Predict the prevalence and incidence of Parkinson's disease using fractal interpolation-LSTM model.

The investigation of the prediction of disease population is a noticeable exploration topic in the field of sciences. As a type of neurological disease, the incidence and prevalence of Parkinson's disease are still difficult to accurately study. In this paper, a method is proposed to forecast the number of incident cases (NumIn), incidence rate (InRa), the number of prevalent cases (NumPr), and prevalence rate (PrRa) of Parkinson's disease in ten countries selected. Using past data on the incidence rate, the number of prevalent cases, and the prevalence rate from 1990 to 2019, three types of fractal interpolations with different fractal dimensions are constructed for reconstructing the past data, where the vertical scaling factors are determined by the method proposed in this article. Then, the Long Short-Term Memory (LSTM) model is employed to forecast the values of NumIn, InRa, NumPr, and PrRa with Parkinson's disease in 2020. Meanwhile, the autoregressive integrated moving average model is used to predict the values compared with the LSTM model. The evaluation metrics employed for error calculation include the root mean square error and the coefficient of determination (R2). According to the proposed optimal criteria, the best predicted results are the average of three types of prediction values based on the LSTM model by analyzing and comparing eight predicted results.

Improved soil moisture, nutrients, and economic benefits using plastic mulchs in balsa-based agroforestry systems.

The manufacture of wind turbine blades generally uses balsa wood as the base materials, and it is crucial to explore new regions for cultivating balsa trees to achieve carbon neutrality in the future. Xishuangbanna may be China's only area with a tropical climate suitable for the large-scale planting of balsa trees. The present study investigated the key soil elements influencing the growth of balsa plantations and the effects of different cultivation practices on soil environments and economic benefits in Xishuangbanna, China. We found that the height of balsa stems after growing 4 years reached 5.8 m; the increment of diameter at breast height (DBH) reached 27.7 cm and volume of balsa stems reached 196.0 m3 ha-1 in Xishuangbanna of China. It is of the utmost importance to improve the contents of soil exchangeable magnesium (Mg) and available phosphorus (P) for the growth of balsa trees, and exchangeable aluminium (Al) inhibited the growth of balsa trees. The practice of plastic film mulching not only improved soil moisture in the 40‒100-cm soil layer in the dry season and in the 0-60-cm soil layer in the rainy season but also enhanced soil nitrate nitrogen when compared with no plastic-mulching practice in balsa plantations. The comprehensive economic benefits of balsa/coriander/ginger/taro plantations were significantly improved by implementing plastic film mulching, as compared to balsa plantations. We conclude that balsa tree can be cultivated in Xishuangbanna, China, and its successful cultivation provides opportunities for China's wind power development.

Changing soil available substrate primarily caused by fertilization management contributed more to soil respiration temperature sensitivity than microbial community thermal adaptation.

Substrate depletion and microbial community thermal adaptation are major mechanisms that regulate the temperature sensitivity (Q10) of soil microbial respiration. Traditionally, the Q10 of soil microbial respiration is measured using laboratory incubation, which has limits in the continuous input of available substrates and the time scale for microbial community thermal adaptation. How the available substrate and the soil microbial community regulate the Q10 of soil microbial respiration under natural warming conditions remains unclear. To fill this gap in knowledge, a long-term field experiment was conducted consisting of two years of soil respiration observations combined with a soil available substrate and microbial community thermal adaptation analysis under seasonal warming conditions. The Q10 of soil respiration was calculated using the square root method, and it was more affected by the available substrate than by microbial community thermal adaptation. Fertilization management has a stronger effect on soil available substrate than temperature. As the temperature increased, NH4-N proved itself to be important for the bacterial community in the process of Q10 regulation, while dissolved organic carbon and nitrogen were key factors for the fungal community. Based on the niche breadth of microbial community composition, the changing Q10 of the soil respiration was not only closely associated with the specialist community, but also the generalist and neutralist communities. Furthermore, bacterial community thermal adaptation primarily occurred through shifts in the abundances of specialists and neutralists, while changes in species richness and species replacement occurred for the fungal generalists and neutralists. This work indicates that changing available nitrogen and DOC primarily caused by fertilization management contributed more in regulating the Q10 of soil microbial respiration than microbial community thermal adaptation, and there are different mechanisms for bacterial and fungal community thermal adaptation under warming.

