Abstract
Chronic low-grade inflammation is widely involved in the development and progression of metabolic syndrome, which can lead to type 2 diabetes mellitus (T2DM). Dysregulation of proinflammatory and anti-inflammatory cytokines not only impairs insulin secretion by pancreatic β-cells but also results in systemic complications in late diabetes. In our previous work, metabolites produced by Paenibacillus bovis sp. nov. BD3526, which were isolated from Tibetan yak milk, demonstrated antidiabetic effects in Goto–Kakizaki (GK) rats. In this work, we used single-cell RNA sequencing (scRNA-seq) to further explore the impact of BD3526 metabolites on the intestinal cell composition of GK rats. Oral administration of the metabolites significantly reduced the number of adipocytes in the colon tissue of GK rats. In addition, cluster analysis of immune cells confirmed that the metabolites reduced the expression of interleukin (IL)-1β in macrophages in the colon and increased the numbers of dendritic cells (DCs) and regulatory T (Treg) cells. Further mechanistic studies of DCs confirmed that activation of the WNT/β-catenin pathway in DCs promoted the expression of IL-10 and transforming growth factor (TGF)-β, thereby increasing the number of Treg cells.
Highlights
Chronic low-grade inflammation is typical of metabolic syndromes such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) (Ridker et al, 1997; Ridker, 2000; Pradhan et al, 2001; Tilg and Moschen, 2008; Donath and Shoelson, 2011; Hotamisligil, 2017)
The BD3526 metabolites were added at a ratio of 5% (v/v) to Caco-2 cells that had been cultured for 4 days; addition of 10% sterile skim milk was used as a negative control
Gene Ontology (GO) analysis of these differentially expressed genes (DEGs) showed that some of the GO classifications that were enriched in the DEGs were related to cellular immunity; these GO classifications included IL-1 receptor binding, CXCR chemokine receptor binding, type I interferon biosynthesis process, and regulation of the IL-6 biosynthetic process (Figure 1C)
Summary
Chronic low-grade inflammation is typical of metabolic syndromes such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) (Ridker et al, 1997; Ridker, 2000; Pradhan et al, 2001; Tilg and Moschen, 2008; Donath and Shoelson, 2011; Hotamisligil, 2017). During chronic low-grade inflammatory reactions, proinflammatory cytokines such as interleukin (IL)1β, tumor necrosis factor (TNF)-α, and IL-6 are highly expressed (Ostermann et al, 2019). These cytokines can decrease the stability of the tissue microenvironment and induce the differentiation of immune cells, thereby aggravating disease symptoms. DCs induce the differentiation of Treg cells by promoting the activity of the WNT/β-catenin pathway, and this results in tolerance to the inflammatory response in the intestine and in a reduction in chronic inflammation in the intestine (Manicassamy et al, 2010)
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