Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gut. Although the precise cause of IBD remains unknown, the most accepted hypothesis of IBD pathogenesis to ...date is that an aberrant immune response against the gut microbiota is triggered by environmental factors in a genetically susceptible host. The advancement of next-generation sequencing technology has enabled identification of various alterations of the gut microbiota composition in IBD. While some results related to dysbiosis in IBD are different between studies owing to variations of sample type, method of investigation, patient profiles, and medication, the most consistent observation in IBD is reduced bacterial diversity, a decrease of Firmicutes, and an increase of Proteobacteria. It has not yet been established how dysbiosis contributes to intestinal inflammation. Many of the known IBD susceptibility genes are associated with recognition and processing of bacteria, which is consistent with a role of the gut microbiota in the pathogenesis of IBD. A number of trials have shown that therapies correcting dysbiosis, including fecal microbiota transplantation and probiotics, are promising in IBD.
Intestinal immune homeostasis is regulated by gut microbiota, including beneficial and pathogenic microorganisms. Imbalance in gut bacterial constituents provokes host proinflammatory responses ...causing diseases such as inflammatory bowel disease (IBD). The development of next-generation sequencing technology allows the identification of microbiota alterations in IBD. Several studies have shown reduced diversity in the gut microbiota of patients with IBD. Advances in gnotobiotic technology have made possible analysis of the role of specific bacterial strains in immune cells in the intestine. Using these techniques, we have shown that
Clostridium butyricum
as a probiotic induces interleukin-10-producing macrophages in inflamed mucosa via the Toll-like receptor 2/myeloid differentiation primary response gene 88 pathway to prevent acute experimental colitis. In this review, we focus on the new approaches for the role of specific bacterial strains in immunological responses, as well as the potential of bacterial therapy for IBD treatments.
The cancer stem cell (CSC) theory highlights a self-renewing subpopulation of cancer cells that fuels tumour growth. The existence of human CSCs is mainly supported by xenotransplantation of ...prospectively isolated cells, but their clonal dynamics and plasticity remain unclear. Here, we show that human LGR5
colorectal cancer cells serve as CSCs in growing cancer tissues. Lineage-tracing experiments with a tamoxifen-inducible Cre knock-in allele of LGR5 reveal the self-renewal and differentiation capacity of LGR5
tumour cells. Selective ablation of LGR5
CSCs in LGR5-iCaspase9 knock-in organoids leads to tumour regression, followed by tumour regrowth driven by re-emerging LGR5
CSCs. KRT20 knock-in reporter marks differentiated cancer cells that constantly diminish in tumour tissues, while reverting to LGR5
CSCs and contributing to tumour regrowth after LGR5
CSC ablation. We also show that combined chemotherapy potentiates targeting of LGR5
CSCs. These data provide insights into the plasticity of CSCs and their potential as a therapeutic target in human colorectal cancer.
Abstract
Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but ...the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8
+
tissue-resident memory CD8
+
T (CD8
+
Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69
+
CD103
−
CD8
+
Trm cell enrichment in NASH resolution livers. The reduction of liver CD8
+
Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8
+
Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69
+
CD8
+
Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8
+
Trm in fibrosis resolution.
Human colorectal tumors bear recurrent mutations in genes encoding proteins operative in the WNT, MAPK, TGF-β, TP53 and PI3K pathways. Although these pathways influence intestinal stem cell niche ...signaling, the extent to which mutations in these pathways contribute to human colorectal carcinogenesis remains unclear. Here we use the CRISPR-Cas9 genome-editing system to introduce multiple such mutations into organoids derived from normal human intestinal epithelium. By modulating the culture conditions to mimic that of the intestinal niche, we selected isogenic organoids harboring mutations in the tumor suppressor genes APC, SMAD4 and TP53, and in the oncogenes KRAS and/or PIK3CA. Organoids engineered to express all five mutations grew independently of niche factors in vitro, and they formed tumors after implantation under the kidney subcapsule in mice. Although they formed micrometastases containing dormant tumor-initiating cells after injection into the spleen of mice, they failed to colonize in the liver. In contrast, engineered organoids derived from chromosome-instable human adenomas formed macrometastatic colonies. These results suggest that 'driver' pathway mutations enable stem cell maintenance in the hostile tumor microenvironment, but that additional molecular lesions are required for invasive behavior.
Neuroimmune crosstalk in the gut and liver Teratani, Toshiaki; Mikami, Yohei; Kanai, Takanori
International immunology,
09/2022, Letnik:
34, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Abstract
It has long been assumed that the nervous system exerts distinct effects on immune functions, given the large number of immune disorders that are affected by mental stress. In fact, many ...different immune cells have been shown to possess a wide variety of neurotransmitter receptors and receive signals from various neurotransmitters, including acetylcholine and noradrenaline. Compared with the findings on local neuroimmune interactions, limited experimental techniques have so far failed to capture a comprehensive overview of neuroimmune interactions between distant organs and the autonomic nervous system in vivo, and the molecular mechanisms underlying local immune regulation of the nervous system have long remained unclear. However, the recent rapid progress in genetic recombination, microscopy and single-cell analysis has deepened our understanding of the anatomical and physiological functions of peripheral nerves at each organ to which they belong. Furthermore, the development of optogenetic and chemogenetic methods has enabled the artificial modulation of specific neuronal activities, and there has been remarkable progress in elucidation of the interaction between nerves and immune cells in vivo, particularly in barrier organs such as the gastrointestinal tract, respiratory tract and skin. This review focuses on the immunoregulatory mechanisms governed by the autonomic nervous system and outlines the latest findings in the regulation of enteric and hepatic immunity by the nervous system.
