A Roadmap for the Human Gut Cell Atlas Zilbauer, Matthias; James, Kylie R; Kaur, Mandeep ...
Nature reviews. Gastroenterology & hepatology,
09/2023, Letnik:
20, Številka:
9
Journal Article
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The number of studies investigating the human gastrointestinal tract using various single-cell profiling methods has increased substantially in the past few years. Although this increase provides a ...unique opportunity for the generation of the first comprehensive Human Gut Cell Atlas (HGCA), there remains a range of major challenges ahead. Above all, the ultimate success will largely depend on a structured and coordinated approach that aligns global efforts undertaken by a large number of research groups. In this Roadmap, we discuss a comprehensive forward-thinking direction for the generation of the HGCA on behalf of the Gut Biological Network of the Human Cell Atlas. Based on the consensus opinion of experts from across the globe, we outline the main requirements for the first complete HGCA by summarizing existing data sets and highlighting anatomical regions and/or tissues with limited coverage. We provide recommendations for future studies and discuss key methodologies and the importance of integrating the healthy gut atlas with related diseases and gut organoids. Importantly, we critically overview the computational tools available and provide recommendations to overcome key challenges.
Immunometabolism considers the relationship between metabolism and immunity. Typically, researchers focus on either the metabolic pathways within immune cells that affect their function or the impact ...of immune cells on systemic metabolism. A more holistic approach that considers both these viewpoints is needed. On September 5–8, 2022, experts in the field of immunometabolism met for the Keystone symposium “Immunometabolism at the Crossroads of Obesity and Cancer” to present recent research across the field of immunometabolism, with the setting of obesity and cancer as an ideal example of the complex interplay between metabolism, immunity, and cancer. Speakers highlighted new insights on the metabolic links between tumor cells and immune cells, with a focus on leveraging unique metabolic vulnerabilities of different cell types in the tumor microenvironment as therapeutic targets and demonstrated the effects of diet, the microbiome, and obesity on immune system function and cancer pathogenesis and therapy. Finally, speakers presented new technologies to interrogate the immune system and uncover novel metabolic pathways important for immunity.
Immunometabolism considers the relationship between metabolism and immunity. Typically, researchers focus on either the metabolic pathways within immune cells that affect their function or the impact of immune cells on systemic metabolism. This report presents recent research across the field of immunometabolism, with the setting of obesity and cancer as an ideal example of the complex interplay between metabolism, immunity, and cancer.
Little is known about how interactions between diet, intestinal stem cells (ISCs) and immune cells impact early stage intestinal tumorigenesis. We show that a high fat diet (HFD) reduces the ...expression of the major histocompatibility complex II (MHC-II) genes in intestinal epithelial cells including ISCs. This decline in epithelial MHC-II expression in a HFD correlates with reduced intestinal microbiome diversity. Microbial community transfer experiments suggest that epithelial MHC-II expression is regulated by intestinal flora. Mechanistically, pattern recognition receptor (PRR) and IFNg signaling regulate epithelial MHC-II expression. MHC-II− ISCs exhibit greater tumor-initiating capacity than their MHC-II+ counterparts upon loss of the tumor suppressor Apc coupled with a HFD, suggesting a role for epithelial MHC-II-mediated immune surveillance in suppressing tumorigenesis. ISC-specific genetic ablation of MHC-II increases tumor burden in a cell autonomous manner. Thus, HFD perturbs a microbiome–stem cell-immune cell interaction that contributes to tumor initiation in the intestine.
The mechanisms that link pro-obesity high fat (HFD) diets to increased colon cancer risk are not well understood. Beyaz and colleagues demonstrate that a HFD promotes intestinal tumor initiation by suppressing a microbiome – stem cell – immune cell crosstalk that is mediated by MHC-II expression on intestinal stem cells.
A fundamental question in biology is to decipher how the same genomic information in an organism can give rise to diverse cellular states that are phenotypically and functionally distinct. Epigenetic ...mechanisms utilize genomic information to establish unique gene expression patterns that cells acquire in different fates during development or in response to environmental perturbations such as diet. Although it is understood that a particular cell fate-specific gene expression pattern relies on the establishment of a specific chromatin organization that is shaped by the activities of chromatin-modifying enzymes and transcription factors, the precise mechanisms that they employ for epigenetic regulation during cellular differentiation and in response to diet are unclear. Here, we dissect the mechanisms underlying epigenetic regulation of cell fate in two different models: regulation of iNKT cell development by the H3K27me3 histone demethylases and dietary regulation of intestinal stem cell fate. First, we interrogated the biological significance of H3K27me3 histone demethylases (UTX and JMJD3) during iNKT development. iNKT cells are innate-like lymphocytes that protect against infection, autoimmune disease, and cancer. We showed that the H3K27me3 histone demethylase UTX is an essential cell-intrinsic factor that controls an iNKT lineage specific gene expression program and epigenetic landscape in a demethylase activity dependent manner. UTX-deficient iNKT cells exhibited impaired expression of iNKT signature genes due to a decrease in activation-associated H3K4me3 and an increase in repressive H3K27me3 marks within the promoters that UTX occupies. Notably, we identified JunB as a novel regulator of iNKT development and showed that target genes of both JunB and iNKT master transcription factor PLZF are UTX-dependent. Moreover, we demonstrated that UTX-mediated regulation of super-enhancer accessibility is a key mechanism for iNKT lineage commitment. Altogether, these findings reveal how UTX regulates iNKT cell development through multiple epigenetic mechanisms. Second, we assessed the cellular and molecular mechanisms through which pro-obesity diets regulate tissue stem and progenitor cell function. We showed that high-fat diet (HFD)-induced obesity augments the numbers and function of Lgr5+ intestinal stem cells of the mammalian intestine. Mechanistically, we found that a HFD activated the lipid-sensing transcription factor peroxisome proliferator-activated receptor delta (PPAR-δ) in intestinal stem cells and progenitor cells (non-intestinal stem cells) and pharmacological activation of PPAR-δ recapitulated the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhanced the self-renewal potential of these organoid bodies in a PPAR-δ-dependent manner. Notably, HFD- and agonist-activated PPAR-δ signalling endowed organoid-initiating capacity to progenitors, and enforced PPAR-δ signalling permitted these progenitors to form in vivo tumors after loss of the tumor suppressor Apc. These findings highlight how diet-modulated PPAR-δ activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumors. Overall, these studies delineate the epigenetic mechanisms that control cell state-specific gene expression patterns through the regulation of transcription by histone-modifying enzymes and transcription factors.
