Succinate Produced by Intestinal Microbes Promotes Specification of Tuft Cells to Suppress Ileal Inflammation

Banerjee, Amrita; Herring, Charles A.; Chen, Bob; Kim, Hyeyon; Simmons, Alan J.; Southard-Smith, Austin N.; Allaman, Margaret M.; White, James R.; Macedonia, Mary Catherine; McKinley, Eliot T.; Ramirez‐Solano, Marisol; Scoville, Elizabeth; Liu, Qi; Wilson, Keith T.; Coffey, Robert J.; Washington, Mary Kay; Goettel, Jeremy A.; Lau, Ken S.

doi:10.1053/j.gastro.2020.08.029

Cited by 149 publications

(182 citation statements)

References 46 publications

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“…Although all three NM2 isoforms are detectable in the brush border proteome ( McConnell et al. , 2011 ), our analysis of recently generated single-cell RNAseq (scRNAseq) data from the intestinal tract ( Banerjee et al. , 2020 ; Southard-Smith et al.…”

Section: Resultsmentioning

confidence: 99%

Nonmuscle myosin-2 contractility-dependent actin turnover limits the length of epithelial microvilli

Chinowsky

Pinette

Meenderink

et al. 2020

MBoC

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Brush border microvilli enable functions that are critical for epithelial homeostasis, including solute uptake and host defense. However, mechanisms that regulate the assembly and morphology of these protrusions are poorly understood. The parallel actin bundles that support microvilli have their pointed-end rootlets anchored in a filamentous meshwork referred to as the “terminal web.” Although classic EM studies revealed complex ultrastructure, the composition and function of the terminal web remains unclear. Here we identify non-muscle myosin-2C (NM2C) as a component of the terminal web. NM2C is found in a dense, isotropic layer of puncta across the sub-apical domain, which transects the rootlets of microvillar actin bundles. Puncta are separated by ∼210 nm, the expected size of filaments formed by NM2C. In intestinal organoid cultures, the terminal web NM2C network is highly dynamic and exhibits continuous remodeling. Using pharmacological and genetic perturbations in cultured intestinal epithelial cells, we found that NM2C controls the length of growing microvilli by regulating actin turnover in a manner that requires a fully active motor domain. Our findings answer a decades old question on the function of terminal web myosin and hold broad implications for understanding apical morphogenesis in diverse epithelial systems. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]

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Section: Resultsmentioning

confidence: 99%

Nonmuscle myosin-2 contractility-dependent actin turnover limits the length of epithelial microvilli

Chinowsky

Pinette

Meenderink

et al. 2020

MBoC

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“…Collectively, intestinal tuft cells can be positively regulated by ILC2-derived IL-13 (Figure 2), leading to tuft cell expansion via activating crypt progenitor cells and thus directly regulating anti-helminth responses, raising the question whether this tuft cell-ILC2 circuit might play a role in IBD as well. Indeed, decreased tuft cell counts were recently described in CD patients at inflamed ileal tissue sites (99). Moreover, using a model of acute DSS colitis, a beneficial role of Dclk + tuft cells on intestinal barrier integrity was observed (100).…”

Section: Stem and Progenitor Cells-ilcsmentioning

confidence: 94%

“…In line with this, reduced IL-25 levels were found in the inflamed gut mucosa of IBD patients with active disease, which correlated with an increased disease severity ( 101 ), suggesting the loss of intestinal tuft cells and their IL-25 secretion as disease-driving factor in IBD. In the murine ileum, tuft cells could be reconstituted together with local ILC2 frequencies and classical type-2 cytokines by the administration of the microbiota-derived metabolite succinate, finally resolving ileal inflammation ( 99 ). This implies an in vivo relevance of the ILC2-driven tuft cell regulation upon intestinal inflammation in CD patients and might additionally explain the recently described protective role of helminth infections in the development of IBD ( 99 ).…”

Section: Ilc–iec Interactionsmentioning

confidence: 99%

“…In the murine ileum, tuft cells could be reconstituted together with local ILC2 frequencies and classical type-2 cytokines by the administration of the microbiota-derived metabolite succinate, finally resolving ileal inflammation ( 99 ). This implies an in vivo relevance of the ILC2-driven tuft cell regulation upon intestinal inflammation in CD patients and might additionally explain the recently described protective role of helminth infections in the development of IBD ( 99 ).…”

