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Intestinal organoid coculture systems: current approaches, challenges, and future directions. 肠道类器官共培养系统:目前的方法、挑战和未来的方向。
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-03-01 Epub Date: 2024-12-23 DOI: 10.1152/ajpgi.00203.2024
Ghanyah Al-Qadami, Anita Raposo, Chia-Chi Chien, Chenkai Ma, Ilka Priebe, Maryam Hor, Kim Fung

The intestinal microenvironment represents a complex and dynamic ecosystem, comprising a diverse range of epithelial and nonepithelial cells, a protective mucus layer, and a diverse community of gut microbiota. Understanding the intricate interplay between these components is essential for uncovering the mechanisms underlying intestinal health and disease. The development of intestinal organoids, three-dimensional (3-D) mini-intestines that closely mimic the architecture, cellular diversity, and functionality of the intestine, offers a powerful platform for investigating different aspects of intestinal physiology and pathology. However, current intestinal organoid models, mainly adult stem cell-derived organoids, lack the nonepithelial and microbial components of the intestinal microenvironment. As such, several coculture systems have been developed to coculture intestinal organoids with other intestinal elements including microbes (bacteria and viruses) and immune, stromal, and neural cells. These coculture models allow researchers to recreate the complex intestinal environment and study the intricate cross talk between different components of the intestinal ecosystem under healthy and pathological conditions. Currently, there are several approaches and methodologies to establish intestinal organoid cocultures, and each approach has its own strengths and limitations. This review discusses the existing methods for coculturing intestinal organoids with different intestinal elements, focusing on the methodological approaches, strengths and limitations, and future directions.

肠道微环境是一个复杂而动态的生态系统,由多种上皮和非上皮细胞、保护性黏液层和多种肠道微生物群组成。了解这些成分之间错综复杂的相互作用对于揭示肠道健康和疾病的潜在机制至关重要。肠道类器官的开发,3D微型肠道,密切模仿肠道的结构,细胞多样性和功能,为研究肠道生理和病理的不同方面提供了一个强大的平台。然而,目前的肠道类器官模型,主要是成体干细胞衍生的类器官,缺乏肠道微环境的非上皮和微生物成分。因此,已经开发了几种共培养系统来与其他肠道成分(包括微生物(细菌和病毒)、免疫细胞、基质细胞和神经细胞)共培养肠道类器官。这些共培养模型使研究人员能够重现复杂的肠道环境,并研究健康和病理条件下肠道生态系统不同组成部分之间的复杂串扰。目前,建立肠道类器官共培养有多种途径和方法,每种方法都有其优势和局限性。本文综述了肠道类器官与不同肠道元素共培养的现有方法,重点介绍了方法方法、优势和局限性,并展望了未来的发展方向。
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引用次数: 0
Single-cell transcriptomics predict novel potential regulators of acute epithelial restitution in the ischemia-injured intestine.
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-03-01 Epub Date: 2025-01-24 DOI: 10.1152/ajpgi.00194.2024
Elizabeth C Rose, Jeremy M Simon, Ismael Gomez-Martinez, Scott T Magness, Jack Odle, Anthony T Blikslager, Amanda L Ziegler

Intestinal ischemic injury damages the epithelial barrier and predisposes patients to life-threatening sepsis unless that barrier is rapidly restored. There is an age dependency in intestinal recovery in that neonates are the most susceptible to succumb to disease of the intestinal barrier compared with older patients. We have developed a pig model that demonstrates age-dependent failure of intestinal barrier restitution in neonatal pigs, which can be rescued by the direct application of juvenile pig mucosal tissue, but the mechanisms of rescue remain undefined. We hypothesized that by identifying a subpopulation of restituting enterocytes by their expression of cell migration transcriptional pathways, we can then predict novel upstream regulators of age-dependent restitution response programs. Superficial mucosal epithelial cells from recovering ischemic jejunum of juvenile pigs underwent single-cell transcriptomics and the predicted upstream regulator, colony stimulating factor-1 (CSF-1), was interrogated in our model. A subcluster of absorptive enterocytes expressed several cell migration pathways key to restitution. Differentially expressed genes in this subcluster predicted their upstream regulation by colony stimulating factor-1 (CSF-1). We validated age-dependent induction of CSF-1 by ischemia and documented that CSF-1 and colony-stimulating factor-1 receptor (CSF1R) co-localized in ischemic juvenile, but not neonatal, wound-adjacent epithelial cells and in the restituted epithelium of juveniles and rescued neonates. Furthermore, the CSF-1 blockade reduced restitution in vitro, and CSF-1 improved barrier function in injured neonatal pigs in preliminary ex vivo experiments. These studies validate an approach to inform potential novel therapeutic targets, such as CSF-1, to improve outcomes in neonates with intestinal injury in a unique pig model.NEW & NOTEWORTHY These studies validate an approach to identify and predict upstream regulation of restituting epithelium in a unique pig intestinal ischemic injury model. Identification of potential molecular mediators of restitution, such as CSF-1, will inform the development of targeted therapeutic interventions for the medical management of patients with ischemia-mediated intestinal injury.

