Hippocrates has been cited as saying “death sits in the bowels” and “bad digestion is the root of all evil” in around 400 B.C., suggesting the important role of the human intestine in health and disease. Gut microbiota (GM) is the collective community of microorganisms living in the gastrointestinal (GI) tract. Approximately 100 trillions of microorganisms, consisting mainly of bacteria, inhabits in the human GI tract [1]. Viruses, protozoa and eukaryotic organisms, such as fungi, are also present in a small number. In the adult GI tract about 90% of the bacteria fit in the phyla Bacteroidetes (Gram-negative) and Firmicutes (Gram-positive), while other phyla are present in much lower abundance, such as Actinobacteria (Gram-positive), namely Bifidobacterium, Proteobacteria (Gram-negative) and Verrucomicrobia (Gram-negative), namely Akkermansia muciniphila (Gram-negative) ^[1][2][1,2].

In spite of the fact that people have several hundreds of microbial species inside their gut, newer findings obtained by the Human Microbiome Project and other relevant studies demonstrate that microbial composition is highly variable between individuals [3]. Bacterial colonization starts in utero and GM composition changes throughout the entire life, but the main changes, in number and in diversity, occur during the breast-feeding period and at the beginning of solid food ingestion. The number, type and function of microorganisms differ throughout the GI tract but the bulk is found inside the large intestine, participating in fermentation of undigested food components, particularly carbohydrates and fibers, among other relevant functions. The main roles of GM in humans are depicted in Figure 1. Apart from affording protection against enteropathogens and absorb nutrients from our diet, GM produces several bioactive compounds, some of which are beneficial to health, namely vitamins and some short chain fatty acids (SCFAs), while others are deleterious, such as some metabolites of degradation of amino acids. In addition, host immune defenses, in particular the mucus barrier, are important to protect tissues against harmful effects of some bacteria.

Factors responsible for an impaired GM composition and/or function, called dysbiosis, include age, diet and lack of exercise, stress, drugs and xenobiotics ^[1][4][5][1,4,5]. There is increasing evidence supporting an association between dysbiosis and diseases, including those of the GI tract, such as inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn disease (CD) and colorectal cancer (CRC) ^[6][7][8][6,7,8], as well as some extra-intestinal metabolic disorders, including obesity, diabetes and its macro- and microvascular complications ^[9][10][11][9,10,11]. Hence, researchers all over the world are searching for therapeutic or nutraceutical interventions able to produce a healthy GM equilibrium, eliminating the harmful bacteria (or pathobionts) without affecting the beneficial ones (symbionts).

Dietary polyphenols are natural compounds present in many foods and beverages, namely in fruits, vegetables, cereals, tea, coffee, and wine, among others. Several preclinical and clinical studies have shown their antioxidant, anti-inflammatory, anti-diabetic, anti-cancer, neuroprotective, and anti-adipogenic properties, suggesting a link between polyphenol-rich food consumption and reduction in the incidence of numerous chronic disorders, highlighting them as good candidates for therapeutic/nutraceutical agents ^{[12][13][14][15]}[12,13,14,15]. However, inside the human body, the chemical structure of the majority of polyphenols is received as a xenobiotic and, thus, the bioavailability of these compounds is highly reduced when compared to that of macro- and micro-nutrients [16]. Because of poor absorption, they are retained in the intestine for longer time where they can promote beneficial effect, namely by affecting the GM community [17]. The impact of dietary polyphenols on gut ecology and the mechanism underlying the putative beneficial effects on GI and extra-intestinal diseases have been depicted during the last decade [18].

There are increasing evidences in favor of an association between dysbiosis and diseases, including those of the GI tract, such as IBD, UC, CD and CRC, but also some extra-intestinal metabolic disorders, such as obesity, diabetes and macro- and microvascular complications ^{[8][9][10][11]}[8,9,10,11]. Figure 2 summarizes some of the main linkages of dysbiosis to GI and extra-intestinal metabolic and vascular diseases.

The gut microbes act in tandem with the defense and immune systems of the host to protect against colonization and invasion of pathogens [21]. Recently, a remarkable amount of experimental data has firmly advocated the important role of GM in human health and disease through several molecular mechanisms. First, the gut microbes have the capacity to increase energy and nutrient extraction from the diet, and it can also alter appetite signaling; second, the human GI flora also offers a physical barrier to protect the host against pathogenic microorganisms, inhibiting their colonization by producing antimicrobial compounds ^{[20][47][48][49]}[20,47,48,49]. During metabolism of xenobiotics, the host and its intestinal microbes generates molecules that play crucial part in exchanging information among host cells and its microbial symbionts. Furthermore, there are relevant uremic toxins derived from the intestinal microbial metabolism of proteins, amino acids and other metabolites, including mainly phenols and indoles bounded to proteins and products of metabolism of phenylalanine and tyrosine, such as p-cresol (PC) and p-cresyl sulfate (PCS), and of tryptophan degradation, such as indoxyl sulfate (IS) and indoleacetic acid [50]. Finally, amines and polyamines are also originated by GM metabolism. A major example is choline, a crucial nutrient for lipid metabolism that is metabolized into toxic trimethylamine and further converted to trimethylamine-N-oxide (TMAO) in the liver, which is a promoter of cardiovascular and renal diseases ^[51][52][51,52].

