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Nrf2/ASPM axis regulated vasculogenic mimicry formation in hepatocellular carcinoma under hypoxia. Nrf2/ASPM轴调控缺氧条件下肝细胞癌血管生成模拟的形成
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-03 DOI: 10.1007/s00535-024-02140-9
Yueyao Zhang, Na Che, Song Wang, Jie Meng, Nan Zhao, Jiyuan Han, Xueyi Dong, Yanlei Li, Jing Mo, Xiulan Zhao, Tieju Liu

Background: Hypoxic microenvironment is a common feature of most solid tumors including hepatocellular carcinoma (HCC). Vasculogenic mimicry (VM) formation by tumor cells could provide blood supply to tumor cells under hypoxia. NFE2 like basic leucine zipper (bZIP) transcription factor 2 (Nrf2), a regulator of cellular homeostasis, may promote tumor progression in the hypoxic conditions. However, the role and regulatory mechanisms of Nrf2 in HCC are not fully elucidated.

Methods: Nrf2 and assembly factor for spindle microtubules (ASPM) expression modulations were conducted by lentiviral transfections. Western blot, immunofluorescence, ChIP-qPCR, dual-luciferase reporter gene assay, flow cytometry, RNA sequencing, multiple bioinformatics databases analysis, cell function assays in vitro, mouse model in vivo and human HCC tissues were employed to assess the effect of Nrf2/ASPM axis on HCC progression under hypoxia.

Results: Nrf2 and ASPM expression facilitated epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) feature, and VM formation of HCC cells under hypoxia. Furthermore, Nrf2-regulated ASPM expression, via binding directly to the promoter region of ASPM and transcriptionally promoting ASPM expression. ASPM re-expression in Nrf2 knockdown cells or ASPM knockdown in Nrf2 overexpression cells reversed the cellular function caused by Nrf2. Meantime, retinol metabolism pathway was disrupted following abnormal ASPM expression. Nrf2/ASPM axis in murine models accelerated tumor growth and VM, corroborating in vitro findings. All-trans retinoic acid treatment reversed stemness and VM of HCC cells in vitro and in vivo. Clinically, Nrf2 and ASPM expressions were related to poor prognosis of HCC patients.

Conclusions: Nrf2 drives EMT, CSCs characteristics and VM in HCC under hypoxia through the modulation of ASPM. Retinol metabolism pathway was dysregulated in HCC cells with ASPM overexpression. Nrf2/ASPM axis and related pathway provided potential therapeutic target for HCC.

背景:缺氧微环境是包括肝细胞癌(HCC)在内的大多数实体瘤的共同特征。肿瘤细胞形成的血管生成模拟(VM)可为缺氧环境下的肿瘤细胞提供血液供应。NFE2与碱性亮氨酸拉链(bZIP)转录因子2(Nrf2)一样,是细胞稳态的调节因子,可能会在缺氧条件下促进肿瘤进展。然而,Nrf2在HCC中的作用和调控机制尚未完全阐明:方法:通过慢病毒转染对Nrf2和纺锤体微管组装因子(ASPM)的表达进行调控。采用Western印迹、免疫荧光、ChIP-qPCR、双荧光素酶报告基因检测、流式细胞术、RNA测序、多种生物信息学数据库分析、体外细胞功能检测、体内小鼠模型和人类HCC组织等方法,评估Nrf2/ASPM轴在缺氧条件下对HCC进展的影响:结果:Nrf2和ASPM的表达促进了缺氧条件下HCC细胞的上皮-间质转化(EMT)、癌症干细胞(CSCs)特征和VM形成。此外,Nrf2通过直接与ASPM的启动子区域结合并转录促进ASPM的表达,从而调控ASPM的表达。在Nrf2敲除的细胞中重新表达ASPM或在Nrf2过表达的细胞中敲除ASPM可逆转Nrf2引起的细胞功能。同时,ASPM 的异常表达会破坏视黄醇代谢途径。小鼠模型中的 Nrf2/ASPM 轴加速了肿瘤的生长和 VM,证实了体外研究结果。全反式维甲酸治疗可逆转体外和体内 HCC 细胞的干性和 VM。在临床上,Nrf2和ASPM的表达与HCC患者的不良预后有关:结论:在缺氧条件下,Nrf2通过调节ASPM驱动HCC的EMT、CSCs特征和VM。ASPM过表达的HCC细胞中视黄醇代谢途径失调。Nrf2/ASPM轴及相关通路为HCC提供了潜在的治疗靶点。
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引用次数: 0
Response to the letter by Buldukoglu et al. regarding our manuscript "Body mass index and survival among patients with advanced biliary tract cancer: a single-institutional study with nationwide data-based validation". 对 Buldukoglu 等人就我们的手稿 "晚期胆道癌患者的体重指数和生存率:一项基于全国数据验证的单机构研究 "所写来信的回复。
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-06 DOI: 10.1007/s00535-024-02143-6
Shinya Takaoka, Tsuyoshi Hamada, Yousuke Nakai, Hideo Yasunaga, Mitsuhiro Fujishiro
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引用次数: 0
Resistant starch reduces glycolysis by HK2 and suppresses high-fructose corn syrup-induced colon tumorigenesis. 抗性淀粉通过 HK2 减少糖酵解,抑制高果糖玉米糖浆诱导的结肠肿瘤发生。
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-14 DOI: 10.1007/s00535-024-02138-3
Ying Zhang, Weiyi Shen, Zhehang Chen, Jiamin He, Lijun Feng, Lan Wang, Shujie Chen