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引用次数: 0
Progressive impairment in gastric and duodenal slow waves and autonomic function during progression of type 2 diabetes in rats.
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-02-24 DOI: 10.1152/ajpgi.00278.2024
Gaojue Wu, Fei Li, Yan Li, Shiying Li, Md Jahangir Alam, Jiande Dz Chen

The abnormalities of gastrointestinal (GI) slow waves play key roles in the pathophysiology of diabetic gastroparesis that is highly prevent in type 2 diabetes (T2D). While relatively well-investigated in diabetic enteric neuropathy, abnormalities and progressive impairments of gastric slow waves (GSW) and duodenal slow waves (DSW) are under-investigated during the progression of T2D. The aim of this study was to explore alterations in GSW and DSW during the development of diabetes induced by high fat diet (HFD) followed with a low dose of streptozotocin (STZ). Weekly recordings of the slow waves from healthy, pre-diabetic to diabetes stages exhibited a progressively decreased percentage of normal slow waves (%NSW) starting after HFD feeding (pre-diabetic stage) in the fasting state and starting after STZ injection (diabetic stage) in the postprandial state. The postprandial increase in the power of slow waves observed in normal control rats was absent starting from 2 weeks after HFD and persisted after STZ. The mechanism might be attributed to both progressively increased blood glucose (BG) and the impaired autonomic function in view of the following results: 1) The %NSW was negatively correlated with the fasting BG; 2) During the oral glucose tolerance test, %NSW of DSW and BG exhibited a positive correlation in rats with HbA1C <5.0%, but a negative correlation in rats with HbA1C ≥ 5.0%; 3) In comparison with baseline (healthy stage) of the same cohort, plasma pancreatic polypeptide (reflecting vagal activity) was progressively decreased whereas, plasma norepinephrine (reflecting sympathetic activity) was progressively increased.

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引用次数: 0
Plasticity of enteric neurotransmission varies during day-night cycles and with feeding state.
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-02-01 Epub Date: 2025-01-06 DOI: 10.1152/ajpgi.00286.2024
Anita J L Leembruggen, Gunes S Yildiz, Justin P Hardee, Lincon A Stamp, Joel C Bornstein, Marlene M Hao

The circadian cycle is a fundamental biological rhythm that governs many physiological functions across nearly all living organisms. In the gastrointestinal tract, activities such as gut motility, hormone synthesis, and communication between the gut, central nervous system, and microbiome all fluctuate in alignment with the circadian cycle. The enteric nervous system (ENS) is critical for coordinating many of these activities; however, how its activity is governed by the circadian cycle remains unknown. In this study, we used live calcium imaging to examine alterations in enteric neurotransmission during the 24-h day/night cycle in mice. In addition, given the role of food timing as a potent circadian entrainer, we also investigated the impact of an acute 13-h fast on ENS activity. Our findings reveal that enteric neuronal activity typically increases during the dark phase but shifts to the light phase following an acute fast. Importantly, these changes in neuronal activity were not accompanied by alterations in the gene expression of associated neurotransmitter receptors.NEW & NOTEWORTHY Neuronal activity in the enteric nervous system changes during the 24-h day/night cycle, with increased neuronal function detected at night when mice are feeding and active. However, following an acute fast, neuronal sensitivity becomes more pronounced during the day. These changes in neuronal function did not correlate with changes in neurotransmitter receptor gene expression levels.

