ABSTRACT
Ageing is defined as the degeneration of physiological functions in numerous tissues and organs of an organism, which occurs with age. As we age, the gut undergoes a series of changes and weaknesses that may contribute to overall ageing. Emerging evidence suggests that ß-nicotinamide mononucleotide (NMN) plays a role in regulating intestinal function, but there is still a lack of literature on its role in maintaining the colon health of ageing mice. In our research, Zmpste24-/- mice proved that NMN prolonged their life span and delayed senescence. This study was designed to investigate the effects of long-term intervention on regulating colon function in ageing mice. Our results indicated that NMN improved the pathology of intestinal epithelial cells and intestinal permeability by upregulating the expression of intestinal tight junction proteins and the number of goblet cells, increasing the release of anti-inflammatory factors, and increasing beneficial intestinal bacteria. NMN increased the expression of the proteins SIRT1, NMNAT2, and NMNAT3 and decreased the expression of the protein P53. It also regulated the activity of ISCs by increasing Wnt/ß-catenin and Lgr5. Our findings also revealed that NMN caused a significant increase in the relative abundance of Akkermansia muciniphila and Bifidobacterium pseudolongum and notable differences in metabolic pathways related to choline metabolism in cancer. In summary, NMN supplementation can delay frailty in old age, aid healthy ageing, and delay gut ageing.
Subject(s)
Longevity , Nicotinamide Mononucleotide , Mice , Animals , Nicotinamide Mononucleotide/metabolism , Nicotinamide Mononucleotide/pharmacology , Aging , Dietary Supplements , Colon/metabolismABSTRACT
Aging-induced cognitive impairment is associated with a loss of metabolic homeostasis and plasticity. An emerging idea is that targeting key metabolites is sufficient to impact the function of other organisms. Therefore, more metabolism-targeted therapeutic intervention is needed to improve cognitive impairment. We first conducted untargeted metabolomic analyses and 16S rRNA to identify the aging-associated metabolic adaption and intestinal microbiome change. Untargeted metabolomic analyses of plasma revealed L-arginine metabolic homeostasis was altered during the aging process. Impaired L-arginine metabolic homeostasis was associated with low abundance of intestinal Akkermansia muciniphila (AKK) colonization in mice. Long-term supplementation of AKK outer membranes protein-Amuc_1100, rescued the L-arginine level and restored cognitive impairment in aging mice. Mechanically, Amuc_1100 acted directly as a source of L-arginine and enriched the L-arginine-producing bacteria. In aged brain, Amuc_1100 promoted the superoxide dismutase to alleviated oxidation stress, and increased nitric oxide, derivatives of L-arginine, to improve synaptic plasticity. Meanwhile, L-arginine repaired lipopolysaccharide-induced intestinal barrier damage and promoted growth of colon organoid. Our findings indicated that aging-related cognitive impairment was closely associated with the disorders of L-arginine metabolism. AKK-derived Amuc_1100, as a potential postbiotic, targeting the L-arginine metabolism, might provide a promising therapeutic strategy to maintain the intestinal homeostasis and cognitive function in aging.
Subject(s)
Cognitive Dysfunction , Verrucomicrobia , Mice , Animals , RNA, Ribosomal, 16S , Homeostasis , ArginineABSTRACT
OBJECTIVES: This study aimed to confirm whether premedication with pronase before endoscopy improves mucosal visualization and increases precancerous lesion and cancer lesion detection rates. MATERIALS AND METHODS: From June 2018 to April 2019, out-patients scheduled for endoscopy from 13 hospitals were screened to be randomly allocated in a 2:1 ratio to premedication with pronase (group A) and water (group B). The primary endpoint was mucosal visibility scores, and the secondary endpoint was precancerous and cancer lesion detection rates. This trial was registered at Chinese Clinical Trial Registry, and the registration number was ChiCTR1800016853. RESULTS: Group A showed significantly lower mucosal visibility scores (better mucosal visibility) of esophagus, stomach, and duodenum than group B, with all P -values <0.001. The overall cancer detection rates between group A and group B were 0.83 and 1.08%, and overall detection rates of precancerous and cancer lesion were 4.4 and 4.9%, both without significant difference ( P =1.000 and 0.824). In addition, the flushing volume (milliliter) of group A (10.52±23.41) was less than group B (36.30±52.11) ( P <0.001), and the flushing frequency of group A (0.46±1.01) was fewer than group B (1.62±2.12) ( P <0.001). CONCLUSIONS: Premedication with pronase could achieve better mucosal visibility and decrease flushing frequency and volume, but may not increase lesion detection rates.