Background: The intake of high-fructose corn syrup (HFCS) may increase the risk of colorectal cancer (CRC). This study aimed to explore the potential effects and mechanisms of resistant starch (RS) in HFCS-induced colon tumorigenesis.

Methods: The azoxymethane/dextran sodium sulfate (AOM/DSS) and ApcMin/+ mice models were used to investigate the roles of HFCS and RS in CRC in vivo. An immunohistochemistry (IHC) staining analysis was used to detect the expression of proliferation-related proteins in tissues. 16S rRNA sequencing for microbial community, gas chromatography for short-chain fatty acids (SCFAs), and mass spectrometry analysis for glycolysis products in the intestines were performed. Furthermore, lactic acid assay kit was used to detect the glycolysis levels in vitro.

Results: RS suppressed HFCS-induced colon tumorigenesis through reshaping the microbial community. Mechanistically, the alteration of the microbial community after RS supplement increased the levels of intestinal SCFAs, especially butyrate, leading to the suppression of glycolysis and CRC cell proliferation by downregulating HK2.

Conclusions: Our study identified RS as a candidate of protective factors in CRC and may provide a potential target for HFCS-related CRC treatment.

背景:摄入高果糖玉米糖浆(HFCS)可能会增加罹患结直肠癌(CRC)的风险。本研究旨在探讨抗性淀粉(RS)在 HFCS 诱导的结肠肿瘤发生中的潜在作用和机制:方法:采用偶氮甲烷/葡聚糖硫酸钠(AOM/DSS)和 ApcMin/+ 小鼠模型研究 HFCS 和 RS 在体内 CRC 中的作用。免疫组化(IHC)染色分析用于检测组织中增殖相关蛋白的表达。对微生物群落进行了 16S rRNA 测序,对短链脂肪酸(SCFAs)进行了气相色谱分析,对肠道中的糖酵解产物进行了质谱分析。此外,还使用乳酸测定试剂盒检测体外糖酵解水平:结果:RS 通过重塑微生物群落抑制了 HFCS 诱导的结肠肿瘤发生。从机理上讲,补充 RS 后微生物群落的改变提高了肠道 SCFAs(尤其是丁酸盐)的水平,从而通过下调 HK2 抑制了糖酵解和 CRC 细胞的增殖:我们的研究发现 RS 是保护 CRC 的候选因子,可能为 HFCS 相关的 CRC 治疗提供潜在靶点。
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引用次数: 0
Cancer risk by length of Barrett's esophagus in Japanese population: a nationwide multicenter retrospective cohort study. 日本人患癌症的风险与巴雷特食管长度有关:一项全国性多中心回顾性队列研究。
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-16 DOI: 10.1007/s00535-024-02139-2
Sho Fukuda, Kenta Watanabe, Dai Kubota, Nobutake Yamamichi, Yu Takahashi, Yoshitaka Watanabe, Kyoichi Adachi, Norihisa Ishimura, Tomoyuki Koike, Hideyuki Sugawara, Kiyotaka Asanuma, Yasuhiko Abe, Takashi Kon, Eikichi Ihara, Kazuhiro Haraguchi, Yoshihiro Otsuka, Rie Yoshimura, Yugo Iwaya, Takuma Okamura, Noriaki Manabe, Akira Horiuchi, Mio Matsumoto, Kengo Onochi, So Takahashi, Tatsuki Yoshida, Yosuke Shimodaira, Katsunori Iijima

Background: The cancer risk for each length of Barrett's esophagus (BE) in Japanese is unknown. This nationwide, multi-institutional study aims to clarify the cancer risk by length of BE in the general Japanese population.

