Monocyte-derived macrophages (Mφs) are crucial regulators during muscularis inflammation. However, it is unclear which micro-environmental factors are responsible for monocyte recruitment and anti-inflammatory Mφ differentiation in this paradigm. Here, we investigate Mφ heterogeneity at different stages of muscularis inflammation and determine how environmental cues can attract and activate tissue-protective Mφs. Results showed that muscularis inflammation induced marked alterations in mononuclear phagocyte populations associated with a rapid infiltration of Ly6c+ monocytes that locally acquired unique transcriptional states. Trajectory inference analysis revealed two main pro-resolving Mφ subpopulations during the resolution of muscularis inflammation, i.e. Cd206+ MhcIIhi and Timp2+ MhcIIlo Mφs. Interestingly, we found that damage to the micro-environment upon muscularis inflammation resulted in EGC activation, which in turn stimulated monocyte infiltration and the consequent differentiation in anti-inflammatory CD206+ Mφs via CCL2 and CSF1, respectively. In addition, CSF1-CSF1R signaling was shown to be essential for the differentiation of monocytes into CD206+ Mφs and EGC proliferation during muscularis inflammation. Our study provides a comprehensive insight into pro-resolving Mφ differentiation and their regulators during muscularis inflammation. We deepened our understanding in the interaction between EGCs and Mφs, thereby highlighting pro-resolving Mφ differentiation as a potential novel therapeutic strategy for the treatment of intestinal inflammation.

The gastrointestinal tract harbors a complex resident microbial ecosystem, comprising over 500 species, spanning commensals, mutualist, opportunistic, and professional pathogens thriving on undigested food components originating from the diet and endogenous secretions. Despite this high concentration of food and bacterial antigens, a healthy gut has a near absent level of inflammation, a status called intestinal immune homeostasis. This immune homeostasis is built and maintained in the presence, and interestingly, with cooperation of the microbiota. The microbiota ferments undigested food components into a wide variety of metabolites, some of which interact with the intestinal immune system. In particular short‐chain fatty acids, aryl hydrocarbon receptor ligands, and bile acid metabolites have been involved in the induction of intestinal immune homeostasis. The production of these metabolites is influenced by the microbial load and community structure, as well as the availability of substrates and the gut environment which are directly or indirectly modulated by food intake. In this manuscript, the factors that influence the production of these metabolites and their interaction with the immune cells that play key roles in maintaining intestinal immune homeostasis in the healthy gut are reviewed.

Diverticulosis is the presence of small, bulging pouches in the lining of the intestinal colonic mucosal and submucosal layers. This condition is usually asymptomatic. The few patients (25%) that do develop abdominal symptoms are diagnosed with symptomatic uncomplicated diverticular disease (SUDD). Up to now it is not clear which pathophysiological events trigger the transition from asymptomatic diverticulosis to SUDD. However, data from Barbaro and colleagues published in the current issue of Neurogastroenterology and Motility showed extensive axonal sprouting and increased macrophage infiltration in SUDD compared to asymptomatic diverticulosis patients. Thereby they provide more evidence suggesting that enteric neuro‐plasticity, whether or not affected by infiltrating macrophages, may underlie the development of symptoms in diverticulosis.

Enteric glial cells (EGCs) have been recently recognized as key components of the colonic tumor microenvironment (TME) indicating their potential role in colorectal cancer (CRC) pathogenesis. Although EGCs modulate immune responses in other intestinal diseases, their interaction with the CRC immune cell compartment remains unclear. Through a combination of single-cell and bulk RNA sequencing, both in CRC murine models and patients, we found that EGCs acquire a reactive and immunomodulatory phenotype that drives tumor-associated macrophage (TAM) differentiation. Tumor-infiltrating monocytes direct CRC EGC phenotypic and functional switch via IL-1R signaling pathway. In turn, tumor EGCs promote monocyte differentiation towards pro-tumorigenic SPP1+ TAMs via secretion of IL-6. Finally, the distinct tumor EGC phenotype correlates with worse disease outcome in patients suffering from CRC. Our study reveals a previously unexplored and crucial neuroimmune interaction between EGCs and TAMs in the colorectal TME, providing important insights into CRC pathogenesis.

Crohn's disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibro-stenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate complex intercellular interactions leading to fibro- stenosis in CD, we analysed the transcriptome of cells isolated from the transmural ileum of CD patients, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from non-CD patients. Our computational analysis revealed that pro-fibrotic signals from a subset of monocyte-derived cells expressing CD150 induce a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. The transcription factor TWIST1 was identified as a key modulator of fibroblast activation and extracellular matrix (ECM) production. Therapeutic inhibition of TWIST1 inhibits fibroblast activation, reducing ECM production and deposition. These findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibro- stenosis in CD.