Subject(s)
Endoscopy, Gastrointestinal , Precancerous Conditions , Humans , Pronase/therapeutic use , Prospective Studies , PremedicationABSTRACT
Gut microbiome is integral to the pathogenesis of ulcerative colitis. A novel probiotic Lactobacillus intestinalis (L. intestinalis) exerts a protective effect against dextran sodium sulfate-induced colitis in mice. Based on flow cytometry, colitis-associated Th17 cells are the target of L. intestinalis, which is supported by the lack of protective effects of L. intestinalis in T cell-null Rag1-/- mice or upon anti-IL-17-A antibody-treated mice. Although L. intestinalis exerts no direct effect on T cell differentiation, it decreases C/EBPA-driven gut epithelial SAA1 and SAA2 production, which in turn impairs Th17 cell differentiation. Cometabolism of L. intestinalis ALDH and host ALDH1A2 contributed to elevated biosynthesis of retinoic acid (RA), which accounts for the anti-colitis effect in RAR-α -mediated way. In a cohort of ulcerative colitis patients, it is observed that fecal abundance of L. intestinalis is negatively associated with the C/EBPA-SAA1/2-Th17 axis. Finally, L. intestinalis has a synergistic effect with mesalazine in alleviating murine colitis. In conclusion, L. intestinalis and associated metabolites, RA, have potential therapeutic effects for suppressing colonic inflammation by modulating the crosstalk between intestinal epithelia and immunity.
Subject(s)
Colitis, Ulcerative , Colitis , Humans , Animals , Mice , Colitis, Ulcerative/drug therapy , Th17 Cells/metabolism , Colitis/chemically induced , Colitis/drug therapy , Epithelial Cells/metabolism , Tretinoin/metabolism , Tretinoin/pharmacology , Tretinoin/therapeutic useABSTRACT
Declined numbers and weakened functions of intestinal stem cells (ISCs) impair the integrity of the intestinal epithelium during aging. However, the impact of intestinal microbiota on ISCs in this process is unclear. Here, using premature aging mice (telomerase RNA component knockout, Terc-/-), natural aging mice, and in vitro colonoid models, we explore how heat-inactivated Bifidobacterium adolescentis (B. adolescentis) affects colon senescence. We find that B. adolescentis could mitigate colonic senescence-related changes by enhancing intestinal integrity and stimulating the regeneration of Lgr5+ ISCs via Wnt/ß-catenin signaling. Furthermore, we uncover the involvement of Paneth-like cells (PLCs) within the colonic stem-cell-supporting niche in the B. adolescentis-induced ISC regeneration. In addition, we identify soluble polysaccharides (SPS) as potential effective components of B. adolescentis. Overall, our findings reveal the role of heat-inactivated B. adolescentis in maintaining the ISCs regeneration and intestinal barrier, and propose a microbiota target for ameliorating colon senescence.
Subject(s)
Bifidobacterium adolescentis , Mice , Animals , Hot Temperature , Intestines , Stem Cells , Intestinal Mucosa , ColonABSTRACT
BACKGROUND: The interplay between gut microbiota and tumor microenvironment (TME) in the pathogenesis of colorectal cancer (CRC) is not well explored. Here, we elucidated the functional role of Bifidobacterium adolescentis (B.a) on CRC and investigated its possible mechanism on the manipulation of cancer-associated fibroblasts (CAFs) in CRC. METHODS: Different CRC animal models and various cell line models were established to explore the function of B.a on CRC. The single-cell RNA sequencing (scRNA-seq) or flow cytometry was used to detect the cell subsets in the TME of CRC. Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), or immunofluorescence staining were performed to examine the activation of Wnt signaling and growth arrest specific 1 (GAS1) on CD143+ CAFs. Chromatin immunoprecipitation quantitative real-time PCR (CHIP-qPCR) was performed to investigate the regulation of transcription factor 4 (TCF4) on GAS1. Multi-immunofluorescence assay examined the expression level of CD143 and GAS1 on tissue microarray. RESULTS: We found that B.a abundance was significantly reduced in CRC patients from two independent cohorts and the bacteria database of GMrepo. Supplementation with B.a suppressed ApcMin/+ spontaneous or AOM/DSS-induced tumorigenesis in mice. scRNA-seq revealed that B.a facilitated a subset of CD143+ CAFs by inhibiting the infiltration of Th2 cells, while promoting the TNF-alpha+ B cells in TME. CD143+ CAFs highly expressed GAS1 and exhibited tumor suppressive effect. Mechanistically, GAS1 was activated by the Wnt/ß-catenin signaling in CD143+ CAFs. B.a abundance was correlated with the expression level of CD143 and GAS1. The level of CD143+ CAFs predicted the better survival outcome in CRC patients. CONCLUSIONS: These results highlighted that B.a induced a new subset of CD143+ CAFs by Wnt signaling-regulated GAS1 to suppress tumorigenesis and provided a novel therapeutic target for probiotic-based modulation of TME in CRC.