Methods: Consecutive subjects who underwent upper endoscopic screening at 17 centers between 2013 and 2017 and had at least one follow-up endoscopy by December 2022 were included. The presence/absence of BE and, if present, its length were retrospectively assessed using the retrieved endoscopic images recorded at baseline. Information on the subsequent occurrence of esophageal adenocarcinoma and other upper gastrointestinal cancers was also collected. Cancer incidence was calculated and expressed as %/year.

Results: A total of 33,478 subjects were enrolled, and 17,884 (53.4%), 10,641 (31.8%), 4889 (14.6%), and 64 (0.2%) were diagnosed as absent BE, BE < 1 cm, 1-3 cm, and ≥ 3 cm, respectively. During a median follow-up of 80 months, 11 cases of esophageal adenocarcinoma developed. The annual incidence of esophageal adenocarcinoma is 0%/year for absent BE, 0.0032 (0.00066-0.013)%/year for BE < 1 cm, 0.026 (0.011-0.054)%/year for 1-3 cm, and 0.58 (0.042-2.11)%/year for ≥ 3 cm, respectively. Meanwhile, the incidence of esophageal squamous cell carcinoma and gastric cancer were 0.039 (0.031-0.049)%/year and 0.16 (0.14-0.18)%/year, respectively.

Conclusions: By enrolling a large number of subjects with long-term follow-up, this study demonstrated that the risk of cancer increased steadily with increasing length of BE in the Japanese population. Therefore, it is important to consider the length of BE when determining the management strategy for BE.

背景:日本人中不同长度的巴雷特食管(BE)的癌症风险尚不清楚。这项全国性、多机构研究旨在明确日本普通人群中不同长度的巴雷特食管的癌症风险:方法:纳入 2013 年至 2017 年期间在 17 个中心接受上消化道内镜筛查并在 2022 年 12 月前至少接受过一次随访内镜检查的连续受试者。通过检索基线时记录的内镜图像,回顾性评估是否存在BE以及BE的长度。此外,还收集了随后发生的食管腺癌和其他上消化道癌症的信息。癌症发病率以%/年的形式计算:共有 33,478 名受试者被纳入研究,其中 17,884 人(53.4%)、10,641 人(31.8%)、4889 人(14.6%)和 64 人(0.2%)被诊断为无 BE、BE 结论:通过对大量受试者进行长期随访,本研究表明,在日本人群中,癌症风险随着BE时间的延长而稳步上升。因此,在确定 BE 的治疗策略时,必须考虑 BE 的持续时间。
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引用次数: 0
Advances in omics data for eosinophilic esophagitis: moving towards multi-omics analyses 嗜酸性粒细胞食管炎的组学数据研究进展:向多组学分析迈进
IF 6.3 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-09-19 DOI: 10.1007/s00535-024-02151-6
Kazuhiro Matsuyama, Shingo Yamada, Hironori Sato, Justin Zhan, Tetsuo Shoda

Eosinophilic esophagitis (EoE) is a chronic, allergic inflammatory disease of the esophagus characterized by eosinophil accumulation and has a growing global prevalence. EoE significantly impairs quality of life and poses a substantial burden on healthcare resources. Currently, only two FDA-approved medications exist for EoE, highlighting the need for broader research into its management and prevention. Recent advancements in omics technologies, such as genomics, epigenetics, transcriptomics, proteomics, and others, offer new insights into the genetic and immunologic mechanisms underlying EoE. Genomic studies have identified genetic loci and mutations associated with EoE, revealing predispositions that vary by ancestry and indicating EoE’s complex genetic basis. Epigenetic studies have uncovered changes in DNA methylation and chromatin structure that affect gene expression, influencing EoE pathology. Transcriptomic analyses have revealed a distinct gene expression profile in EoE, dominated by genes involved in activated type 2 immunity and epithelial barrier function. Proteomic approaches have furthered the understanding of EoE mechanisms, identifying potential new biomarkers and therapeutic targets. However, challenges in integrating diverse omics data persist, largely due to their complexity and the need for advanced computational methods. Machine learning is emerging as a valuable tool for analyzing extensive and intricate datasets, potentially revealing new aspects of EoE pathogenesis. The integration of multi-omics data through sophisticated computational approaches promises significant advancements in our understanding of EoE, improving diagnostics, and enhancing treatment effectiveness. This review synthesizes current omics research and explores future directions for comprehensively understanding the disease mechanisms in EoE.