Integration of metabolomics and network pharmacology to reveal the protective mechanism underlying Qibai Pingfei capsule on chronic obstructive pulmonary disease.

In this study, we have employed metabolomics technology in combination with network pharmacology to ascertain the key metabolites and hub genes. The objective was to explore the pathway of Qibai Pingfei Capsule (QBPF) in treating COPD through metabolomics. We identified 96 differential metabolites in the lung tissues of rats belonging to control and model groups, out of which 47 were observed to be critical (VIP >2, p < 0.05). Furthermore, 16 important differential metabolites were reversed after QBPF treatment. Using network pharmacology, we identified 176 core targets of 81 drug-active ingredients. Our comprehensive analysis of network pharmacology and metabolomics enabled us to identify a core target, prostaglandin-endoperoxide synthase 2 (PTGS2), and a core metabolic pathway for glutathione metabolism. Finally, the result of molecular docking showed that PTGS2 had strong binding activity to 18 compounds including Fumarine and Kaempferol, etc.. PTGS2 is a marker of ferroptosis, so we wanted to explore whether QBPF could inhibit ferroptosis in COPD. The results showed that ferroptosis was involved in the pathogenesis of COPD, and QBPF could inhibit the occurrence of ferroptosis. In conclusion, the mechanism of QBPF for treating COPD may be related to PTGS2 expression, glutathione metabolism and ferroptosis.

Clinical application of a novel stent-assisted in situ intestinal bypass in preventing postoperative anastomotic leakage for low-mid rectal cancer: A retrospective study.

This study aimed to investigate the safety and feasibility of a novel stent-assisted in situ intestinal bypass for low-mid rectal cancer patients. Patients who were diagnosed with rectal cancer and received laparoscopic low anterior rectal resection plus a novel stent-assisted in situ intestinal bypass were respectively included from March 2022 to June 2022. Biofragmentable intestinal stent with a protective sleeve was placed in the proximal colon before anastomosis, and feces could be discharged through the protective sleeve without touching the anastomosis, which achieved an in situ bypass of feces. Perioperative characteristics and short-term outcomes were collected. Rectal imaging was performed each week after surgery for the first 3 weeks to surveil the stent and feces delivery. Follow-ups were conducted for more than 3 months. Thirty patients who successfully received surgery were included in this study. There were 18 (60.0%) males and 12 (40.0%) females. As for perioperative characteristics, operation time was 213.8 ± 43.0 minutes, blood loss was 53.3 ± 24.6 mL, time to first flatus via protective sleeve after surgery was 3.2 ± 1.1 days, postoperative hospital stay was 11.8 ± 1.6 days, and time to discharge stent was 22.4 ± 3.2 days. As for short-term outcomes, 6 patients suffered from pneumonia, urinary tract infection or incision infection. During the follow-up, there was no anastomotic leakage or mortality. This novel stent-assisted in situ intestinal bypass is safe and feasible, it might be an applicable way to prevent postoperative anastomotic leakage for patients with low-mid rectal cancer.

PacBio sequencing of human fecal samples uncovers the DNA methylation landscape of 22 673 gut phages.

Gut phages have an important impact on human health. Methylation plays key roles in DNA recognition, gene expression regulation and replication for phages. However, the DNA methylation landscape of gut phages is largely unknown. Here, with PacBio sequencing (2120×, 4785 Gb), we detected gut phage methylation landscape based on 22 673 gut phage genomes, and presented diverse methylation motifs and methylation differences in genomic elements. Moreover, the methylation rate of phages was associated with taxonomy and host, and N6-methyladenine methylation rate was higher in temperate phages than in virulent phages, suggesting an important role for methylation in phage-host interaction. In particular, 3543 (15.63%) phage genomes contained restriction-modification system, which could aid in evading clearance by the host. This study revealed the DNA methylation landscape of gut phage and its potential roles, which will advance the understanding of gut phage survival and human health.

Carnobacterium maltaromaticum boosts intestinal vitamin D production to suppress colorectal cancer in female mice.