Subject(s)
Bifidobacterium adolescentis , Cancer-Associated Fibroblasts , Colorectal Neoplasms , Mice , Animals , Cancer-Associated Fibroblasts/metabolism , Cancer-Associated Fibroblasts/pathology , Wnt Signaling Pathway/genetics , Colorectal Neoplasms/pathology , Carcinogenesis/genetics , Carcinogenesis/metabolism , Tumor MicroenvironmentABSTRACT
Despite the promising antitumor activity of RAF/MEK inhibitors for RAS-driven cancers, not all patients respond to these therapies. Adaptive resistance has been reported as a major culprit in non-responders, which can be reversed by SHP2 inhibitors (SHP2is) in multiple cancer cells; however, the underlying mechanisms remain unknown. In this study, we found that KRAS-mutant gastric cancer cells respond to MEK inhibitors (MEKis) with adaptive resistance. Markedly, SHP2 activation accompanied by ERK signaling restoration in MEKi-treated cells, and a MEKi and SHP2i combination had a synergistic effect on downstream signaling blockade. In vivo, SHP099 combined with AZD6244 (selumetinib) was highly efficacious for the treatment of xenografts. Mechanistically, SHP2 was found to interact with the scaffold protein KSR1 through its protein tyrosine phosphatase domain. KSR1 knockdown sensitized cells to AZD6244, whereas a KSR1 activating mutation (S269A) diminished the synergistic anti-proliferative effect of SHP2i and MEKi. Interestingly, activated SHP2, during adaptive resistance to MEKis, impaired the interaction with KSR1, activating KSR1 to promote MAPK signaling. In conclusion, SHP2 promotes adaptive resistance to MEKis by activating KSR1; selumetinib combined with SHP099 might be an available therapeutic strategy for KRAS-mutant gastric cancers.
Subject(s)
Protein Tyrosine Phosphatase, Non-Receptor Type 11 , Proto-Oncogene Proteins p21(ras) , Stomach Neoplasms , Humans , Cell Line, Tumor , Mitogen-Activated Protein Kinase Kinases/metabolism , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Signal Transduction , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolismABSTRACT
With the increasing number of aged population and growing burden of healthy aging demands, a rational standard for evaluation aging is in urgent need. The advancement of medical testing technology and the prospering of artificial intelligence make it possible to evaluate the biological status of aging from a more comprehensive view. In this review, we introduced common aging biomarkers and concluded several famous aging clocks. Aging biomarkers reflect changes in the organism at a molecular or cellular level over time while aging clocks tend to be more of a generalization of the overall state of the organism. We expect to construct a framework for aging evaluation measurement from both micro and macro perspectives. Especially, population-specific aging clocks and multi-omics aging clocks may better fit the demands to evaluate aging in a comprehensive and multidimensional manner and make a detailed classification to represent different aging rates at tissue/organ levels. This framework will promisingly provide a crucial basis for disease diagnosis and intervention assessment in geroscience.