嗜酸性粒细胞食管炎(EoE)是一种以嗜酸性粒细胞聚集为特征的食管慢性过敏性炎症疾病,在全球的发病率越来越高。嗜酸性粒细胞食管炎严重影响患者的生活质量,并对医疗资源造成巨大负担。目前,美国食品和药物管理局仅批准了两种治疗食管水肿的药物,这凸显了对其管理和预防进行更广泛研究的必要性。基因组学、表观遗传学、转录物组学、蛋白质组学等全局组学技术的最新进展为研究咽喉炎的遗传和免疫机制提供了新的视角。基因组研究确定了与咽喉炎相关的基因位点和突变,揭示了因血统不同而异的易感性,并表明咽喉炎的遗传基础十分复杂。表观遗传学研究发现,DNA 甲基化和染色质结构的变化会影响基因表达,从而影响咽鼓管病理学。转录组分析揭示了咽喉炎患者独特的基因表达谱,其中主要是参与激活的 2 型免疫和上皮屏障功能的基因。蛋白质组学方法进一步加深了对咽喉炎发病机制的了解,确定了潜在的新生物标记物和治疗靶点。然而,整合各种 omics 数据的挑战依然存在,这主要是由于它们的复杂性和对先进计算方法的需求。机器学习正在成为分析广泛而复杂的数据集的重要工具,有可能揭示出咽喉炎发病机制的新方面。通过复杂的计算方法整合多组学数据,有望极大地促进我们对咽喉炎的了解、改善诊断和提高治疗效果。本综述综合了当前的组学研究,并探讨了全面了解咽喉炎疾病机制的未来方向。
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引用次数: 0
CRAFITY score as a predictive marker for refractoriness to atezolizumab plus bevacizumab therapy in hepatocellular carcinoma: a multicenter retrospective study 将 CRAFITY 评分作为肝细胞癌阿特珠单抗加贝伐单抗治疗难治性的预测指标:一项多中心回顾性研究
IF 6.3 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-09-18 DOI: 10.1007/s00535-024-02150-7
Masayuki Ueno, Haruhiko Takeda, Atsushi Takai, Hiroki Morimura, Norihiro Nishijima, Satoru Iwamoto, Shunsuke Okuyama, Makoto Umeda, Takeshi Seta, Atsuyuki Ikeda, Tomoyuki Goto, Shin’ichi Miyamoto, Takahisa Kayahara, Yoshito Uenoyama, Kazuyoshi Matsumura, Shigeharu Nakano, Masako Mishima, Tadashi Inuzuka, Yuji Eso, Ken Takahashi, Hiroyuki Marusawa, Yukio Osaki, Etsuro Hatano, Hiroshi Seno

Background

Although atezolizumab plus bevacizumab (Atezo/Bev) therapy has been used as the preferred first-line treatment for advanced hepatocellular carcinoma (HCC), up to 26% of patients do not achieve disease control, suggesting alternative treatments might be more beneficial for such patients. We investigated key predictors for refractoriness to Atezo/Bev therapy, particularly in the first-line setting.

Methods

We retrospectively analyzed 302 patients with HCC who received Atezo/Bev therapy between October 2020 and September 2022 across nine hospitals in Japan. Refractoriness was defined as best overall response (BOR) of progressive disease or stable disease and a progression-free survival (PFS) of < 180 days (RECIST v1.1). Clinical benefit was defined as BOR of partial/complete response or stable disease with PFS of ≥ 180 days. Baseline characteristics and potential predictors, identified through literature review, were compared between these groups. Stratifications of overall survival (OS), and PFS were also assessed.

Results

Refractoriness was observed in 126 (41.7%) patients, while 154 (51.0%) achieved clinical benefit. Due to a significant association between the treatment line and refractory rate, the subsequent analysis focused on the first-line cohort (n = 214; 72 [33.6%] patients showed refractoriness). Among 13 potential predictors, the CRP and AFP in immunotherapy (CRAFITY) score had the best predictive performance, with refractory rates of 24.6%, 44.6%, and 57.9% in CRAFITY-0, 1, and 2 patients, respectively (p < 0.001). OS and PFS were also well-stratified by this scoring system.

Conclusions

Approximately one-third of patients were refractory to first-line Atezo/Bev therapy. The CRAFITY score demonstrated superior performance in predicting refractoriness.