Carnobacterium maltaromaticum was found to be specifically depleted in female patients with colorectal cancer (CRC). Administration of C. maltaromaticum reduces intestinal tumor formation in two murine CRC models in a female-specific manner. Estrogen increases the attachment and colonization of C. maltaromaticum via increasing the colonic expression of SLC3A2 that binds to DD-CPase of this bacterium. Metabolomic and transcriptomic profiling unveils the increased gut abundance of vitamin D-related metabolites and the mucosal activation of vitamin D receptor (VDR) signaling in C. maltaromaticum-gavaged mice in a gut microbiome- and VDR-dependent manner. In vitro fermentation system confirms the metabolic cross-feeding of C. maltaromaticum with Faecalibacterium prausnitzii to convert C. maltaromaticum-produced 7-dehydrocholesterol into vitamin D for activating the host VDR signaling. Overall, C. maltaromaticum colonizes the gut in an estrogen-dependent manner and acts along with other microbes to augment the intestinal vitamin D production to activate the host VDR for suppressing CRC.

Roseburia intestinalis generated butyrate boosts anti-PD-1 efficacy in colorectal cancer by activating cytotoxic CD8+ T cells.

OBJECTIVE: Roseburia intestinalis is a probiotic species that can suppress intestinal inflammation by producing metabolites. We aimed to study the role of R. intestinalis in colorectal tumourigenesis and immunotherapy. DESIGN: R. intestinalis abundance was evaluated in stools of patients with colorectal cancer (CRC) (n=444) and healthy controls (n=575). The effects of R. intestinalis were studied in ApcMin/+ or azoxymethane (AOM)-induced CRC mouse models, and in syngeneic mouse xenograft models of CT26 (microsatellite instability (MSI)-low) or MC38 (MSI-high). The change of immune landscape was evaluated by multicolour flow cytometry and immunohistochemistry staining. Metabolites were profiled by metabolomic profiling. RESULTS: R. intestinalis was significantly depleted in stools of patients with CRC compared with healthy controls. R. intestinalis administration significantly inhibited tumour formation in ApcMin/+ mice, which was confirmed in mice with AOM-induced CRC. R. intestinalis restored gut barrier function as indicated by improved intestinal permeability and enhanced expression of tight junction proteins. Butyrate was identified as the functional metabolite generated by R. intestinalis. R. intestinalis or butyrate suppressed tumour growth by inducing cytotoxic granzyme B+, interferon (IFN)-γ+ and tumour necrosis factor (TNF)-α+ CD8+ T cells in orthotopic mouse models of MC38 or CT26. R. intestinalis or butyrate also significantly improved antiprogrammed cell death protein 1 (anti-PD-1) efficacy in mice bearing MSI-low CT26 tumours. Mechanistically, butyrate directly bound to toll-like receptor 5 (TLR5) receptor on CD8+ T cells to induce its activity through activating nuclear factor kappa B (NF-κB) signalling. CONCLUSION: R. intestinalis protects against colorectal tumourigenesis by producing butyrate, which could also improve anti-PD-1 efficacy by inducing functional CD8+ T cells. R. intestinalis is a potential adjuvant to augment anti-PD-1 efficacy against CRC.

Parabacteroides distasonis uses dietary inulin to suppress NASH via its metabolite pentadecanoic acid.

Non-alcoholic steatohepatitis (NASH) is the severe form of non-alcoholic fatty liver disease, and is characterized by liver inflammation and fat accumulation. Dietary interventions, such as fibre, have been shown to alleviate this metabolic disorder in mice via the gut microbiota. Here, we investigated the mechanistic role of the gut microbiota in ameliorating NASH via dietary fibre in mice. Soluble fibre inulin was found to be more effective than insoluble fibre cellulose to suppress NASH progression in mice, as shown by reduced hepatic steatosis, necro-inflammation, ballooning and fibrosis. We employed stable isotope probing to trace the incorporation of 13C-inulin into gut bacterial genomes and metabolites during NASH progression. Shotgun metagenome sequencing revealed that the commensal Parabacteroides distasonis was enriched by 13C-inulin. Integration of 13C-inulin metagenomes and metabolomes suggested that P. distasonis used inulin to produce pentadecanoic acid, an odd-chain fatty acid, which was confirmed in vitro and in germ-free mice. P. distasonis or pentadecanoic acid was protective against NASH in mice. Mechanistically, inulin, P. distasonis or pentadecanoic acid restored gut barrier function in NASH models, which reduced serum lipopolysaccharide and liver pro-inflammatory cytokine expression. Overall this shows that gut microbiota members can use dietary fibre to generate beneficial metabolites to suppress metabolic disease.

Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in mice.

BACKGROUND: Obesity is a risk factor for colorectal cancer (CRC). The role of gut microbiota in mediating the cancer-promoting effect of obesity is unknown. METHODS: Azoxymethane (AOM)-treated, ApcMin/+ and germ-free mice were gavaged with feces from obese individuals and control subjects respectively. The colonic tumor load and number were recorded at the endpoint in two carcinogenic models. The gut microbiota composition and colonic transcriptome were assessed by metagenomic sequencing and RNA sequencing, respectively. The anticancer effects of bacteria depleted in fecal samples of obese individuals were validated. FINDINGS: Conventional AOM-treated and ApcMin/+ mice receiving feces from obese individuals showed significantly increased colon tumor formation compared with those receiving feces from control subjects. AOM-treated mice receiving feces from obese individuals showed impaired intestinal barrier function and significant upregulation of pro-inflammatory cytokines and activation of oncogenic Wnt signaling pathway. Consistently, transferring feces from obese individuals to germ-free mice led to increased colonic cell proliferation, intestinal barrier function impairment, and induction of oncogenic and proinflammatory gene expression. Moreover, germ-free mice transplanted with feces from obese human donors had increased abundance of potential pathobiont Alistipes finegoldii, and reduced abundance of commensals Bacteroides vulgatus and Akkermansia muciniphila compared with those receiving feces from human donors with normal body mass index (BMI). Validation experiments showed that B. vulgatus and A. muciniphila demonstrated anti-proliferative effects in CRC, while A. finegoldii promoted CRC tumor growth. INTERPRETATION: Our results supported the role of obesity-associated microbiota in colorectal carcinogenesis and identified putative bacterial candidates that may mediate its mechanisms. Microbiota modulation in obese individuals may provide new approaches to prevent or treat obesity-related cancers including CRC. FUNDING: This work was funded by National Key Research and Development Program of China (2020YFA0509200/2020YFA0509203), National Natural Science Foundation of China (81922082), RGC Theme-based Research Scheme Hong Kong (T21-705/20-N), RGC Research Impact Fund Hong Kong (R4632-21F), RGC-CRF Hong Kong (C4039-19GF and C7065-18GF), RGC-GRF Hong Kong (14110819, 14111621), and NTU Start-Up Grant (021337-00001).

Targeting non-coding RNA H19: A potential therapeutic approach in pulmonary diseases.

Non-coding RNA is still one of the most popular fields in biology research. In recent years, people paid more attention to the roles of H19 in lung diseases, which expressed abnormally in various pathological process. Therefore, this review focus on the regulatory role of H19 in asthma, pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), lung injury, pneumonia, lung cancer, etc. And the potential therapeutic agents and molecular treatments of H19 are collected. The aim is to demonstrate its underlying mechanism in pulmonary diseases and to guide the basic research targeting H19 into clinical drug translation.

Impact of Surgery on Non-Functional Pancreatic Neuroendocrine Tumors ≤2†cm: Analyses With Propensity Score-Based Inverse Probability of Treatment Weighting.

Purpose: The impact of surgery on non-functional pancreatic neuroendocrine tumors (NF-PNETs) ≤2 cm is controversial. This study sought to demonstrate the impact of surgery on the prognosis of NF-PNETs ≤2 cm with different biological behaviors. Methods: Patients with NF-PNETs ≤2 cm from 2004 to 2015 in the Surveillance, Epidemiology, and End Results database were included in this study. An inverse probability of treatment weighting (IPTW) method was used to reduce the selection bias. Kaplan-Meier survival analysis and Cox proportional hazards regression were used to evaluate the effect of surgery on the prognosis. Results: In the IPTW-adjusted Cox proportional hazards regression analysis, surgery improved the cancer-specific survival (CSS) in the overall cohort (hazard ratio [HR], 0.187; 95% confidence interval [CI], 0.102-0.343; p < 0.001), patients with poorly differentiated or undifferentiated tumor grades (HR, 0.238; 95% CI, 0.105-0.64; p < 0.001), patients with distant metastasis (HR, 0.102; 95% CI, 0.021-0.496; p = 0.005), and patients with local invasion (HR, 0.059; 95% CI, 0.005-0.683; p = 0.002). Surgery did not improve the CSS in patients with lymph node metastasis only (HR, 0.26; 95% CI, 0.0462-1.461; p = 0.126) or patients with well or moderate differentiation while without distant and lymph node metastasis (HR, 0.387; 95% CI, 0.146-1.028; p = 0.057). Conclusions: Among patients with NF-PNETs ≤2 cm, different biological behaviors correlate with different prognostic impacts of surgery. As long as distant metastasis does not occur and the grade is well-moderately differentiated, these patients will not benefit from surgery no matter whether lymph node metastasis occurs or not. However, when local invasion appears in this group of patients, surgery should be performed. Moreover, patients with a tumor grade of poorly differentiated or undifferentiated or those with distant metastases may benefit from surgery.

