Biology subjects

Ho, G.-T.

Publications and source records attributed to Ho, G.-T..

5 recordsLinked to original sources

bioRxiv2025

Tissue resident colonic macrophages persist through acute inflammation and adapt to aid tissue repair

Macrophages are crucial for the maintenance of intestinal homeostasis, are considered key proinflammatory effector cells during intestinal inflammation and are implicated in tissue repair following injury or inflammation. Whether these roles are attributed to distinct subsets of macrophages or if macrophages retain a degree of plasticity in the intestine remains poorly understood. Here, through a combination of single cell RNA sequencing, lineage-tracing and immunofluorescence imaging, we define three major subpopulations of murine, colonic macrophages on the basis of CD11c and CD163 expression. These macrophages occupy discrete anatomical niches and display distinct replenishment kinetics. They all accumulate during acute colitis and Cx3cr1-based fate mapping shows that they persist through to inflammation resolution. Moreover, marked transcriptional differences exist between the macrophages present in health and their counterparts in the post-inflammation environment, demonstrating that inflammation leads to transcriptional rewiring of the resident macrophages in a subset-specific manner. Intriguingly, there were minimal transcriptional changes between long-lived macrophages and their recently differentiated counterparts, indicating the environment exerted a greater influence than ontogeny or the time of residency on their functional states in resolution.

immunology↗

bioRxiv2025

Loss of HMGCS2-mediated intestinal stem cell ketogenesis is a metabolic barrier to mucosal healing in Ulcerative colitis

Human colonic epithelial cells express high levels of 3-Hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the crucial mitochondrial enzyme responsible for the production ketone bodies, predominantly beta-hydroxybutyrate ({beta}HB). Ketogenesis is an important metabolic pathway responsible for energy production in states of fasting and in the intestine ketone bodies are also important in regulating intestinal stem cell (ISC) homeostasis and regeneration. Using combined single-cell and spatial transcriptomics, organoids and prospective longitudinal mucosal analysis, we demonstrated a profound loss of ISC HMGCS2-mediated ketogenesis with consequential detrimental effect on Ulcerative colitis (UC), a chronic inflammatory bowel disease that affects [~]4 million individuals worldwide. We show that {beta}HB restores UC ISC metabolic function, reduces cellular stress with further evidence of epigenetic programming key for restoration of ISC function. Furthermore, low colonic HMGCS2 expression is associated with treatment failure of multiple biological immune therapies in UC. Our findings reveal the crucial role for HMGCS2 and loss of ketogenesis as the tipping point for pathogenic epithelial dysfunction and importantly, a promising metabolic therapeutic target for UC.

cell biology↗

bioRxiv2025

DYNAMIC CHANGES TO THE INTESTINAL ENVIRONMENT OCCUR THROUGHOUT RECOVERY FROM EXPERIMENTAL ISCHAEMIC STROKE

Stroke survivors experience a plethora of complications during recovery, including gastrointestinal symptoms. Intestinal dysfunction is reported to occur rapidly following stroke in both humans and animal models and alterations such as reduced barrier integrity, lymphocyte loss, and an altered microbiota have been suggested to contribute to poor neurological outcomes. Despite the persistence of gastrointestinal symptoms in many stroke survivors, how the intestinal environment changes over the course of stroke recovery remains poorly understood. Here, we use an experimental model of ischemic stroke to profile the gastrointestinal tract over a three month period of recovery.We have shown that experimental stroke leads to structural alterations to the colon, impaired transit times and an altered bacterial community composition. No impairments to barrier function were detected at any time point and transit times recover within 2 weeks post stroke. In contrast, structural and bacterial community alterations remain up to 3 months post stroke and are accompanied by abnormalities that develop only during chronic recovery, such as altered antibody coating of bacteria. These results suggest that the gastrointestinal system is dynamically altered over the course of experimental stroke recovery and that certain defects persist chronically after stroke.

immunology↗

bioRxiv2024

Inflammation-associated monocytes express ACOD1 to curtail inflammatory behaviour in IBD and experimental colitis

Monocytes are essential for replenishing homeostatic macrophages in the intestine. However, they also accumulate in significant numbers when intestinal homeostasis is disrupted in diseases, such as inflammatory bowel disease (IBD). The molecular pathways governing monocyte behaviour across these different contexts remain poorly understood. Here, we profile the monocyte / macrophage compartment in human IBD using single-cell RNA sequencing and identify a discrete population of monocytes that accumulate in IBD, which we term inflammation associated monocytes (IAMs). These can be identified by the expression of CD319, CD274 and CCRL2, and demonstrate increased expression of IBD susceptibility genes. By performing cross-species analysis, we show an analogous population of IAMs accumulate during chemically induced colitis in mice. Using transgenic fate mapping approaches, we show these cells likely derive from a discrete precursor in the bone marrow (BM) and are locally imprinted to produce heightened IL-1{beta} and TNF in mouse and humans. Importantly, we show that co-incident with a hyper-inflammatory phenotype, these same cells uniquely and specifically express aconitate decarboxylase (ACOD1) in response to local Toll-like receptor (TLR) and interferon (IFN) receptor signalling, to limit unrestricted cytokine production. Thus, the intestinal environment after injury instructs both inflammation and recovery specifically within a transitioning population of monocytes that are absent in health.

immunology↗

bioRxiv2020

Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease.

BackgroundSuccess in personalised medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay (PEA) to identify diagnostic and prognostic biomarkers in inflammatory bowel disease (IBD). MethodsWe conducted a prospective case-control study in an inception cohort of 552 patients (328 IBD, 224 non-IBD), profiling proteins recruited across 6 centres. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross validation was used to examine the performance of diagnostic and prognostic proteins. ResultsA total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls including Matrix Metalloproteinase-12 (Holm adjusted p=4.1x10-23) and Oncostatin-M (OSM, p=3.7x10-16). Nine of these proteins associate with cis- germline variation (59 independent SNPs). Fifteen proteins, all members of TNF independent pathways including interleukin-1 and OSM predicted escalation, over a median follow-up of 518 (IQR 224-756) days. Nested cross-validation of the entire data set allows characterisation of 5-protein-models (96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7, and IL8) which define a high-risk subgroup in IBD (HR 3.90, 95% CI: 2.43-6.26), or allows distinct 2, and 3 protein models for UC and CD respectively. ConclusionWe have characterised a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and predicts the evolution of disease over time. The technology could be suitable as a point of care testing in defining risk. Further prospective work is required to characterise the utility of the approach.

immunology↗