 weeks, RS2 reversed the weight gain and hepatic steatosis induced by high-fat diet. Serum and fecal LPS, colonic IL-2 and hepatic IL-4 mRNA expressions decreased while colonic mucin 2 mRNA and protein expressions increased in the HFRS compared to the HF and the control group. 16s rRNA sequencing of fecal microbial DNA demonstrated that RS2 decreased the abundance of pathogen taxa associated with obesity, inflammation, and aging including Desulfovibrio (Proteobacteria phylum), Ruminiclostridium 9, Lachnoclostridium, Helicobacteria, Oscillibacter, Alistipes, Peptococcus, and Rikenella. Additionally, RS2 increased the colonic butyric acid by 2.6-fold while decreasing the isobutyric and isovaleric acid levels by half compared to the HF group. Functional analyses based on Clusters of Orthologous Groups showed that RS2 increased carbohydrate while decreasing amino acid metabolism. These findings demonstrate that RS2 can reverse weight gain, hepatic steatosis, inflammation, and increased intestinal permeability in aged mice on high-fat diet mediated by changes in gut microbiome and metabolites.
Metastasis is the leading cause of death for colorectal cancer (CRC) patients, and the spreading tumor cells adhesion to endothelial cells is a critical step for extravasation and further distant metastasis. Previous studies have documented the important roles of gut microbiota-host interactions in the CRC malignancy, and Fusobacterium nucleatum ( F. nucleatum ) was reported to increase proliferation and invasive activities of CRC cells. However, the potential functions and underlying mechanisms of F. nucleatum in the interactions between CRC cells and endothelial cells and subsequent extravasation remain unclear. Here, we uncovered that F. nucleatum enhanced the adhesion of CRC cells to endothelial cells, promoted extravasation and metastasis by inducing ICAM1 expression. Mechanistically, we identified that F. nucleatum induced a new pattern recognition receptor ALPK1 to activate NF-κB pathway, resulting in the upregulation of ICAM1. Interestingly, the abundance of F. nucleatum in tumor tissues of CRC patients was positively associated with the expression levels of ALPK1 and ICAM1. Moreover, high expression of ALPK1 or ICAM1 was significantly associated with a shorter overall survival time of CRC patients. This study provides a new insight into the role of gut microbiota in engaging into the distant metastasis of CRC cells.
The interplay between gut microbiota and the host immune system is emerging as a factor in the pathogenesis of colorectal cancer. Here, we set out to identify the effect of Akkermansia muciniphila (A. muciniphila) on colorectal cancer pathogenesis. A. muciniphila abundance was significantly reduced in patients with colorectal cancer from two independent clinical cohorts and the GMrepo dataset. Supplementation with A. muciniphila suppressed colonic tumorigenesis in ApcMin/+ mice and the growth of implanted HCT116 or CT26 tumors in nude mice. Mechanistically, A. muciniphila facilitated enrichment of M1-like macrophages in an NLRP3-dependent manner in vivo and in vitro. As a consequence, NLRP3 deficiency in macrophages attenuated the tumor-suppressive effect of A. muciniphila. In addition, we revealed that TLR2 was essential for the activation of the NF-κB/NLRP3 pathway and A. muciniphila induced M1-like macrophage response. We observed positive correlations between M1-like macrophages, NLRP3/TLR2 and A. muciniphila in patients with colorectal cancer, which corroborated these findings. In summary, A. muciniphila–induced M1-like macrophages provide a therapeutic target in the colorectal cancer tumor microenvironment.
Osteoarthritis (OA) is a common joint disease characterized by progressive loss of cartilage and reduction in lubricating synovial fluid, which lacks effective treatments currently. Here, we propose a hydrogel-based miRNA delivery strategy to rejuvenate impaired cartilage by creating a regenerative microenvironment to mitigate chondrocyte senescence that mainly contributes to cartilage breakdown during OA development. An aging-related miRNA, miR-29b-5p, was first found to be markedly down-regulated in OA cartilage, and their up-regulation suppressed the expression of matrix metalloproteinases and senescence-associated genes ( P16 INK4a /P21 ) via ten-eleven-translocation enzyme 1 (TET1). An injectable bioactive self-assembling peptide nanofiber hydrogel was applied to deliver agomir-29b-5p, which was functionalized by conjugating a stem cell–homing peptide SKPPGTSS for endogenous synovial stem cell recruitment simultaneously. Sustained miR-29b-5p delivery and recruitment of synovial stem cells and their subsequent differentiation into chondrocytes led to successful cartilage repair and chondrocyte rejuvenation. This strategy enables miRNA-based therapeutic modality to become a viable alternative for surgery in OA treatment.
Emerging evidence has shown that open reading frames inside lncRNA could encode micropeptides. However, their roles in cellular energy metabolism and tumor progression remain largely unknown. Here, we identified a 94-amino acid-length micropeptide encoded by lncRNA LINC00467 in colorectal cancer. We also characterized its conservation across higher mammals, localization to mitochondria, and the concerted local functions. This peptide enhanced the ATP synthase construction by interacting with the subunit α and γ (ATP5A and ATP5C), increased ATP synthase activity and mitochondrial oxygen consumption rate, and thereby promoted colorectal cancer cell proliferation. Hence, this micropeptide was termed as "ATP synthase associated peptide" (ASAP). Furthermore, loss of ASAP suppressed patient-derived xenograft growth with attenuated ATP synthase activity and mitochondrial ATP production. Clinically, high expression of ASAP and LINC00467 predicted poor prognosis of colorectal cancer patients. Taken together, our findings revealed a colorectal cancer-associated micropeptide as a vital player in mitochondrial metabolism and provided a therapeutic target for colorectal cancer.
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