Transmission Line Object Detection Method Based on Contextual Information Enhancement and Joint Heterogeneous Representation.

Transmission line inspection plays an important role in maintaining power security. In the object detection of the transmission line, the large-scale gap of the fittings is still a main and negative factor in affecting the detection accuracy. In this study, an optimized method is proposed based on the contextual information enhancement (CIE) and joint heterogeneous representation (JHR). In the high-resolution feature extraction layer of the Swin transformer, the convolution is added in the part of the self-attention calculation, which can enhance the contextual information features and improve the feature extraction ability for small objects. Moreover, in the detection head, the joint heterogeneous representations of different detection methods are combined to enhance the features of classification and localization tasks, which can improve the detection accuracy of small objects. The experimental results show that this optimized method has a good detection performance on the small-sized and obscured objects in the transmission line. The total mAP (mean average precision) of the detected objects by this optimized method is increased by 5.8%, and in particular, the AP of the normal pin is increased by 18.6%. The improvement of the accuracy of the transmission line object detection method lays a foundation for further real-time inspection.

PVformer: Pedestrian and Vehicle Detection Algorithm Based on Swin Transformer in Rainy Scenes.

Pedestrian and vehicle detection plays a key role in the safe driving of autonomous vehicles. Although transformer-based object detection algorithms have made great progress, the accuracy of detection in rainy scenarios is still challenging. Based on the Swin Transformer, this paper proposes an end-to-end pedestrian and vehicle detection algorithm (PVformer) with deraining module, which improves the image quality and detection accuracy in rainy scenes. Based on Transformer blocks, a four-branch feature mapping model was introduced to achieve deraining from a single image, thereby mitigating the influence of rain streak occlusion on the detector performance. According to the trouble of small object detection only by visual transformer, we designed a local enhancement perception block based on CNN and Transformer. In addition, the deraining module and the detection module were combined to train the PVformer model through transfer learning. The experimental results show that the algorithm performed well on rainy days and significantly improved the accuracy of pedestrian and vehicle detection.

Assessment of GF3 Full-Polarimetric SAR Data for Dryland Crop Classification with Different Polarimetric Decomposition Methods.

Crop classification is one of the most important agricultural applications of remote sensing. Many studies have investigated crop classification using SAR data, while few studies have focused on the classification of dryland crops by the new Gaofen-3 (GF3) SAR data. In this paper, taking Hengshui city as the study area, the performance of the Freeman-Durden, Sato4, Singh4 and multi-component decomposition methods for dryland crop type classification applications are evaluated, and the potential of full-polarimetric GF3 data in dryland crop type classification are also investigated. The results show that the multi-component decomposition method produces the most accurate overall classifications (88.37%). Compared with the typical polarization decomposition techniques, the accuracy of the classification results using the new decomposition method is improved. In addition, the Freeman method generally yields the third-most accurate results, and the Sato4 (87.40%) and Singh4 (87.34%) methods yield secondary results. The overall classification accuracy of the GF3 data is very positive. These results demonstrate the great promising potential of GF3 SAR data for dryland crop monitoring applications.

Meta-analysis of mucosal microbiota reveals universal microbial signatures and dysbiosis in gastric carcinogenesis.