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引用次数: 0
Local tissue response to a C-X-C motif chemokine ligand 12 therapy for fecal incontinence in a rabbit model. 局部组织对C-X-C基序趋化因子配体12治疗兔模型大便失禁的反应。
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1152/ajpgi.00343.2024
Hannah M Ruetten, Shannon S Lankford, Abolfazl S Abdolmaleki, Nicholas Edenhoffer, Gopal Badlani, James K Williams

This study aimed to determine if local injection of C-X-C motif chemokine ligand 12 (CXCL12) reduces sphincter fibrosis, restores sphincter muscle content, vascularization, and innervation, and recruits progenitor cells in a rabbit model of anal sphincter injury and incontinence. Adult female rabbits were assigned to three groups: uninjured/no treatment (control), injured/treated (treated), and injured/no treatment (untreated) (n = 4 each). Injured groups were anesthetized, and a section of external anal sphincter was removed at the 9 o'clock position. The treated sphincters were injected with 200 ng of human recombinant CXCL12 6 wk after injury, and necropsy was performed 6-wk post-treatment. The external anal sphincter was removed, fixed, embedded in paraffin, sectioned, and mounted to slides for histologic analysis of collagen and muscle content and fiber characteristics: innervation, vascularization, and progenitor cell content. Compared with controls, untreated had significantly decreased total skeletal muscle, indistinct muscle layers, and disorganized circumferential and inner longitudinal layers at the injury site. Untreated also had significantly increased collagen fiber density at the injury site compared with treated and controls. Cells staining positive for CD34 within the skeletal muscle layer were increased in treated and untreated compared with controls. Staining density for markers of nerves and vascular endothelium, cells staining positive for CD34 within the mucosa/submucosae, and cells staining positive for PAX7 were similar among all groups. Local injection of CXCL12 reduces postinjury fibrosis and results in statistically similar muscle content and organization between treated animals and controls. Further studies are needed for this promising new treatment for postparturient anal sphincter injury.NEW & NOTEWORTHY Local injection of CXCL12 cytokine reduces postinjury fibrosis in a rabbit model of anal sphincter injury and fecal incontinence. The larger size of the rabbits aided in targeted injury and treatment. Further studies are needed to explore noninvasive treatment options for postparturient anal sphincter injury.

本研究旨在确定在兔肛门括约肌损伤和失禁模型中,局部注射CXCL12是否能减少括约肌纤维化,恢复括约肌内容物、血管化和神经支配,并募集祖细胞。将成年母兔分为3组:未受伤/未治疗组(对照组)、受伤/治疗组(治疗组)和受伤/未治疗组(未治疗组),每组n=4只。损伤组麻醉后,于9点钟位置切除一段肛门外括约肌。损伤后6周,向治疗后的括约肌注射人重组CXCL12 200ng,治疗后6周进行尸检。取出肛门外括约肌,固定,石蜡包埋,切片,载玻片,进行胶原、肌肉含量和纤维特征的组织学分析;神经支配、血管形成和祖细胞含量。与对照组相比,未经治疗的骨骼肌总量明显减少,肌肉层不清晰,损伤部位的周向和内纵向层紊乱。与治疗组和对照组相比,未治疗组损伤部位的胶原纤维密度也显著增加。与对照组相比,治疗组和未治疗组骨骼肌层内CD34染色阳性的细胞增加。神经和血管内皮标记物、粘膜/粘膜下CD34染色阳性细胞、PAX7染色阳性细胞的染色密度各组间相似。局部注射CXCL12可减少损伤后纤维化,治疗动物和对照组的肌肉含量和组织在统计学上相似。这种治疗产后肛门括约肌损伤的新方法有待进一步研究。
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引用次数: 0
Gut microbiota of patients insusceptible to olanzapine-induced fatty liver disease relieves hepatic steatosis in rats. 对奥氮平诱发的脂肪肝不敏感的患者的肠道微生物群能缓解大鼠的肝脂肪变性。
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-02-01 Epub Date: 2024-12-16 DOI: 10.1152/ajpgi.00167.2024
Qian Wu, Jing Wang, Chuyue Tu, Peiru Chen, Yahui Deng, Lixiu Yu, Xiaojin Xu, Xiangming Fang, Weiyong Li