背景尽管阿特珠单抗加贝伐单抗(Atezo/Bev)疗法已被用作晚期肝细胞癌(HCC)的首选一线治疗方法,但仍有高达26%的患者未能实现疾病控制,这表明替代疗法可能对这类患者更有益。我们研究了Atezo/Bev治疗难治性的关键预测因素,尤其是在一线治疗中。方法我们回顾性分析了2020年10月至2022年9月期间在日本9家医院接受Atezo/Bev治疗的302例HCC患者。难治性的定义是疾病进展或疾病稳定的最佳总反应(BOR)和< 180天的无进展生存期(PFS)(RECIST v1.1)。临床获益定义为部分/完全应答或病情稳定且 PFS ≥ 180 天。通过文献综述确定的基线特征和潜在预测因素在这些组别之间进行了比较。结果 126 例(41.7%)患者出现耐药,154 例(51.0%)患者获得临床获益。由于治疗线与难治率之间存在显著关联,后续分析主要集中在一线队列(n = 214;72 [33.6%]患者出现难治)。在 13 个潜在预测因子中,免疫治疗中的 CRP 和 AFP(CRAFITY)评分的预测效果最好,CRAFITY-0、1 和 2 患者的难治率分别为 24.6%、44.6% 和 57.9%(p <0.001)。结论约三分之一的患者对一线 Atezo/Bev 治疗难治。CRAFITY评分在预测难治性方面表现优异。
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引用次数: 0
Association of pancreatic atrophy patterns with intraductal extension of early pancreatic ductal adenocarcinoma: a multicenter retrospective study 胰腺萎缩模式与早期胰腺导管腺癌导管内扩展的关系:一项多中心回顾性研究
IF 6.3 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-09-16 DOI: 10.1007/s00535-024-02149-0
Mika Miki, Atsuhiro Masuda, Mamoru Takenaka, Hideyuki Shiomi, Takao Iemoto, Hidetaka Tsumura, Masahiro Tsujimae, Hirochika Toyama, Keitaro Sofue, Eisuke Ueshima, Shunsuke Omoto, Akihiro Yoshida, Tomohiro Fukunaga, Hidekazu Tanaka, Ryota Nakano, Shogo Ota, Takashi Kobayashi, Arata Sakai, Maki Kanzawa, Tomoo Itoh, Yuzo Kodama

Background

Focal pancreatic parenchymal atrophy (FPPA) and upstream pancreatic atrophy (UPA) may indicate the presence of early pancreatic cancer. In early pancreatic cancer, the tumor occasionally spreads laterally along the main pancreatic duct, presenting challenges in determining the extent of surgical resection. This study aimed to investigate the association of pancreatic atrophy pattern and intraductal cancer extension.

Methods

Thirty-two patients with early-stage pancreatic cancer who underwent surgery at five participating centers were enrolled. Pancreatic atrophy was defined as the narrowing of parenchyma compared to the surrounding parenchyma and was classified as either FPPA (partial atrophy surrounding the pancreatic duct stenosis) or UPA (global atrophy caudal to the site of duct stenosis). Intraductal cancer extension was defined as an extension exceeding 10 mm.

Results

Preoperative computed tomography revealed FPPA, UPA, and no parenchymal atrophy in 13, 13, and 6 patients. Cases with FPPA or UPA showed significantly longer cancer extensions than those without atrophy (P = 0.005 and P = 0.03, respectively). Intraductal cancer extension was present in all but one case of FPPA. 69% (9/13) of the cases with UPA showed intraductal cancer extension, whereas cases without atrophy showed no intraductal cancer extension. Importantly, two patients with FPPA or UPA showed positive resection margins during surgery and three patients with FPPA or UPA showed recurrence in the remnant pancreas.

Conclusions

The presence of FPPA and UPA indicates lateral cancer extension in early-stage pancreatic cancer. Preoperative assessment of the pancreatic parenchyma may provide valuable insights for determining the extent of surgical resection.

