L-Cells are the Functional Neuropod Cell in Human Gastrointestinal Tract and are Dysregulated in Inflammatory Bowel Disease (IBD)

Neuropod cells are a newly discovered type of enteroendocrine cell (EEC) that connect the gut and brain functionally into one circuit. In the mouse colon, neuropod cells express various peptide hormones, such as Pyy and Glp1, presynaptic proteins, and make synaptic contacts with sensory neurons. While their function is not fully elucidated, they play a significant role in relaying signals to the brainstem upon sensing nutrients and microbial factors in the gut lumen. Their occurrence in the human gastrointestinal tract is currently not established. In this study, we showed that PYY-expressing cells (L-cells) in the human colon exhibit characteristics of neuropod cells. Utilizing advanced histological methods and confocal microscopy we found that L-cells of the healthy human colon possess distinctive morphology, express synaptic proteins, and exist proximal to sensory neurons. This agrees with our meta-analysis of single-cell RNA sequencing (scRNA-Seq) data that showed that human colonic L-cells express pre- and post-synaptic genes. As inflammatory conditions could affect colonic neuropod cells, we aimed to profile the phenotypic and transcriptional changes of neuropod cells both in human and murine colon in Inflammatory Bowel Disease (IBD) and experimental colitis, respectively. In human IBD, the abundance of neuropod cells and spatial proximity to sensory neurons were decreased in the colon of ulcerative colitis (UC) and Crohns disease (CD) patients. L-cells in IBD patients display genes related to innate and adaptive immunity, including antigen presentation genes suggesting a role in immune regulation. We further confirmed the effects of intestinal inflammation in neuropod cells by utilizing the DSS mouse model of colitis, where we showed that acute DSS colitis induced spatially distinct effects on the abundance of neuropod cells and impaired the synaptic connection with sensory neurons. Overall, these findings extend early murine characterizations to the human system and highlight the complex interactions between colonic neuropod cells and the enteric nervous and immune systems during inflammatory diseases.