Olanzapine-induced fatty liver disease continues to pose vital therapeutic challenges in the treatment of psychiatric disorders. In addition, we observed that some patients were less prone to hepatic steatosis induced by olanzapine. Therefore, we aimed to investigate the role and the underlying mechanism of the intestinal flora in olanzapine-mediated hepatic side effects and explore the possible countermeasures. Our results showed that patients with different susceptibilities to olanzapine-induced fatty liver disease had different gut microbial diversity and composition. Furthermore, we performed fecal microbiota treatment (FMT), and confirmed that the gut microbiome of patients less prone to the fatty liver caused by olanzapine exhibited an alleviation against fatty liver disease in rats. In terms of mechanism, we revealed that the cross talk of leptin with the gut-short-chain fatty acid (SCFA)-liver axis play a critical role in olanzapine-related fatty degeneration in liver. These findings propose a promising strategy for overcoming the issues associated with olanzapine application and will hopefully inspire future in-depth research of fecal microbiota-based therapy in olanzapine-induced fatty liver disease.NEW & NOTEWORTHY Patients who were less inclined to have olanzapine-induced fatty liver had different gut microbiota profiles than did those in the susceptible cohort. Lachnospiraceae, Ruminococcaceae, Oscillospiraceae, Butyricicoccaceae, and Christensenellaceae were enriched in patients who were less prone to fatty liver disease caused by olanzapine. Fecal microbiota treatment (FMT) with these fecal samples promoted short-chain fatty acid (SCFA) production, which attenuated the circulating leptin and inhibited FASN and ACC1, thereby suppressing lipid synthesis in the liver, ultimately leading to alleviation of hepatic steatosis.

奥氮平诱发的脂肪肝仍然是治疗精神疾病的重要挑战。此外,我们还观察到一些患者不易发生奥氮平诱导的肝脂肪变性。因此,我们旨在研究肠道菌群在奥氮平介导的肝脏副作用中的作用和潜在机制,并探索可能的对策。我们的研究结果表明,对奥氮平诱导的脂肪肝易感性不同的患者,其肠道微生物的多样性和组成也不同。此外,我们还进行了粪便微生物群治疗(FMT),证实奥氮平导致脂肪肝的易感性较低的患者的肠道微生物群对大鼠脂肪肝有缓解作用。在机制方面,我们发现瘦素与肠道-短链脂肪酸(SCFA)-肝脏轴的串联在奥氮平相关的肝脏脂肪变性中发挥了关键作用。这些发现为克服与奥氮平应用相关的问题提出了一种前景广阔的策略,并有望激励未来对基于粪便微生物群的奥氮平诱发脂肪肝治疗进行深入研究。
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引用次数: 0
Bile acid sequestrant inhibits gluconeogenesis via inducing hepatic cysteine dioxygenase type 1 to reduce cysteine availability. 胆汁酸螯合剂通过诱导肝脏半胱氨酸双加氧酶1型降低半胱氨酸可用性来抑制糖异生。
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-02-01 Epub Date: 2025-01-16 DOI: 10.1152/ajpgi.00353.2024
David J Matye, Huaiwen Wang, Yifeng Wang, Lei Xiong, Tiangang Li

Bile acid sequestrants such as cholestyramine (ChTM) are gut-restricted bile acid-binding resins that block intestine bile acid absorption and attenuate hepatic bile acid signaling. Bile acid sequestrants induce hepatic bile acid synthesis to promote cholesterol catabolism and are cholesterol-lowering drugs. Bile acid sequestrants also reduce blood glucose in clinical trials and are approved drugs for treating hyperglycemia in type-2 diabetes. However, the mechanisms mediating the glucose-lowering effect of bile acid sequestrants are still incompletely understood. Here we showed that ChTM treatment decreased hepatic glucose production in Western diet-fed mice with paradoxically induced hepatic gluconeogenic genes. Cysteine dioxygenase type 1 (CDO1) mediates cysteine conversion to taurine and its expression is repressed by bile acids. We show that ChTM induced hepatic CDO1 and selectively reduced hepatic cysteine availability. Knockdown of liver CDO1 increased liver cysteine and glucose production in mice, whereas hepatocytes cultured in cystine-deficient medium showed reduced glucose production. By using dietary protein-restricted and cystine-modified Western diets that selectively alter hepatic cysteine availability, we found that reduced hepatic cysteine availability strongly inhibited glucose production in mice. Interestingly, chronic dietary protein restriction also prevented Western diet-induced obesity, which was fully reversed by restoring dietary cystine intake alone. Consistently, reduced cysteine availability dose-dependently inhibited adipogenesis in vitro. In conclusion, we report that the glucose-lowering effect of bile acid sequestrants is mediated by a CDO1-induced hepatic cysteine restriction mimetic effect. Furthermore, the anti-obesity effect of dietary protein restriction is largely mediated by reduced dietary cysteine intake.NEW & NOTEWORTHY Hepatic cysteine availability is a key driver of hepatic gluconeogenesis. Bile acid sequestrant inhibits gluconeogenesis by inducing CDO1-mediated cysteine catabolism to reduce cysteine availability. Dietary protein restriction causes hepatic cysteine deficiency without overall amino acid deficiency. The glucose-lowering effect of dietary protein restriction is largely mediated by lower dietary cysteine intake. The anti-obesity effect of chronic dietary protein restriction is largely mediated by lower dietary cysteine intake.

