Cross-talk between the gut microbiota and monocyte-like macrophages mediates an inflammatory response to promote colitis-associated tumourigenesis

Abstract

ObjectiveMacrophages are among the most abundant cells in the colon tumour microenvironment, and there is a close relationship among monocytes, macrophages and the gut microbiota. Alterations in the gut microbiota are involved in tumour development, but the underlying mechanisms remain unclear. We aim to elucidate the temporal changes in macrophage subsets and functions, and how these dynamics are regulated by microbial cues in the initiation of colitis-associated cancer.DesignA mouse model of colitis-associated tumourigenesis was established to determine macrophage dynamics. The role of monocyte-like macrophage (MLM) was confirmed by targeting its chemotaxis. The effects of the gut microbiota were assessed by antibiotic treatment and faecal microbiota transplantation.ResultsA selective increase in MLMs was observed in the initial stages of colitis-associated cancer, with an enhanced secretion of inflammatory cytokines. MLM accumulation was regulated by CCL2 expression of colonic epithelial cells, which was influenced by bacteria-derived lipopolysaccharide (LPS). LPS further stimulated interleukin 1β production from MLMs, inducing interleukin-17-producing T-helper cell activation to promote inflammation. These observations were also supported by altered microbial composition associated with human colitis and colorectal cancer, evolving transcriptional signature and immune response during human colitis-associated tumourigenesis.ConclusionsThe gut microbiota uses LPS as a trigger to regulate MLM accumulation in a chemokine-dependent manner and generate a precancerous inflammatory milieu to facilitate tumourigenesis.

Ramulus Mori (Sangzhi) Alkaloids (SZ-A) Ameliorate Glucose Metabolism Accompanied by the Modulation of Gut Microbiota and Ileal Inflammatory Damage in Type 2 Diabetic KKAy Mice

“…LPS production is also responsible for inducing monocyte-and macrophage-mediated inflammation in the intestine (Wang et al, 2020). Gut macrophages, which reside in the connective tissue underlying the gut epithelium, the lamina propria, are considered key players for the maintenance of intestinal homeostasis and inflammation (Yang et al, 2020). We observed that in ileal tissues, the percentage of macrophages (CD11c + /F4/80 + ) and the cell mass of CD11c-positive monocytes were significantly decreased with both doses of SZ-A compared with the control (Figure 4F).…”

Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer

“…The overall importance of TLR4 signaling on acute colitis and CAC development has been intensely studied in murine models using TLR4 -/mice and TLR4 inhibitors, such as TAK-242 or antagonist TLR4 antibodies (15,24,35). Although complete deletion of TLR4 in TLR4 -/mice did not protect from severe DSS-induced inflammation (36), the specific lack of TLR4 signaling on colonic epithelial cells inhibited CAC development, as well as recruitment and activation of Cyclooxygenase (Cox)-2 expressing macrophages in the AOM/ DSS model (14,16).…”

“…As macrophages are the immune cells in the lamina propia with the strongest TLR4 expression, we further investigated the impact of TAK-242 and Abx treatment on macrophages. Of note, CAC is associated with a strong infiltration of myeloid cells into the lamina propia (24). Mice suffering from AOM/DSS induced CAC exhibited higher LPMCs counts than ctrl mice.…”

YYFZBJS Inhibits Colorectal Tumorigenesis by Remodeling Enterotoxigenic Bacteroides Fragilis Mediated M2 Macrophage Polarization in Vivo and in Vitro

“…Accumulating data also indicated that the percentage of M2 macrophage is inversely related to increasing the risk for the progression of cancer [46,47]. For CRC patients, increased numbers of M2 macrophage had been found in peripheral blood, tumor-draining lymph node (DLN), and tumor microenvironment [48].…”