Changed GM composition have been reported in IBDs subjects when compared to controls, though no uniform pattern of alterations has yet been observed ^[53][54][53,54]. The mechanisms underlying the association between GM dysbiosis and evolution of IBDs include the pro-inflammatory and pro-oxidative profile generated in the intestinal lumen and adjacent layers ^[55][56][55,56]. In addition, debates are also going on regarding the crucial role of heat shock proteins (HSPs) in the pathogenesis of IBD, namely due to their participation in several relevant biochemical pathways, such as folding, translocation, and ubiquitinylation of intracellular proteins, as well as due to their capacity to excite innate and adaptive immune response, thus serving as primary autoimmune response targets [57]. The Th17/Treg cells balance, characterized by pro-inflammatory and anti-inflammatory cytokines, which is pivotal for the host’s intestinal homeostasis and induction or inhibition of colonic inflammation, is highly influenced by GM composition. Under inflammatory conditions, including IBD and other GI diseases, antigens derived from a dysbiotic GM activate immune cells (namely Th1 and Th17), causing tissue damage, reduction of mucus layer, and exacerbated penetration of microbes in the intestinal tissues. Consequently, there is an augmented uptake of microbial antigens and toll-like receptor (TLR) ligands that perpetuate the immune responses ^[8][58][8,58].

As above referred, the composition of intestinal microflora is affected by several factors, including lifestyle habits, particularly diet and exercise, which are risk factors for cardiometabolic diseases, such as obesity and T2DM. These conditions have been viewed as the result of an intricate crosstalk between individual genetics, environment influences, including the dietary pattern, as well as the intestinal microflora [59]. Increasing evidences coming from preclinical and clinical studies support the existence of a dysbiotic GM in obesity and T2DM, characterized by lower diversity and resilience [60]. The putative association between dysbiosis and the development of obesity, T2DM and its serious vascular complications has been suggested based on several distinct mechanisms (Figure 2). In brief, GM dysbiosis is a trigger for gut barrier integrity breakdown, with changes on the expression of tight proteins, followed by augmented permeability and consequent translocation from the gut lumen to the bloodstream of bacteria fragments, namely lipopolysaccharide (LPS) and peptidoglycan (PG), and uremic toxins, thus inducing endotoxemia, also referred as a low-grade inflammation state ^[61][62][61,62]. The so-called microbe-associated molecular pattern (MAMP) cause a pro-inflammatory response by binding to toll-like receptors (TLRs), namely TLR4, which evokes a cascade of responses that culminate in pro-inflammatory molecules’ release, which will then affect glucose and insulin metabolism and/or signaling [63]. This is further fueled by advanced glycation end products (AGEs) and other oxidative pathways which are deeply involved in the metabolic impairment in obesity and diabetes development. Concomitantly, several evidences strongly suggest that signals coming from the dysbiotic GM modulate immunometabolism by interfering with epithelial and immune cells, generating an immune-inflammatory milieu that favors the progression of diabetes and its complication [10]. In fact, diabetic gut dysbiosis seems to contribute not only to obesity and diabetes development but also to the progression of some of its main microvascular complications, including diabetic retinopathy (DR) and nephropathy (DN). It is suggested that an increase of circulating bacterial endotoxins, particularly LPS, might play a major role in the low-grade inflammation typical of obesity, diabetes and microvascular complications. The translocation of bacterial components and other microbial-derived products through the impaired intestinal barrier to the systemic circulation can contribute to the pro-inflammatory and pro-oxidative profile found in DN and DR, as well as to the overactivated innate and adaptive immunity [10]. These mechanisms, overall, can be pivotal to the progression of metabolic and vascular complications of diabetes (Figure 2).

The question remains whether dysbiosis is directly linked to metabolic disorders, particularly obesity, T2DM and its vascular complications, or whether the impaired GM composition is an adaptation to alteration of host’s diet and other modulatory factors. There following findings might help to achieve valid answers: (i) microbiota transfer from lean donors into subjects with metabolic disease causes amelioration of insulin sensitivity and (ii) change in human’s diet patterns promote a quick and reversible alteration in the composition of dominant GM members ^[64][65][64,65].