Section: Ilc–iec Interactionsmentioning

confidence: 99%

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Innate Lymphoid Cells as Regulators of Epithelial Integrity: Therapeutic Implications for Inflammatory Bowel Diseases

2021

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The occurrence of epithelial defects in the gut relevantly contributes to the pathogenesis of inflammatory bowel diseases (IBD), whereby the impairment of intestinal epithelial barrier integrity seems to represent a primary trigger as well as a disease amplifying consequence of the chronic inflammatory process. Besides epithelial cell intrinsic factors, accumulated and overwhelmingly activated immune cells and their secretome have been identified as critical modulators of the pathologically altered intestinal epithelial cell (IEC) function in IBD. In this context, over the last 10 years increasing levels of attention have been paid to the group of innate lymphoid cells (ILCs). This is in particular due to a preferential location of these rather newly described innate immune cells in close proximity to mucosal barriers, their profound capacity to secrete effector cytokines and their numerical and functional alteration under chronic inflammatory conditions. Aiming on a comprehensive and updated summary of our current understanding of the bidirectional mucosal crosstalk between ILCs and IECs, this review article will in particular focus on the potential capacity of gut infiltrating type-1, type-2, and type-3 helper ILCs (ILC1s, ILC2s, and ILC3s, respectively) to impact on the survival, differentiation, and barrier function of IECs. Based on data acquired in IBD patients or in experimental models of colitis, we will discuss whether the different ILC subgroups could serve as potential therapeutic targets for maintenance of epithelial integrity and/or mucosal healing in IBD.

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“…All publicly available datasets are listed in Supplementary Table 6, including the human colorectal carcinoma inDrop data deposited to the Gene Expression Omnibus (GEO) to accompany this manuscript (GSE158636). inDrop scRNA-seq data were generated with according to published protocols (Southard-Smith, et al 2020; Banerjee et al, 2020). The dropkick Python package is available for download via “pip” from the Python Package Index (PyPI) at https://pypi.org/project/dropkick/.…”

Section: Data and Code Availabilitymentioning

confidence: 99%

Automated quality control and cell identification of droplet-based single-cell data using dropkick

Heiser

Wang

Chen

et al. 2020

Preprint

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A major challenge for droplet-based single-cell sequencing technologies is distinguishing true cells from uninformative barcodes in datasets with disparate library sizes confounded by high technical noise (i.e. batch-specific ambient RNA). We present dropkick, a fully automated software tool for quality control and filtering of single-cell RNA sequencing (scRNA-seq) data with a focus on excluding ambient barcodes and recovering real cells bordering the quality threshold. By automatically determining dataset-specific training labels based on predictive global heuristics, dropkick learns a gene-based representation of real cells and ambient noise, calculating a cell probability score for each barcode. Using simulated and real-world scRNA-seq data, we benchmarked dropkick against a conventional thresholding approach and EmptyDrops, a popular computational method, demonstrating greater recovery of rare cell types and exclusion of empty droplets and noisy, uninformative barcodes. We show for both low and high-background datasets that dropkick’s weakly supervised model reliably learns which genes are enriched in ambient barcodes and draws a multidimensional boundary that is more robust to dataset-specific variation than existing filtering approaches. dropkick provides a fast, automated tool for reproducible cell identification from scRNA-seq data that is critical to downstream analysis and compatible with popular single-cell analysis Python packages.

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Succinate Produced by Intestinal Microbes Promotes Specification of Tuft Cells to Suppress Ileal Inflammation

Abstract: BASIC AND TRANSLATIONAL AT cell expansion reduced chronic intestinal inflammation in mice. Strategies to support tuft cells might be developed for treatment of CD.

Cited by 149 publications

References 46 publications

Nonmuscle myosin-2 contractility-dependent actin turnover limits the length of epithelial microvilli

Nonmuscle myosin-2 contractility-dependent actin turnover limits the length of epithelial microvilli

Innate Lymphoid Cells as Regulators of Epithelial Integrity: Therapeutic Implications for Inflammatory Bowel Diseases

Automated quality control and cell identification of droplet-based single-cell data using dropkick

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