背景局灶性胰腺实质萎缩(FPPA)和上游胰腺萎缩(UPA)可能预示着早期胰腺癌的存在。在早期胰腺癌中,肿瘤偶尔会沿主胰管横向扩散,这给确定手术切除范围带来了挑战。本研究旨在探讨胰腺萎缩模式与导管内癌延伸的关系。胰腺萎缩被定义为与周围实质组织相比实质组织变窄,分为FPPA(胰管狭窄周围部分萎缩)或UPA(胰管狭窄部位尾部整体萎缩)。导管内癌扩展的定义是扩展范围超过 10 毫米。结果术前计算机断层扫描显示,分别有 13、13 和 6 例患者出现 FPPA、UPA 和无实质萎缩。有 FPPA 或 UPA 的病例的癌延伸明显长于无萎缩的病例(分别为 P = 0.005 和 P = 0.03)。除一例 FPPA 病例外,其他所有病例都存在导管内癌延伸。69%(9/13)的 UPA 患者出现导管内癌扩展,而无萎缩的患者则没有导管内癌扩展。重要的是,两例 FPPA 或 UPA 患者在手术中显示切除边缘阳性,三例 FPPA 或 UPA 患者在残余胰腺中显示复发。术前对胰腺实质的评估可为确定手术切除范围提供有价值的见解。
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引用次数: 0
Multisample lipidomic profiles of irritable bowel syndrome and irritable bowel syndrome-like symptoms in patients with inflammatory bowel disease: new insight into the recognition of the same symptoms in different diseases 炎症性肠病患者肠易激综合征和肠易激综合征类似症状的多样本脂质体图谱:对不同疾病中相同症状识别的新见解
IF 6.3 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-09-10 DOI: 10.1007/s00535-024-02148-1
Guorong Chen, Xuan Wu, Huiting Zhu, Kemin Li, Junhai Zhang, Shijie Sun, Huifen Wang, Miao Wang, Bing Shao, Hui Li, Yanli Zhang, Shiyu Du

Background

Overlapping clinical manifestations of irritable bowel syndrome (IBS) and IBS-like symptoms in patients with inflammatory bowel disease (IBD-IBS) present challenges in diagnosis and management. Both conditions are associated with alterations in metabolites, but few studies have described the lipid profiles. Our aim was to pinpoint specific lipids that contribute to the pathogenesis of IBS and IBD-IBS by analyzing multiple biologic samples.

Methods

Diarrhea-predominant IBS (IBS-D) patients (n = 39), ulcerative colitis in remission with IBS-like symptoms patients (UCR-IBS) (n = 21), and healthy volunteers (n = 35) were recruited. IBS-D patients meet the Rome IV diagnostic criteria, and UCR-IBS patients matched mayo scores ≤ two points and Rome IV diagnostic criteria. Serum, feces, and mucosa were collected for further analysis. Lipid extraction was carried out by ultra-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS).

Results

Lipidomics of mucosa and serum samples significantly differed among the three groups. Feces showed the most altered lipid species, and the enrichment analysis of 347 differentially abundant metabolites via KEGG pathway analysis revealed that alpha-linolenic acid metabolism was significantly altered in the two groups (P < 0.01). The ratio of omega-6/omega-3 fatty acid were imbalance in serum samples.

Conclusions

This study revealed a comprehensive lipid composition pattern between IBS-D patients and UCR-IBS patients. We found several distinctive lipids involved in alpha-linolenic acid metabolism, reflecting an imbalance in the omega-6/omega-3 fatty acid ratio. Compared to mucosa and serum samples, fecal samples might have more advantages in lipidomics studies due to the convenience of sample collection and effectiveness in reflecting metabolic information.

