Cartoon adapted from Clark I. 2021 and Muus C. 2021, created using BioRender.

ENTERIC NERVOUS SYSTEM AND NEURO-IMMUNE INTERACTION

Our group investigates the gut–brain axis and neuroimmunology, focusing on regional coding of the enteric nervous system (ENS), neuro–innate immune crosstalk, and multiscale regulation of inflammation. We developed dedicated enteric neuroscience platforms—including RAISIN-V2-Seq and in vivo ENS Perturb-seq—and integrated them with STARmap PLUS spatial transcriptomics (Nature, 2023) to map gut–brain circuitry and resolve in situ cellular communication in health and disease. Using this framework, we generated the first multidimensional single-cell atlas of enteric neurons across intestinal segments, microbiota states, and inflammatory conditions (Science, 2025; FASI media report “Gut Neurons Decoded”), redefining ENS regional specialization and neuro-immune interactions. We further identified progenitor-like enteric neurons in adult mice and uncovered microbiota- and inflammation-driven cell-state transitions regulated by Edf1 and Mitf, linking neuronal plasticity to gut physiology and site-specific intestinal pathogenesis.

INNATE SENSING AGAINST GUT PATHOGENS

Innate immunity constitutes the first line of defense against enteric pathogens, activated by PRRs (including cGAS, RIG-I, NOD, and inflammasomes) that sense PAMPs and DAMPs, with membrane-bound organelles acting as platforms for innate immune signaling. We developed an organelle-specific proximity labeling technique (Nature Cell Biology, 2015) and identified two TRIM14-centered complexes mediating spatiotemporal type I IFN signaling: the autophagosomal TRIM14–USP14 complex stabilizes cGAS against DNA viruses (Molecular Cell, 2016), and the mitochondrial WHIP–TRIM14–PPP6C complex regulates RIG-I trafficking and activation in RNA virus defense (Molecular Cell, 2017). Using scRNA-seq, we further analyzed SARS-CoV-2 entry receptors (ACE2, TMPRSS2, CTSL) and revealed their expression correlations with age and smoking, while uncovering immune networks and drug targets for COVID-19 and ARDS (Nature Medicine, 2021).

GASTROINTESTINAL TUMOR MICROENVIRONMENT

The tumor microenvironment (TME) comprises cancer cells and non-malignant components including myeloid cells, neurons, stromal cells, adipocytes and microbes, yet key questions remain regarding its spatiotemporal formation, cellular recruitment and remodeling, immune checkpoint regulation underlying T-cell evasion, and microbiome functions in tumorigenesis. We identified Beclin-1 as a neutrophil-specific immune checkpoint in pre B-ALL (JCI, 2019), supporting the clinical correlation between neutrophil infiltration and poor cancer prognosis. Targeting neutrophils and the Beclin-1–IL-21 axis represents a novel strategy to complement CAR-T therapy, which is often hindered by CD19/CD20 loss in B-ALL. Furthermore, using a myeloid-specific Tak1-deficient mouse model, we discovered that Odoribacter splanchnicus drives Th17 accumulation via IL-1β/IL-6 to suppress colitis and colon cancer, revealing a microbiota-mediated mechanism in intestinal tumorigenesis (Cell Host & Microbe, 2021).

OPTOGENETICS IN GUT BIOLOGY AND DISEASES

We have developed a suite of genetically encoded optogenetic tools paired with upconversion nanoparticles for deep-tissue, long-range light-mediated targeted regulation —— OptoCRAC, LiCa, OptoPB, Sunbody and Moonbody, PhotoSMOC, OptoCAR, pNUTs—— to begin to decode the core logic of calcium-dependent immune activation, membrane-contact site dynamics，type I IFN signaling, intrabody mechanism，liquid-liquid phase separation and nucleolar compartmentation, CAR-T activation (eLife, 2015; Trends in Biotechnology, 2017; Chemical Science, 2017; Advanced Biology, 2021; Nature Communications, 2021; Nature Chemical Biology, 2021; Nucleic Acids Research, 2022), fundamental to understanding gut neuroimmunology. Our pioneering work in optogenetics has led to an invited review on optogenetics and cell physiology in Physiological Reviews, 2022.