Graphical Abstract
Graphical Abstract
The liver is the largest organ in the human body and is responsible for the metabolism and storage of the three principal nutrients: carbohydrates, fats, and proteins. In addition, the liver ...contributes to the breakdown and excretion of alcohol, medicinal agents, and toxic substances and the production and secretion of bile. In addition to its role as a metabolic centre, the liver has recently attracted attention for its function in the liver-brain axis, which interacts closely with the central nervous system via the autonomic nervous system, including the vagus nerve. The liver-brain axis influences the control of eating behaviour in the central nervous system through stimuli from the liver. Conversely, neural signals from the central nervous system influence glucose, lipid, and protein metabolism in the liver. The liver also receives a constant influx of nutrients and hormones from the intestinal tract and compounds of bacterial origin via the portal system. As a result, the intestinal tract and liver are involved in various immunological interactions. A good example is the co-occurrence of primary sclerosing cholangitis and ulcerative colitis. These heterogeneous roles of the liver-brain axis are mediated via the vagus nerve in an asymmetrical manner. In this review, we provide an overview of these interactions, mainly with the liver but also with the brain and gut.
This article is part of the special Issue on ‘Cross Talk between Periphery and the Brain’.
•The autonomic nervous system regulates glucose and lipid metabolism.•Asymmetries in the vagus nerve regulate multimodal intestinal functions.•The liver and brain bidirectionally communicate via humoral and neural networks.•The liver-brain axis regulates intestinal homeostasis.
Indole compounds are extracted from indigo plants and have been used as blue or purple dyes for hundreds of years. In traditional Chinese medicine, herbal agents in combination with Qing-Dai (also ...known as indigo naturalis) have been used to treat patients with ulcerative colitis (UC) and to remedy inflammatory conditions. Recent studies have noted that indole compounds can be biosynthesized from tryptophan metabolites produced by various enzymes derived from intestinal microbiota. In addition to their action on indole compounds, the intestinal microbiota produce various tryptophan metabolites that mediate critical functions through distinct pathways and enzymes. Furthermore, some indole compounds, such as indigo and indirubin, act as ligands for the aryl hydrocarbon receptor. This signaling pathway stimulates mucosal type 3 innate lymphoid cells to produce interleukin-22, which induces antimicrobial peptide and tight junction molecule production, suggesting a role for indole compounds during the mucosal healing process. Thus, indole compounds may represent a novel treatment strategy for UC patients. In this review, we describe the origin and function of this indole compound-containing Chinese herb, as well as the drug development of indole compounds.
Colorectal tumor is a heterogeneous disease, with varying clinical presentation and prognosis in patients. To establish a platform encompassing this diversity, we generated 55 colorectal tumor ...organoid lines from a range of histological subtypes and clinical stages, including rare subtypes. Each line was defined by gene expression signatures and optimized for organoid culture according to niche factor requirements. In vitro and in xenografts, the organoids reproduced the histopathological grade and differentiation capacity of their parental tumors. Notably, we found that niche-independent growth is predominantly associated with the adenoma-carcinoma transition reflecting accumulation of multiple mutations. For matched pairs of primary and metastatic organoids, which had similar genetic profiles and niche factor requirements, the metastasis-derived organoids exhibited higher metastatic capacity. These observations underscore the importance of genotype-phenotype analyses at a single-patient level and the value of our resource to provide insights into colorectal tumorigenesis and patient-centered therapeutic development.
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•An organoid library with diverse colorectal tumor grades and subtypes was established•A refined culture method improves colorectal tumor organoid establishment efficiency•Tumor organoids faithfully recapitulate clinical phenotypes of patient tumors•Niche factor dependency decreases along with adenoma-carcinoma transition
Fujii et al. generated a comprehensive organoid library from colorectal cancer patients. Each organoid line was characterized by gene expression and as xenografts recapitulating the original clinical phenotype. By optimizing niche factor requirements and derivation efficiency, they were able to encompass a range of clinical stages and rare subtypes and reveal that niche-independent growth is progressively associated with the adenoma-carcinoma transition.
Abstract
The pathophysiology of inflammatory bowel diseases (IBDs) involves immunological, genetic and environmental factors. Through its ability to sense environmental stimuli, the autonomic nervous ...system plays a key role in the development and persistence of IBDs. The vagus nerve (VN), which contains sensory and motor neurons, travels throughout the body to innervate the gut and other visceral organs in the thoracic and abdominopelvic cavities. Recent studies show that the VN has anti-inflammatory effects via the release of acetylcholine, in what is known as the cholinergic anti-inflammatory pathway (CAIP). In the gut immune system, the CAIP is proposed to be activated directly by signals from the gut and indirectly by signals from the liver, which receives gut-derived bioactive substances via the portal vein and senses the status of the gut. The gut–brain axis and liver–brain–gut reflex arc regulate a wide variety of peripheral immune cells to maintain homeostasis in the gut. Therefore, targeting the neural reflex by methods such as VN stimulation is now under investigation for suppressing intestinal inflammation associated with IBDs. In this review, we describe the role of the VN in the regulation of intestinal immunity, and we discuss novel therapeutic approaches for IBDs that target neuroimmune interactions.
Regulation of intestinal immunity by the vagus nerve
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