Subject(s)
Artificial Intelligence , CLOCK Proteins , BiomarkersABSTRACT
BACKGROUND AND GOALS: There are currently no standard treatments for chronic atrophic gastritis and traditional Chinese medicine may be effective. This study aims to investigate the efficacy and safety of Weierkang pills in treating chronic atrophic gastritis. MATERIALS AND METHODS: There were 108 patients in our study. They were randomly assigned to 2 groups. In group A, patients received Weierkang pills and patients in group B received folic acid combined with teprenone. Symptoms, endoscopic scores, and biopsy specimens were compared at baseline and 3 months after treatment. Meanwhile, the expressions of vascular endothelial growth factor and trefoil factor 3 (TFF3) in biopsy specimens were also compared. RESULTS: Our study showed that the total effective rates of atrophy/intestinal metaplasia in group A reached the same level as group B (51.7% vs. 40.0%, P =0.419). Weierkang significantly improved the total effective rate of atrophy/intestinal metaplasia in gastric angle compared with group B (64.7% vs. 33.3%, P =0.024). Weierkang can significantly lower the total Kyoto risk score (2.6±1.1 vs. 3.3±1.0, P =0.002) and atrophy score (1.4±0.6 vs. 1.8±0.5, P =0.001) after treatment. In addition, Weierkang improves symptoms (1.3±1.3 vs. 2.3±1.8, P =0.003) and epigastric pain (0.2±0.4 vs. 0.5±0.6, P =0.041). The expression of TFF3 in gastric mucosa decreased significantly after treatment with Weierkang ( P =0.002). CONCLUSIONS: Weierkang can improve the endoscopic appearance and pathologic changes of chronic atrophic gastritis patients. Symptoms also improved. TFF3 may be involved the pathophysiology mechanism.
Subject(s)
Gastritis, Atrophic , Helicobacter Infections , Helicobacter pylori , Stomach Neoplasms , Humans , Gastritis, Atrophic/drug therapy , Gastritis, Atrophic/metabolism , Gastritis, Atrophic/pathology , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/therapeutic use , Gastric Mucosa/pathology , Atrophy/metabolism , Atrophy/pathology , Metaplasia/metabolism , Metaplasia/pathology , Helicobacter Infections/drug therapy , Stomach Neoplasms/pathologyABSTRACT
Extrachromosomal circular DNA (eccDNA) has been shown to play an important role in the amplification of tumor genes and the maintenance of intra-tumor genetic heterogeneity, although its complex functional mechanism still remains to be elucidated. As the top three common malignancies in the world, colorectal cancer (CRC) has been threatening human life and health, whose tumorigenesis and development may have elusive connection with eccDNAs. Here, we described the extensive distribution of eccDNAs in the CRC tissues using Circle-seq, which range in size from hundreds to thousands of base pairs (bp). The distribution in tumor tissues had aggregation and tendency compared with random in tumor-adjacent tissues, accompanied with smaller and more regular circle lengths. After sequencing and restoring, we found that the shedding sites of eccDNAs in CRC had similar tendency in chromosome distribution, and focused on tumor-associated genes. Meanwhile, we combined RNA sequencing to explore the correlation of eccDNA differential expression in the gene transcription and signaling pathways, confirming a connection between eccDNA and RNA somewhere. Subsequently, we validated eccDNAs in CRC cell lines and the potential consistency of the junction sites of eccDNAs in CRC tissues and cell lines. Using fragments of the cationic amino acid transporter SLC7A1 to synthesize eccDNAs, we discovered the role of eccDNAs in different regions within the gene.
ABSTRACT
Deep learning based computer-aided diagnosis technology demonstrates an encouraging performance in aspect of polyp lesion detection on reducing the miss rate of polyps during colonoscopies. However, to date, few studies have been conducted for tracking polyps that have been detected in colonoscopy videos, which is an essential and intuitive issue in clinical intelligent video analysis task (e.g. lesion counting, lesion retrieval, report generation). In the paradigm of conventional tracking-by-detection system, detection task for lesion localization is separated from the tracking task for cropped lesions re-identification. In the multi object tracking problem, each target is supposed to be tracked by invoking a tracker after the detector, which introduces multiple inferences and leads to external resource and time consumption. To tackle these problems, we proposed a plug-in module named instance tracking head (ITH) for synchronous polyp detection and tracking, which can be simply inserted into object detection frameworks. It embeds a feature-based polyp tracking procedure into the detector frameworks to achieve multi-task model training. ITH and detection head share the model backbone for low level feature extraction, and then low level feature flows into the separate branches for task-driven model training. For feature maps from the same receptive field, the region of interest head assigns these features to the detection head and the ITH, respectively, and outputs the object category, bounding box coordinates, and instance feature embedding simultaneously for each specific polyp target. We also proposed a method based on similarity metric learning. The method makes full use of the prior boxes in the object detector to provide richer and denser instance training pairs, to improve the performance of the model evaluation on the tracking task. Compared with advanced tracking-by-detection paradigm methods, detectors with proposed ITH can obtain comparative tracking performance but approximate 30% faster speed. Optimized model based on Scaled-YOLOv4 detector with ITH illustrates good trade-off between detection (mAP 91.70%) and tracking (MOTA 92.50% and Rank-1 Acc 88.31%) task at the frame rate of 66 FPS. The proposed structure demonstrates the potential to aid clinicians in real-time detection with online tracking or offline retargeting of polyp instances during colonoscopies.