Repeat concussions (or repetitive mild traumatic brain injury rmTBI) are complex pathological processes consisting of a primary insult and long-term secondary complications and are also a ...prerequisite for chronic traumatic encephalopathy (CTE). Recent evidence implies a significant role of autophagy-mediated dysfunctional mitochondrial clearance, mitophagy, in the cascade of secondary deleterious events resulting from TBI. C18-ceramide, a bioactive sphingolipid produced in response to cell stress and damage, and its synthesizing enzyme (CerS1) are precursors to selective stress-mediated mitophagy. A transporter, p17, mediates the trafficking of CerS1, induces C18-ceramide synthesis in the mitochondrial membrane, and acts as an elimination signal in cell survival. Whether p17-mediated mitophagy occurs in the brain and plays a causal role in mitochondrial quality control in secondary disease development after rmTBI are unknown. Using a novel repetitive less-than-mild TBI (rlmTBI) injury paradigm, ablation of mitochondrial p17/C18-ceramide trafficking in p17 knockout (KO) mice results in a loss of C18-ceramide-induced mitophagy, which contributes to susceptibility and recovery from long-term secondary complications associated with rlmTBI. Using a ceramide analog with lipid-selenium conjugate drug, LCL768 restored mitophagy and reduced long-term secondary complications, improving cognitive deficits in rlmTBI-induced p17KO mice. We obtained a significant reduction of p17 expression and a considerable decrease of CerS1 and C18-ceramide levels in cortical mitochondria of CTE human brains compared with age-matched control brains. These data demonstrated that p17/C18-ceramide trafficking is an endogenous neuroprotective mitochondrial stress response following rlmTBI, thus suggesting a novel prospective strategy to interrupt the CTE consequences of concussive TBI.
Administration of a single dose of anti-CD40L mAb at the time of allogeneic BM transplantation tolerizes peripheral alloreactive T cells and permits establishment of mixed hematopoietic chimerism in ...mice. Once engrafted, mixed chimeras are systemically tolerant to donor Ags through a central deletion mechanism and will accept any donor organ indefinitely. We previously found that the PD-1/PD-L1 pathway is required for CD8 T-cell tolerance in this model. However, the cell population that must express PD-1 and the role of other inhibitory molecules were unknown. Here, we report that LAG-3 is required for long-term peripheral CD8 but not CD4 T-cell tolerance and that this requirement is CD8 cell-extrinsic. In contrast, adoptive transfer studies revealed a CD8 T cell–intrinsic requirement for CTLA4/B7.1/B7.2 and for PD-1 for CD8 T-cell tolerance induction. We also observed that both PD-L1 and PD-L2 are independently required on donor cells to achieve T-cell tolerance. Finally, we uncovered a requirement for TGF-β signaling into T cells to achieve peripheral CD8 but not CD4 T-cell tolerance in this in vivo system.
Background & Aims: The colonic epithelium requires continuous renewal by crypt resident intestinal stem cells (ISCs) and transit-amplifying (TA) cells to maintain barrier integrity, especially after ...inflammatory damage. The diet of high-income countries contains increasing amounts of sugar, such as sucrose. ISCs and TA cells are sensitive to dietary metabolites, but whether excess sugar affects their function directly is unknown. Methods: Here, we used a combination of 3-dimensional colonoids and a mouse model of colon damage/repair (dextran sodium sulfate colitis) to show the direct effect of sugar on the transcriptional, metabolic, and regenerative functions of crypt ISCs and TA cells. Results: We show that high-sugar conditions directly limit murine and human colonoid development, which is associated with a reduction in the expression of proliferative genes, adenosine triphosphate levels, and the accumulation of pyruvate. Treatment of colonoids with dichloroacetate, which forces pyruvate into the tricarboxylic acid cycle, restored their growth. In concert, dextran sodium sulfate treatment of mice fed a high-sugar diet led to massive irreparable damage that was independent of the colonic microbiota and its metabolites. Analyses on crypt cells from high-sucrose–fed mice showed a reduction in the expression of ISC genes, impeded proliferative potential, and increased glycolytic potential without a commensurate increase in aerobic respiration. Conclusions: Taken together, our results indicate that short-term, excess dietary sucrose can directly modulate intestinal crypt cell metabolism and inhibit ISC/TA cell regenerative proliferation. This knowledge may inform diets that better support the treatment of acute intestinal injury.
In Fig. 4e of this Article, the labels for 'Control' and 'HFD' were reversed ('Control' should have been labelled blue rather than purple, and 'HFD' should have been labelled purple rather than ...blue). Similarly, in Fig. 4f of this Article, the labels for 'V' and 'GW' were reversed ('V' should have been labelled blue rather than purple, and 'GW' should have been labelled purple instead of blue). The original figure has been corrected online.
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