胆汁酸固存剂如胆酸胺(ChTM)是肠道限制性胆汁酸结合树脂,可阻断肠道胆汁酸吸收并减弱肝胆汁酸信号。胆汁酸螯合剂诱导肝脏胆汁酸合成,促进胆固醇分解代谢,是降胆固醇药物。胆汁酸隔离剂在临床试验中也能降低血糖,并被批准用于治疗2型糖尿病患者的高血糖。然而,介导胆汁酸螯合剂降血糖作用的机制仍不完全清楚。在这里,我们发现中草药治疗降低了西方饮食喂养的具有矛盾诱导的肝脏糖异生基因的小鼠的肝脏葡萄糖生成。半胱氨酸双加氧酶1型(CDO1)介导半胱氨酸转化为牛磺酸,其表达受胆汁酸抑制。我们发现,ChTM诱导肝脏CDO1并选择性地降低肝脏半胱氨酸可用性。敲低肝脏CDO1可增加小鼠肝脏半胱氨酸和葡萄糖的产生,而在缺乏半胱氨酸的培养基中培养的肝细胞显示葡萄糖产生减少。通过使用限制蛋白质和半胱氨酸修饰的西方饮食选择性地改变肝脏半胱氨酸利用率,我们发现肝脏半胱氨酸利用率的降低强烈抑制了小鼠的葡萄糖生成。有趣的是,长期限制饮食中的蛋白质也可以预防西方饮食引起的肥胖,这可以通过单独恢复饮食中的胱氨酸摄入量来完全逆转。一致地,半胱氨酸可用性降低剂量依赖性地抑制体外脂肪生成。总之,我们报道胆汁酸螯合剂的降血糖作用是通过cdo1诱导的肝脏半胱氨酸限制模拟效应介导的。此外,饮食蛋白质限制的抗肥胖作用主要是通过减少饮食中半胱氨酸的摄入量来调节的。
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引用次数: 0
Deleterious impacts of Western diet on jejunum function and health are reversible. 西方饮食对空肠功能和健康的有害影响是可逆的。
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-02-01 Epub Date: 2024-12-23 DOI: 10.1152/ajpgi.00160.2024
Sarah Carpinelli, John Ahlert, Maxwell Rubin, Alex Aratani, Emma Smith, Dana Floyd, Ross M Potter, Layla Al-Nakkash

The goal of this study was to determine whether the influence of a high-fat high-sugar diet (Western diet) on intestinal function and health was reversible. We measured transepithelial short circuit current (Isc), across freshly isolated segments of jejunum from male C57Bl/6J mice randomly assigned to one of the following groups for the study duration: high-fat high-sugar diet for 24 wk (HFHS), HFHS diet for 12 wk then switched to standard chow and water for a further 12 wk (Std), and lean controls (standard chow and water for 24 wk). At the completion of the study, segments of jejunum were frozen for Western blot determination of key proteins involved in secretory and absorptive functions, as well as senescence. Intestinal morphology was assessed. Serum and tissue assays were performed. Basal Isc was significantly decreased (by 42%, P < 0.05) in HFHS versus leans. This decrease in Isc was fully reversed by switching to Std diet. The HFHS-induced decrease in Isc was attributed to a significant loss of calcium-activated chloride channel (ClC2) expression. Changes in inflammatory state (TNF-α) and intestinal health [myeloperoxidase (MPO) activity] were associated with body weight changes. Our data suggests that the reduced basal jejunal Isc in HFHS mice is reversible. Better understanding of Western diet-mediated intestinal disturbances may permit for improved treatment options for gastrointestinal abnormalities in obese individuals.NEW & NOTEWORTHY Our data suggests that the reduced basal jejunal Isc (decreased secretory function) in Western diet-fed mice is reversible. A better understanding of Western diet-mediated intestinal disturbances may permit improved treatment options for gastrointestinal abnormalities in obese individuals.