Subject(s)
Colonic Polyps , Colonoscopy , Colonic Polyps/diagnostic imaging , Colonoscopy/methods , HumansABSTRACT
Recently, there has been an increase in the incidence of malignant tumors among the older population. Moreover, there is an association between aging and cancer. During the process of senescence, the human body suffers from a series of imbalances, which have been shown to further accelerate aging, trigger tumorigenesis, and facilitate cancer progression. Therefore, exploring the junctions of aging and cancer and searching for novel methods to restore the junctions is of great importance to intervene against aging-related cancers. In this review, we have identified the underlying pathogenetic mechanisms of aging-related cancers by comparing alterations in the human body caused by aging and the factors that trigger cancers. We found that the common mechanisms of aging and cancer include cellular senescence, alterations in proteostasis, microbiota disorders (decreased probiotics and increased pernicious bacteria), persistent chronic inflammation, extensive immunosenescence, inordinate energy metabolism, altered material metabolism, endocrine disorders, altered genetic expression, and epigenetic modification. Furthermore, we have proposed that aging and cancer have common means of intervention, including novel uses of common medicine (metformin, resveratrol, and rapamycin), dietary restriction, and artificial microbiota intervention or selectively replenishing scarce metabolites. In addition, we have summarized the research progress of each intervention and revealed their bidirectional effects on cancer progression to compare their reliability and feasibility. Therefore, the study findings provide vital information for advanced research studies on age-related cancers. However, there is a need for further optimization of the described methods and more suitable methods for complicated clinical practices. In conclusion, targeting aging may have potential therapeutic effects on aging-related cancers.
ABSTRACT
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.
Subject(s)
Colorectal Neoplasms , Gastrointestinal Microbiome , Colorectal Neoplasms/microbiology , Endothelial Cells/metabolism , Fusobacterium nucleatum/metabolism , Humans , Intercellular Adhesion Molecule-1/genetics , NF-kappa B/genetics , NF-kappa B/metabolism , Protein Kinases/metabolismABSTRACT
Deep learning-based computer-aided diagnosis techniques have demonstrated encouraging performance in endoscopic lesion identification and detection, and have reduced the rate of missed and false detections of disease during endoscopy. However, the interpretability of the model-based results has not been adequately addressed by existing methods. This phenomenon is directly manifested by a significant bias in the representation of feature localization. Good recognition models experience severe feature localization errors, particularly for lesions with subtle morphological features, and such unsatisfactory performance hinders the clinical deployment of models. To effectively alleviate this problem, we proposed a solution to optimize the localization bias in feature representations of cancer-related recognition models that is difficult to accurately label and identify in clinical practice. Optimization was performed in the training phase of the model through the proposed data augmentation method and auxiliary loss function based on clinical priors. The data augmentation method, called partial jigsaw, can "break" the spatial structure of lesion-independent image blocks and enrich the data feature space to decouple the interference of background features on the space and focus on fine-grained lesion features. The annotation-based auxiliary loss function used class activation maps for sample distribution correction and led the model to present localization representation converging on the gold standard annotation of visualization maps. The results show that with the improvement of our method, the precision of model recognition reached an average of 92.79%, an F1-score of 92.61%, and accuracy of 95.56% based on a dataset constructed from 23 hospitals. In addition, we quantified the evaluation representation of visualization feature maps. The improved model yielded significant offset correction results for visualized feature maps compared with the baseline model. The average visualization-weighted positive coverage improved from 51.85% to 83.76%. The proposed approach did not change the deployment capability and inference speed of the original model and can be incorporated into any state-of-the-art neural network. It also shows the potential to provide more accurate localization inference results and assist in clinical examinations during endoscopies.
