Angiogenesis, a key point in the association of gut microbiota and its metabolites with disease

Abstract

The gut microbiota is a complex and dynamic ecosystem that plays a crucial role in human health and disease, including obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, inflammatory bowel disease, and cancer. Chronic inflammation is a common feature of these diseases and is closely related to angiogenesis (the process of forming new blood vessels), which is often dysregulated in pathological conditions. Inflammation potentially acts as a central mediator. This abstract aims to elucidate the connection between the gut microbiota and angiogenesis in various diseases. The gut microbiota influences angiogenesis through various mechanisms, including the production of metabolites that directly or indirectly affect vascularization. For example, short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate are known to regulate immune responses and inflammation, thereby affecting angiogenesis. In the context of cardiovascular diseases, the gut microbiota promotes atherosclerosis and vascular dysfunction by producing trimethylamine N-oxide (TMAO) and other metabolites that promote inflammation and endothelial dysfunction. Similarly, in neurodegenerative diseases, the gut microbiota may influence neuroinflammation and the integrity of the blood-brain barrier, thereby affecting angiogenesis. In cases of fractures and wound healing, the gut microbiota promotes angiogenesis by activating inflammatory responses and immune effects, facilitating the healing of tissue damage. In cancer, the gut microbiota can either inhibit or promote tumor growth and angiogenesis, depending on the specific bacterial composition and their metabolites. For instance, some bacteria can activate inflammasomes, leading to the production of inflammatory factors that alter the tumor immune microenvironment and activate angiogenesis-related signaling pathways, affecting tumor angiogenesis and metastasis. Some bacteria can directly interact with tumor cells, activating angiogenesis-related signaling pathways. Diet, as a modifiable factor, significantly influences angiogenesis through diet-derived microbial metabolites. Diet can rapidly alter the composition of the microbiota and its metabolic activity, thereby changing the concentration of microbial-derived metabolites and profoundly affecting the host's immune response and angiogenesis. For example, a high animal protein diet promotes the production of pro-atherogenic metabolites like TMAO, activating inflammatory pathways and interfering with platelet function, which is associated with the severity of coronary artery plaques, peripheral artery disease, and cardiovascular diseases. A diet rich in dietary fiber promotes the production of SCFAs, which act as ligands for cell surface or intracellular receptors, regulating various biological processes, including inflammation, tissue homeostasis, and immune responses, thereby influencing angiogenesis. In summary, the role of the gut microbiota in angiogenesis is multifaceted, playing an important role in disease progression by affecting various biological processes such as inflammation, immune responses, and multiple signaling pathways. Diet-derived microbial metabolites play a crucial role in linking the gut microbiota and angiogenesis. Understanding the complex interactions between diet, the gut microbiota, and angiogenesis has the potential to uncover novel therapeutic targets for managing these conditions. Therefore, interventions targeting the gut microbiota and its metabolites, such as through fecal microbiota transplantation (FMT) and the application of probiotics to alter the composition of the gut microbiota and enhance the production of beneficial metabolites, present a promising therapeutic strategy.

Keywords: Angiogenesis; Intestinal microbiota; Lymphangiogenesis; Metabolites.

Fig. 1

The intestinal flora and their metabolites form a complex network that significantly influences angiogenesis and lymphangiogenesis by fine-tuning key biosignaling axes in disease progression (e.g., brain-gut, gut-liver, gut-kidney, gut-skin, gut-heart, gut-skeletal, and gut-metabolism axes, among others), which in turn influences the regression of the disease

Fig. 2

The gut flora and its metabolites exert a critical influence by acting on various signaling pathways within tumor cells. These include modulation of inflammatory processes, interference with tumor immune responses, influence on epithelial-mesenchymal transition (EMT), PI3K/AKT signaling pathways, activation of Toll-like receptors (TLRs), signaling through aromatic hydrocarbon receptor (AHR) and pregnane X receptor (PXR), and lysophosphatidic acid (LPA)-mediated signaling pathways. These actions further regulate the secretion of pro-angiogenic and pro-lymphangiogenic factors by tumor cells, thereby affecting the formation of vascular and lymphatic networks in tumor tissues. These complex biological mechanisms have profound implications for tumor growth, metastasis and survival

Fig. 3

Influencing the composition of the intestinal flora by means of oral antibiotics, probiotics and FMT affects tumour angiogenesis and lymphangiogenesis. In addition, inactivation of flora by local injection may be a potential therapeutic strategy to promote fracture and wound healing