背景:本研究的目的是确定高脂高糖饮食(西方饮食)对肠道功能和健康的影响是否可逆。方法:我们测量了雄性C57Bl/6J小鼠新鲜分离空肠段的经上皮短路电流(Isc),这些小鼠在研究期间随机分为以下组:高脂高糖饮食24周(HFHS), HFHS饮食12周,然后切换到标准食物和水12周(Std),瘦肉对照组(标准食物和水24周)。研究结束后,冷冻空肠各节段,western blot检测参与分泌和吸收功能以及衰老的关键蛋白。观察肠道形态。进行血清和组织分析。结果:基础Isc显著降低(降低42%),Psc完全逆转。hfhs诱导的Isc下降归因于ClC2表达的显著缺失。炎症状态(tnf - α)和肠道健康(MPO活性)的变化与体重变化有关。结论:我们的数据表明HFHS小鼠空肠基底区Isc减少是可逆的。更好地了解西方饮食介导的肠道紊乱可能有助于改善肥胖个体胃肠道紊乱的治疗选择。
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引用次数: 0
In silico integrative scRNA analysis of human colonic epithelium indicates four tuft cell subtypes. 人类结肠上皮细胞的硅学综合 scRNA 分析显示出四种簇细胞亚型。
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-02-01 Epub Date: 2024-11-26 DOI: 10.1152/ajpgi.00182.2024
Aydin I Herik, Sarthak Sinha, Rohit Arora, Caleb Small, Antoine Dufour, Jeff Biernaskie, Eduardo R Cobo, Derek M McKay

This study integrated and analyzed human single-cell RNA sequencing data from four publicly available datasets to enhance cellular resolution, unveiling a complex landscape of tuft cell heterogeneity within the human colon. Four tuft subtypes (TC1-TC4) emerged, as defined by unique gene expression profiles, indicating potentially novel biological functions. Tuft cell 1 (TC1) was characterized by an antimicrobial peptide signature; TC2 had an increased transcription machinery gene expression profile consistent with a progenitor-like cell; TC3 expressed genes related to ganglion (neuronal) development; and TC4 expressed genes related to tight junctions. Our analysis of subtype-specific gene expression and pathway enrichment showed variances in tuft cell subtypes between healthy individuals and those with inflammatory bowel disease (IBD). The frequency of TC1 and TC2 differed between healthy controls and IBD. Relative to healthy controls, TC1 and TC2 in IBD tissue showed an upregulation of gene expression, favoring increased metabolism and immune function. These findings provide foundational knowledge about the complexity of the human colon tuft cell population and hint at their potential contributions to gut health. They provide a basis for future studies to explore the specific roles these cells may play in gut function during homeostasis and disease. We demonstrate the value of in silico approaches for hypothesis generation in relation to the putative functions of low-frequency gut cells for subsequent physiological analyses.NEW & NOTEWORTHY This study reveals the nuanced and novel landscape of human colonic tuft cells through integrative scRNA-seq analysis. Four distinct tuft cell subtypes were identified, varying markedly between healthy and individuals with IBD. We uncovered human colonic tuft cell subtypes with unexpected antimicrobial and progenitor-like gene expression signatures. These insights into tuft cell diversity offer new avenues for understanding gut health and disease pathophysiology.

这项研究整合并分析了来自四个公开数据集的人类单细胞 RNA 测序数据,以提高细胞分辨率,从而揭示人类结肠内簇细胞异质性的复杂情况。根据独特的基因表达谱,出现了四种簇状细胞亚型(TC1-TC4),表明它们可能具有新的生物学功能。簇细胞 1(TC1)具有抗菌肽特征;TC2 的转录机制基因表达谱增加,与祖细胞样细胞一致;TC3 表达与神经节(神经元)发育相关的基因;TC4 表达与紧密连接相关的基因。我们对亚型特异性基因表达和通路富集的分析表明,健康人和炎症性肠病(IBD)患者的簇细胞亚型存在差异。TC1和TC2的频率在健康对照组和IBD之间存在差异。与健康对照组相比,IBD组织中的TC1和TC2表现出基因表达上调,有利于新陈代谢和免疫功能的增强。这些发现提供了有关人类结肠簇细胞群复杂性的基础知识,并暗示了它们对肠道健康的潜在贡献。它们为今后的研究奠定了基础,以探索这些细胞在肠道功能平衡和疾病期间可能发挥的特定作用。我们展示了硅学方法在生成与低频肠道细胞推测功能有关的假设以进行后续生理分析方面的价值。
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引用次数: 0
Rhamnogalacturonan promotes intestinal mucosal repair through increased cell migration. 鼠李糖半乳糖酸通过增加细胞迁移促进肠粘膜修复。
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-02-01 Epub Date: 2025-01-16 DOI: 10.1152/ajpgi.00170.2024
Cristiane H Baggio, Judie Shang, Larissa L Périco, Raquel C Dos Santos, Marilyn H Gordon, Bruna B Da Luz, Matthew Stephens, Adamara M Nascimento, Maria Fernanda P Werner, Pierre-Yves von der Weid, Thales R Cipriani, Wallace K MacNaughton