The consistency of the associations between gastric mucosal microbiome and gastric cancer across studies remained unexamined. We aimed to identify universal microbial signatures in gastric carcinogenesis through a meta-analysis of gastric microbiome from multiple studies. Compositional and ecological profiles of gastric microbes across stages of gastric carcinogenesis were significantly altered. Meta-analysis revealed that opportunistic pathobionts Fusobacterium, Parvimonas, Veillonella, Prevotella and Peptostreptococcus were enriched in GC, while commensals Bifidobacterium, Bacillus and Blautia were depleted in comparison to SG. The co-occurring correlation strengths of GC-enriched bacteria were increased along disease progression while those of GC-depleted bacteria were decreased. Eight bacterial taxa, including Veillonella, Dialister, Granulicatella, Herbaspirillum, Comamonas, Chryseobacterium, Shewanella and Helicobacter, were newly identified by this study as universal biomarkers for robustly discriminating GC from SG, with an area under the curve (AUC) of 0.85. Moreover, H. pylori-positive samples exhibited reduced microbial diversity, altered microbiota community and weaker interactions among gastric microbes. Our meta-analysis demonstrated comprehensive and generalizable gastric mucosa microbial features associated with histological stages of gastric carcinogenesis, including GC associated bacteria, diagnostic biomarkers, bacterial network alteration and H. pylori influence.

Uncovering 1058 Novel Human Enteric DNA Viruses Through Deep Long-Read Third-Generation Sequencing and Their Clinical Impact.

BACKGROUND & AIMS: Lack of viral reference genomes poses a challenge to virome study. We investigated human gut virome and its clinical implication by ultra-deep metagenomic sequencing. METHODS: We extracted sufficient viral DNA from human feces for ultra-deep PacBio sequencing (>10 µg) and Illumina sequencing (>1 µg). Upon de novo assembly and 6 stages of strict filtering, viral genomes were generated and validated in 3 cohorts of 2819 published fecal metagenomes. Diagnostic performance of assembled viruses for colorectal cancer were tested in a training cohort and 2 independent validation cohorts. Virus mapping ratio, evolutionary history, and virus status (lytic or temperate) were also examined. RESULTS: The mean amount of extracted viral DNA increased by 14-fold compared with previous protocols. We obtained PacBio long reads and Illumina short reads with 290-fold higher depth than previous studies. We assembled and validated 1178 contigs as complete viral genomes, of which 1058 were newly identified. Thirteen viral genomes (398-839 kb) that are longer than the largest bacteriophage found in humans (393 kb) were discovered. Phylogenetic tree was constructed based on Hidden Markov Models alignment scores of 4 conserved viral proteins. Incorporating our assembled genomes into the National Center for Biotechnology Information database improved the mapping ratio of published metagenomes ≤18 times. Lytic viruses (75.9% ± 12.2% of total) were predominantly present in our sample. A biomarker panel of 14 novel viruses could discriminate patients with colorectal cancer from controls with an area under the receiver operating characteristics curve of 0.87 in the training cohort, which was validated with areas under the receiver operating characteristics curve of 0.85 and 0.73 in 2 independent cohorts. CONCLUSIONS: We uncovered 1058 novel human gut viruses. These findings can contribute to clinical diagnosis, current viral reference genome, and future virome investigation.

Altered Mycobiota Signatures and Enriched Pathogenic Aspergillus rambellii Are Associated With Colorectal Cancer Based on Multicohort Fecal Metagenomic Analyses.

BACKGROUND & AIMS: The enteric mycobiota is a major component of the human gut microbiota, but its role in colorectal cancer (CRC) remains largely elusive. We conducted a meta-analysis to uncover the contribution of the fungal mycobiota to CRC. METHODS: We retrieved fecal metagenomic data sets from 7 previous publications and established an additional in-house cohort, totaling 1329 metagenomes (454 with CRC, 350 with adenoma, and 525 healthy individuals). Mycobiota composition and microbial interactions were analyzed. Candidate CRC-enriched fungal species (Aspergillus rambellii) was functionally validated in vitro and in vivo. RESULTS: Multicohort analysis revealed that the enteric mycobiota was altered in CRC. We identified fungi that were associated with patients with CRC or adenoma from multiple cohorts. Signature CRC-associated fungi included 6 enriched (A rambellii, Cordyceps sp. RAO-2017, Erysiphe pulchra, Moniliophthora perniciosa, Sphaerulina musiva, and Phytophthora capsici) and 1 depleted species (A kawachii). Co-occurrent interactions among CRC-enriched fungi became stronger in CRC compared with adenoma and healthy individuals. Moreover, we reported the transkingdom interactions between enteric fungi and bacteria in CRC progression, of which A rambellii was closely associated with CRC-enriched bacteria Fusobacterium nucleatum. A rambellii promoted CRC cell growth in vitro and tumor growth in xenograft mice. We further identified that combined fungal and bacterial biomarkers were more accurate than panels with pure bacterial species to discriminate patients with CRC from healthy individuals (the area under the curve relative change increased by 1.44%-10.60%). CONCLUSIONS: This study reveals enteric mycobiota signatures and pathogenic fungi in stages of colorectal tumorigenesis. Fecal fungi can be used, in addition to bacteria, for noninvasive diagnosis of patients with CRC.