ABSTRACT
Akkermansia muciniphila has been proved to play a crucial role in the progression of colitis, but its underlying mechanism remains inconclusive. In this study, we aim to investigate the effect of A. muciniphila on the development of acute colitis and explore the underlying mechanism. We found that the fecal level of A. muciniphila was decreased in ulcerative colitis (UC) patients compared to the healthy people in the GMrepo database. Oral administration of A. muciniphila strain BAA-835 significantly ameliorated the symptoms in dextran sulfate sodium (DSS)-induced acute colitis, evidenced by decreased body weight loss, colon length shortening, and colon histological inflammatory score. In addition, the number of goblet cells and the mucin family were enhanced after A. muciniphila treatment. Furthermore, proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein 1 (MCP-1) had a downward trend. Mechanistically, the expression of NLRP3, caspase-1 p20, and IL-1ß p17 were upregulated in A. muciniphila-treated mice. Additionally, the colon tissues from high-A. muciniphila UC patients had a higher NLRP3 expression than that from low-A. muciniphila UC patients. Moreover, the upregulation of NLRP3 was observed in mouse macrophage Raw264.7 cells and bone marrow-derived macrophage (BMDM) cells after incubation with A. muciniphila. To clarify whether the protective effect of A. muciniphila in colitis depends on NLRP3, we performed the NLRP3-deficient assay in NLRP3-/- mice in vivo. The evidence showed that NLRP3 deficiency eliminated the protective effects of A. muciniphila in acute colitis. In conclusion, A. muciniphila alleviates DSS-induced acute colitis by NLRP3 activation, which enriches the mechanism and provides a new prospect for the probiotic-based treatment of colitis. IMPORTANCE 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. We found that oral administration of A. muciniphila strain BAA-835 significantly ameliorated the symptoms of acute colitis. Mechanistically, the expression of NLRP3 was upregulated in the A. muciniphila group, and the protective effect of A. muciniphila in colitis depends on NLRP3 activation. This enriches the mechanism and provides a new prospect for the probiotic-based treatment of colitis, which would promote a deeper understanding of the complex characteristics of A. muciniphila and provide guidance for the treatment of human colitis in the future.
Subject(s)
Colitis/chemically induced , Colitis/metabolism , Colitis/microbiology , Dextran Sulfate/adverse effects , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Akkermansia , Animals , Bacteria/classification , Caspase 1/metabolism , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/metabolism , Colitis, Ulcerative/microbiology , Colon , Gastrointestinal Microbiome , Goblet Cells/metabolism , Inflammasomes , Inflammatory Bowel Diseases , Interleukin-1beta , Macrophages/metabolism , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Probiotics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Owing to the growing elderly population, age-related problems are gaining increasing attention from the scientific community. With senescence, the intestine undergoes a spectrum of changes and infirmities that are likely the causes of overall aging. Therefore, identification of the aged intestine and the search for novel strategies to rescue it, are required. Although progress has been made in research on some components of the aged intestine, such as intestinal stem cells, the comprehensive understanding of intestinal aging is still limited, and this restricts the in-depth search for efficient strategies. In this concise review, we discuss several aspects of intestinal aging. More emphasis is placed on the appraisal of current and potential strategies to alleviate intestinal aging, as well as future targets to rejuvenate the aged intestine.
ABSTRACT
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.
Subject(s)
Chemokine CCL20/metabolism , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/microbiology , Fusobacterium nucleatum/physiology , Macrophages/cytology , MicroRNAs/metabolism , Animals , Cell Movement , Cell Polarity , Chemokine CCL20/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/physiopathology , Feces/microbiology , Female , Fusobacterium Infections/metabolism , Fusobacterium Infections/microbiology , Fusobacterium Infections/pathology , Fusobacterium Infections/physiopathology , Gastrointestinal Microbiome , Humans , Macrophages/metabolism , Male , Mice , MicroRNAs/genetics , NF-kappa B/genetics , NF-kappa B/metabolism , Neoplasm MetastasisABSTRACT
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.