Mucosal healing is the primary goal for inflammatory bowel disease (IBD) treatment. We previously showed the direct beneficial effects of rhamnogalacturonan (RGal) on intestinal epithelial barrier function. Here, we aimed to evaluate the effect of RGal in intestinal epithelial wound healing. Confluent cancer cell lines and colonoid monolayers were wounded, treated with RGal for 48 h, and assessed using a live cell imaging system. Proliferation and apoptosis of cells were evaluated using 5-ethynyl-2'-deoxyuridine (EdU) and TUNEL assays, respectively. Inhibitors were used to determine the receptor and signaling pathways involved. Female and male mice with DSS-induced colitis were treated orally with RGal for 7 days during the recovery phase. RGal enhanced wound healing in Caco-2, T84, and primary cells by increasing cell migration. Inhibition of pretranscriptional signaling pathways FAK, Src, PI3K, Rho family, and JNK reversed the RGal-induced wound healing. RNAseq data from Caco-2 and primary cells treated with RGal showed the upregulation of the NF-κB pathway at 12 h. Actinomycin D, Bay 11-7082 or JSH-23, and NS-398 treatment significantly reversed the effect of RGal on wound healing, confirming that the response was also transcriptionally dependent and involved NF-κB signaling and downstream COX-2 protein activity. RGal treatment of male mice enhanced recovery from DSS colitis. RGal promoted wound healing in cancer and primary cells by increasing cell migration and accelerated epithelial mucosal healing in male mice. Our findings show a novel mechanism of action of RGal in wound healing that could help in mucosal healing and the resolution of intestinal inflammation.NEW & NOTEWORTHY RGal increases wound healing in colon cancer cell lines and primary cells through increased cell migration and participation of important pretranscriptional signaling pathways and the transcription factor NF-κB. In addition, RGal also accelerates intestinal mucosal healing of male mice with DSS-induced colitis.

粘膜愈合是炎症性肠病(IBD)治疗的主要目标。我们之前已经证明鼠李糖半乳酪酸酯(RGal)对肠上皮屏障功能有直接的有益作用。在这里,我们旨在评估RGal在肠上皮性伤口愈合中的作用。将融合癌细胞系和结肠膜损伤,用RGal处理48小时,并使用活细胞成像系统进行评估。分别用EdU和TUNEL法观察细胞增殖和凋亡情况。使用拮抗剂和抑制剂来确定受体和所涉及的信号通路。雌性和雄性dss诱导结肠炎小鼠在恢复期口服RGal 7天。RGal通过增加细胞迁移,促进Caco-2、T84和原代细胞的伤口愈合。抑制转录前信号通路FAK、Src、PI3K、Rho家族和JNK逆转rgal诱导的伤口愈合。RGal处理Caco-2和原代细胞的RNAseq数据显示,12 h时NF-κB通路上调。放线菌素D、Bay 11-7082或JSH-23和NS-398处理显著逆转了RGal对伤口愈合的作用,证实该反应也是转录依赖的,涉及NF-κB信号传导和下游COX-2蛋白活性。RGal治疗可促进雄性小鼠DSS结肠炎的恢复。在雄性小鼠中,RGal通过增加细胞迁移和加速上皮粘膜愈合来促进癌症和原代细胞的伤口愈合。我们的研究结果显示了RGal在伤口愈合中的一种新的作用机制,可以帮助粘膜愈合和肠道炎症的解决。
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American journal of physiology. Gastrointestinal and liver physiology
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