背景肠易激综合征(IBS)和炎症性肠病(IBD-IBS)患者肠易激综合征样症状的临床表现相互重叠,给诊断和治疗带来了挑战。这两种病症都与代谢物的改变有关,但很少有研究对脂质谱进行描述。我们的目的是通过分析多种生物样本,找出导致 IBS 和 IBD-IBS 发病机制的特定脂质。方法我们招募了腹泻为主的 IBS(IBS-D)患者(39 人)、缓解期溃疡性结肠炎伴 IBS 类症状患者(UCR-IBS)(21 人)和健康志愿者(35 人)。IBS-D患者符合罗马IV诊断标准,UCR-IBS患者符合马约评分≤两分和罗马IV诊断标准。收集血清、粪便和粘膜做进一步分析。结果三组患者粘膜和血清样本的脂质组学差异显著。粪便中的脂质种类变化最大,通过 KEGG 通路分析对 347 种不同含量的代谢物进行富集分析发现,两组中的α-亚麻酸代谢发生了显著变化(P < 0.01)。结论这项研究揭示了 IBS-D 患者和 UCR-IBS 患者之间全面的脂质组成模式。我们发现了几种参与α-亚麻酸代谢的独特脂质,反映了ω-6/ω-3脂肪酸比例的失衡。与粘膜和血清样本相比,粪便样本在脂质组学研究中可能更有优势,因为样本采集方便且能有效反映代谢信息。
{"title":"Multisample lipidomic profiles of irritable bowel syndrome and irritable bowel syndrome-like symptoms in patients with inflammatory bowel disease: new insight into the recognition of the same symptoms in different diseases","authors":"Guorong Chen, Xuan Wu, Huiting Zhu, Kemin Li, Junhai Zhang, Shijie Sun, Huifen Wang, Miao Wang, Bing Shao, Hui Li, Yanli Zhang, Shiyu Du","doi":"10.1007/s00535-024-02148-1","DOIUrl":"https://doi.org/10.1007/s00535-024-02148-1","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Overlapping clinical manifestations of irritable bowel syndrome (IBS) and IBS-like symptoms in patients with inflammatory bowel disease (IBD-IBS) present challenges in diagnosis and management. Both conditions are associated with alterations in metabolites, but few studies have described the lipid profiles. Our aim was to pinpoint specific lipids that contribute to the pathogenesis of IBS and IBD-IBS by analyzing multiple biologic samples.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Diarrhea-predominant IBS (IBS-D) patients (<i>n</i> = 39), ulcerative colitis in remission with IBS-like symptoms patients (UCR-IBS) (<i>n</i> = 21), and healthy volunteers (<i>n</i> = 35) were recruited. IBS-D patients meet the Rome IV diagnostic criteria, and UCR-IBS patients matched mayo scores ≤ two points and Rome IV diagnostic criteria. Serum, feces, and mucosa were collected for further analysis. Lipid extraction was carried out by ultra-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Lipidomics of mucosa and serum samples significantly differed among the three groups. Feces showed the most altered lipid species, and the enrichment analysis of 347 differentially abundant metabolites via KEGG pathway analysis revealed that alpha-linolenic acid metabolism was significantly altered in the two groups (<i>P</i> &lt; 0.01). The ratio of omega-6/omega-3 fatty acid were imbalance in serum samples.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>This study revealed a comprehensive lipid composition pattern between IBS-D patients and UCR-IBS patients. We found several distinctive lipids involved in alpha-linolenic acid metabolism, reflecting an imbalance in the omega-6/omega-3 fatty acid ratio. Compared to mucosa and serum samples, fecal samples might have more advantages in lipidomics studies due to the convenience of sample collection and effectiveness in reflecting metabolic information.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142194801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Gut microbiota and metabolites of cirrhotic portal hypertension: a novel target on the therapeutic regulation. 肝硬化门静脉高压症的肠道微生物群和代谢物:治疗调节的新靶点。
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-19 DOI: 10.1007/s00535-024-02134-7
Yarong Hao, Zhiyuan Hao, Xin Zeng, Yong Lin

Background: The regulatory role of gut microbiota and gut-derived metabolites through the gut-liver axis in the development of cirrhotic portal hypertension (PH) has received increasing attention.

Methods: The review summarized a series of investigations on effects of metabolites derived from microbiota and medicines targeting microbiome including rifaximin, VSL#3, statins, propranolol, FXR agonists as well as drugs derived from bile acids (BAs) on PH progression.

Results: Patients with PH exhibit alterations in gut microbial richness and differential overall microbiota community, and several results clearly displayed the correlation of PH with enrichment of Veillonella dispar or depletion of Clostridiales, Peptostreptococcaceae, Alistipes putredinis, Roseburia faecis and Clostridium cluster IV. The gut-derived metabolites including hydrogen sulfide, tryptophan metabolites, butyric acid, secondary BAs and phenylacetic acid (PAA) participate in a range of pathophysiology process of PH through modulating intrahepatic vascular resistance and portal blood flow associated with the formation and progression of PH. Established and emerging drugs targeting on bacterial translocation and intestinal eubiosis are gradually identified as potential strategies for treatments of liver cirrhosis and PH by modulating intestinal inflammation, splanchnic arterial vasodilation and endothelial dysfunction.

Conclusions: Future explorations should further characterize the alteration of the fecal microbiome and metabolite profiles in PH and elucidate the regulatory mechanism of the intestinal microbiome, gut-derived metabolites and gut microbiota targeted pharmaceutical treatments involved in PH.