Subject(s)
Carcinogenesis/metabolism , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/microbiology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Toll-Like Receptor 2/metabolism , Akkermansia/isolation & purification , Animals , Feces/microbiology , Female , Gastrointestinal Microbiome , HCT116 Cells , Humans , Macrophages/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Probiotics , Toll-Like Receptor 2/genetics , Tumor Microenvironment , Xenograft Model Antitumor AssaysABSTRACT
INTRODUCTION: Patients with atrophic gastritis (AG) or gastric intestinal metaplasia (GIM) have elevated risk of gastric adenocarcinoma. Endoscopic screening and surveillance have been implemented in high incidence countries. The study aimed to evaluate the accuracy of a deep convolutional neural network (CNN) for simultaneous recognition of AG and GIM. METHODS: Archived endoscopic white light images with corresponding gastric biopsies were collected from 14 hospitals located in different regions of China. Corresponding images by anatomic sites containing AG, GIM, and chronic non-AG were categorized using pathology reports. The participants were randomly assigned (8:1:1) to the training cohort for developing the CNN model (TResNet), the validation cohort for fine-tuning, and the test cohort for evaluating the diagnostic accuracy. The area under the curve (AUC), sensitivity, specificity, and accuracy with 95% confidence interval (CI) were calculated. RESULTS: A total of 7,037 endoscopic images from 2,741 participants were used to develop the CNN for recognition of AG and/or GIM. The AUC for recognizing AG was 0.98 (95% CI 0.97-0.99) with sensitivity, specificity, and accuracy of 96.2% (95% CI 94.2%-97.6%), 96.4% (95% CI 94.8%-97.9%), and 96.4% (95% CI 94.4%-97.8%), respectively. The AUC for recognizing GIM was 0.99 (95% CI 0.98-1.00) with sensitivity, specificity, and accuracy of 97.9% (95% CI 96.2%-98.9%), 97.5% (95% CI 95.8%-98.6%), and 97.6% (95% CI 95.8%-98.6%), respectively. DISCUSSION: CNN using endoscopic white light images achieved high diagnostic accuracy in recognizing AG and GIM.
Subject(s)
Endoscopy, Gastrointestinal/methods , Gastritis, Atrophic/diagnosis , Intestines/pathology , Metaplasia/diagnosis , Neural Networks, Computer , Precancerous Conditions/diagnosis , Adenocarcinoma/pathology , Female , Gastritis, Atrophic/pathology , Humans , Male , Middle Aged , Precancerous Conditions/pathology , Risk Factors , Sensitivity and Specificity , Stomach Neoplasms/pathologyABSTRACT
BACKGROUND: Accurate delineation of tumor margin is essential for complete resection of early gastric cancer (EGC). The objective of this study is to assess the performance of magnifying endoscopy with narrow-band imaging (ME-NBI) for the accurate demarcation of EGC margins. METHODS: We searched PubMed, EMBASE, Web of Science, and Cochrane Library databases up to March 2020 to identify eligible studies. The diagnostic accuracy of ME-NBI for EGC margins was calculated, and subgroup analyses were performed based on tumor size, depth of tumor invasion, tumor-occupied site, macroscopic type, histological type, Helicobacter pylori (H. pylori), and endoscopists' experience. Besides, we also evaluated the negative and positive resection rates of the horizontal margin (HM) of EGC after endoscopic submucosal dissection (ESD) and surgery. RESULTS: Ten studies comprising 1018 lesions were eligible in the databases. The diagnostic accuracy of ME-NBI for the demarcation of EGC margins was 92.4% (95% confidence interval (CI): 86.7%-96.8%). According to ME-NBI subgroup analyses, the rate of accurate evaluation of EGC margins was not associated with H. pylori infection status, tumor size, depth of tumor invasion, tumor-occupied site, macroscopic type, histological type, and endoscopists' experience, and no statistical differences were found in subgroup analyses. Moreover, the negative and positive resection rates of HM after ESD and surgery were 97.4% (95% CI: 92.1%-100%) and 2.6% (95% CI: 0.02%-7.9%), respectively. CONCLUSIONS: ME-NBI enables a reliable delineation of the extent of EGC.