The Role of the Microbiota in the Diabetic Peripheral Artery Disease

Abstract

Vascular complications of diabetes mellitus represent a major public health problem. Although many steps forward have been made to define the causes and to find the best possible therapies, the problem remains crucial. In recent years, more and more evidences have defined a link between microbiota and the initiation, promotion, and evolution of atherosclerotic disease, even in the diabetic scenario. There is an urgency to develop the knowledge of modern medicine about the link between gut microbiota and its host’s metabolic pathways, and it would be useful to understand and justify the interindividual diversity of clinical disease presentation of diabetic vascular complication even if an optimization of pharmacological treatment has been made or in the case of young patients where hypertension, dyslipidemia, and diabetes are not able to justify a very quick progress of atherosclerotic process. The aim of the present review is to gather all the best available evidence in this regard and to define a new role of the microbiota in this field, from biomarker to possible therapeutic target.

High Mobility Group Box-1 and Diabetes Mellitus Complications: State of the Art and Future Perspectives

“…In fact, TNF-α promotes the reduction of insulin receptor substrate 1 (IRS-1) mRNA and GLUT4mRNA, leading to insulin resistance and hyperglycemia [12] Moreover, Massaro and coworkers showed that peroxisome proliferator activated receptor (PPAR) alpha/gamma agonists attenuated insulin resistance in human adipocytes, reducing pro-inflammatory mediators including IL-6, CXC-L10 and monocyte chemoattractant protein (MCP-1), supporting the pathogenic role of inflammation in DM development [13]. Hyperglycemic environment is even characterized by enhanced production of reactive oxygen species (ROS), formation of advanced glycation end products (AGEs), activation of protein C kinase (PCK), and activation of polyol pathway [14]. All these factors promote a pro-inflammatory cytokines milieu, including TNF-α, IL-1β, IL-6-IL-8 and HMGB1, which contribute to endothelial damage, development of atherosclerosis and impaired angiogenesis, leading actors in diabetic vascular complications [15].…”

“…Peripheral arterial disease (PAD), and in particular the lower extremities (LE) PAD is a form of atherosclerosis that affects the arteries of the lower limbs, leading to several complications such as critical limb ischemia, acute limb ischemia, tissue necrosis and gangrene [79,80]. It represents a major public health problem and, in 2010, 202 million people globally was affected by PAD [81], with a prevalence of 20-30% in patients with DM [82], the major risk factor for the disease [14]. Different mechanisms contribute to the development of PAD in a diabetic environment and inflammatory process has been widely recognized as the major player of atherosclerotic progression of lower limbs [57,79,83,84].…”

Central and peripheral arterial diseases in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

“…[116][117][118] To date, there are no established therapies to reduce these uremic toxins, except kidney replacement therapy. In this regard, gut microbiota may be an interesting potential therapeutic target, 119 as they produce these uremic toxins and could be manipulated through dietary modifications, medication, or fecal transplantation.…”

Diverse roles of microbial indole compounds in eukaryotic systems

“…Therefore, the abundance of indole compounds in the gut is often evaluated as a biomarker in clinical specimens and has various applications in the pharmaceutical industry (Darkoh et al ., 2015 ). A targeted metabolomics study to identify the role of microbial metabolites in advanced atherosclerosis patients showed that the plasma levels of these metabolites (indole and phenyl derivatives) are correlated with postoperative outcomes, thereby suggesting that these compounds may serve as biomarkers in atherosclerosis (Table 3 ) (Cason et al ., 2018 ; Biscetti et al ., 2019 ).…”

“…Qualitative (composition) or quantitative (population) changes in the gut microbiota can greatly influence the physiology of the host, contributing to several chronic diseases such as malnutrition, obesity, neurological disorders, cancers, inflammatory bowel disease (IBD), type 2 diabetes, atherosclerosis, metabolic syndromes, and liver diseases (Hendrikx & Schnabl, 2019 ). Disruption of symbiosis (dysbiosis) can occur due to multiple factors including diet, environmental factors, stress, aging, drug use, etc., which alter systemic levels of indoles (Biscetti et al ., 2019 ; Shi et al ., 2020 ). Although many microbes can synthesize tryptophan through the chorismate‐linked biosynthetic pathway, proteolytic activities are the major source of tryptophan for gut bacteria.…”