Cigarette smoke promotes colorectal cancer through modulation of gut microbiota and related metabolites.

OBJECTIVE: Cigarette smoking is a major risk factor for colorectal cancer (CRC). We aimed to investigate whether cigarette smoke promotes CRC by altering the gut microbiota and related metabolites. DESIGN: Azoxymethane-treated C57BL/6 mice were exposed to cigarette smoke or clean air 2 hours per day for 28 weeks. Shotgun metagenomic sequencing and liquid chromatography mass spectrometry were parallelly performed on mice stools to investigate alterations in microbiota and metabolites. Germ-free mice were transplanted with stools from smoke-exposed and smoke-free control mice. RESULTS: Mice exposed to cigarette smoke had significantly increased tumour incidence and cellular proliferation compared with smoke-free control mice. Gut microbial dysbiosis was observed in smoke-exposed mice with significant differential abundance of bacterial species including the enrichment of Eggerthella lenta and depletion of Parabacteroides distasonis and Lactobacillus spp. Metabolomic analysis showed increased bile acid metabolites, especially taurodeoxycholic acid (TDCA) in the colon of smoke-exposed mice. We found that E. lenta had the most positive correlation with TDCA in smoke-exposed mice. Moreover, smoke-exposed mice manifested enhanced oncogenic MAPK/ERK (mitogen-activated protein kinase/extracellular signal­regulated protein kinase 1/2) signalling (a downstream target of TDCA) and impaired gut barrier function. Furthermore, germ-free mice transplanted with stools from smoke-exposed mice (GF-AOMS) had increased colonocyte proliferation. Similarly, GF-AOMS showed increased abundances of gut E. lenta and TDCA, activated MAPK/ERK pathway and impaired gut barrier in colonic epithelium. CONCLUSION: The gut microbiota dysbiosis induced by cigarette smoke plays a protumourigenic role in CRC. The smoke-induced gut microbiota dysbiosis altered gut metabolites and impaired gut barrier function, which could activate oncogenic MAPK/ERK signalling in colonic epithelium.

Squalene epoxidase drives cancer cell proliferation and promotes gut dysbiosis to accelerate colorectal carcinogenesis.

OBJECTIVE: Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC). Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is upregulated in CRC. Here, we aim to determine oncogenic function of SQLE and its interplay with gut microbiota in promoting colorectal tumourigenesis. DESIGN: Paired adjacent normal tissues and CRC from two cohorts were analysed (n=202). Colon-specific Sqle transgenic (Sqle tg) mice were generated by crossing Rosa26-lsl-Sqle mice to Cdx2-Cre mice. Stools were collected for metagenomic and metabolomic analyses. RESULTS: SQLE messenger RNA and protein expression was upregulated in CRC (p<0.01) and predict poor survival of patients with CRC. SQLE promoted CRC cell proliferation by inducing cell cycle progression and suppressing apoptosis. In azoxymethane-induced CRC model, Sqle tg mice showed increased tumourigenesis compared with wild-type mice (p<0.01). Integrative metagenomic and metabolomic analyses unveiled gut dysbiosis in Sqle tg mice with enriched pathogenic bacteria, which was correlated to increased secondary bile acids. Consistent with detrimental effect of secondary bile acids, gut barrier function was impaired in Sqle tg mice, with reduced tight junction proteins Jam-c and occludin. Transplantation of Sqle tg mice stool to germ-free mice impaired gut barrier function and stimulated cell proliferation compared with control mice stool. Finally, we demonstrated that terbinafine, a SQLE inhibitor, could be repurposed for CRC by synergising with oxaliplatin and 5-fluorouracil to inhibit CRC growth. CONCLUSION: This study demonstrates that SQLE mediates oncogenesis via cell intrinsic effects and modulation of gut microbiota-metabolite axis. SQLE represents a therapeutic target and prognostic marker in CRC.