背景:肠道微生物群和肠道衍生代谢物通过肠道-肝脏轴在肝硬化门脉高压症(PH)发病中的调控作用日益受到关注:方法:该综述总结了一系列关于微生物群代谢产物和针对微生物群的药物(包括利福昔明、VSL#3、他汀类药物、普萘洛尔、FXR 激动剂以及胆汁酸(BA)衍生药物)对 PH 进展影响的研究:结果:PH 患者的肠道微生物丰富度和整体微生物群落差异发生了改变,一些结果清楚地表明 PH 与 Veillonella dispar 的富集或 Clostridiales、Peptostreptococcaceae、Alistipes putredinis、Roseburia faecis 和 Clostridium cluster IV 的减少相关。肠道来源的代谢物包括硫化氢、色氨酸代谢物、丁酸、次级生物碱和苯乙酸(PAA),它们通过调节与 PH 的形成和发展相关的肝内血管阻力和门静脉血流,参与 PH 的一系列病理生理学过程。通过调节肠道炎症、脾动脉血管扩张和内皮功能障碍,针对细菌转运和肠道濡养的成熟药物和新兴药物逐渐被确定为治疗肝硬化和 PH 的潜在策略:未来的探索应进一步描述 PH 中粪便微生物组和代谢物特征的改变,并阐明 PH 所涉及的肠道微生物组、肠道衍生代谢物和肠道微生物组靶向药物治疗的调控机制。
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引用次数: 0
Definitive chemoradiotherapy induces T-cell-inflamed tumor microenvironment in unresectable locally advanced esophageal squamous cell carcinoma. 对无法切除的局部晚期食管鳞状细胞癌,确定性化放疗可诱导T细胞炎症肿瘤微环境。
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-09-01 Epub Date: 2024-05-31 DOI: 10.1007/s00535-024-02120-z
Takumi Habu, Shogo Kumagai, Hideaki Bando, Takeshi Fujisawa, Saori Mishima, Daisuke Kotani, Masaki Nakamura, Hidehiro Hojo, Shingo Sakashita, Takahiro Kinoshita, Tomonori Yano, Shuichi Mitsunaga, Hiroyoshi Nishikawa, Shohei Koyama, Takashi Kojima

Background: Chemoradiotherapy (CRT) modulates the tumor immune microenvironment of multiple cancer types, including esophageal cancer, which potentially induces both immunogenicity and immunosuppression by upregulating the presentation of tumor-specific antigens and immune checkpoint molecules in tumors, respectively. The prognostic effects of immune modification by CRT in esophageal squamous cell carcinoma (ESCC) remain controversial because of the lack of detailed immunological analyses using paired clinical specimens before and after CRT. We aimed to clarify the immunological changes in the tumor microenvironment caused by CRT and elucidate the predictive importance of clinical response and prognosis and the rationale for the necessity of subsequent programmed cell death protein 1 (PD-1) inhibitor treatment.

Methods: In this study, we performed a comprehensive immunological analysis of paired biopsy specimens using multiplex immunohistochemistry before and after CRT in patients with unresectable locally advanced ESCC.

Results: CRT significantly increased the intra-tumoral infiltration and PD-1 expression of CD8+ T cells and conventional CD4+ T cells but decreased those of regulatory T cells and the accumulation of tumor-associated macrophages. Multivariate analysis of tumor-infiltrating T-cell phenotypes revealed that the density of PD-1+CD8+ T cells in the tumor after CRT could predict a confirmed complete response and favorable survival.

Conclusions: This study showed that CRT improved the immunological characteristics of unresectable locally advanced ESCC and identified the density of PD-1+CD8+ T cells as a predictive factor for prognosis. This finding supports the rationale for the necessity of subsequent PD-1 inhibitor treatment.

背景:化放疗(CRT)可调节包括食管癌在内的多种癌症类型的肿瘤免疫微环境,通过上调肿瘤特异性抗原和免疫检查点分子在肿瘤中的表达,可能诱导免疫原性和免疫抑制。CRT对食管鳞状细胞癌(ESCC)免疫改变的预后影响仍存在争议,因为缺乏使用CRT前后配对临床标本进行的详细免疫学分析。我们的目的是阐明 CRT 引起的肿瘤微环境免疫学变化,并阐明其对临床反应和预后的重要预测作用以及后续程序性细胞死亡蛋白 1(PD-1)抑制剂治疗的必要性:在这项研究中,我们使用多重免疫组化技术对CRT前后不可切除的局部晚期ESCC患者的配对活检标本进行了全面的免疫学分析:结果:CRT明显增加了CD8+ T细胞和常规CD4+ T细胞的瘤内浸润和PD-1表达,但减少了调节性T细胞的浸润和肿瘤相关巨噬细胞的聚集。对肿瘤浸润T细胞表型的多变量分析表明,CRT后肿瘤内PD-1+CD8+ T细胞的密度可预测确诊的完全反应和良好的生存期:本研究表明,CRT改善了不可切除的局部晚期ESCC的免疫学特征,并发现PD-1+CD8+ T细胞的密度是预后的预测因素。这一发现支持了后续PD-1抑制剂治疗的必要性。
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引用次数: 0
期刊
Journal of Gastroenterology
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