Blood Microbiota and Its Products: Mechanisms of Interference with Host Cells and Clinical Outcomes.

In healthy conditions, blood was considered a sterile environment until the development of new analytical approaches that allowed for the detection of circulating bacterial ribosomal DNA. Currently, debate exists on the origin of the blood microbiota. According to advanced research using dark field microscopy, fluorescent in situ hybridization, flow cytometry, and electron microscopy, so-called microbiota have been detected in the blood. Conversely, others have reported no evidence of a common blood microbiota. Then, it was hypothesized that blood microbiota may derive from distant sites, e.g., the gut or external contamination of blood samples. Alteration of the blood microbiota's equilibrium may lead to dysbiosis and, in certain cases, disease. Cardiovascular, respiratory, hepatic, kidney, neoplastic, and immune diseases have been associated with the presence of Gram-positive and Gram-negative bacteria and/or their products in the blood. For instance, lipopolysaccharides (LPSs) and endotoxins may contribute to tissue damage, fueling chronic inflammation. Blood bacteria can interact with immune cells, especially with monocytes that engulf microorganisms and T lymphocytes via spontaneous binding to their membranes. Moreover, LPSs, extracellular vesicles, and outer membrane vesicles interact with red blood cells and immune cells, reaching distant organs. This review aims to describe the composition of blood microbiota in healthy individuals and those with disease conditions. Furthermore, special emphasis is placed on the interaction of blood microbiota with host cells to better understand disease mechanisms.

Exploitation of Natural By-Products for the Promotion of Healthy Outcomes in Humans: Special Focus on Antioxidant and Anti-Inflammatory Mechanisms and Modulation of the Gut Microbiota.

Daily, a lot of food is wasted, and vegetables, fruit, and cereals as well as marine products represent the major sources of unwanted by-products. The sustainability, waste recovery, and revalorization of food by-products have been proposed as the main goals of the so-called circular economy. In fact, food wastes are enriched in by-products endowed with beneficial effects on human health. Grape, olives, vegetables, and rice contain different compounds, such as polyphenols, dietary fibers, polysaccharides, vitamins, and proteins, which exert antioxidant and anti-inflammatory activities, inhibiting pro-oxidant genes and the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kß) pathway, as demonstrated by in vitro and in vivo experiments. Dietary fibers act upon the gut microbiota, expanding beneficial bacteria, which contribute to healthy outcomes. Furthermore, marine foods, even including microalgae, arthropods, and wastes of fish, are rich in carotenoids, polyphenols, polyunsaturated fatty acids, proteins, and chitooligosaccharides, which afford antioxidant and anti-inflammatory protection. The present review will cover the major by-products derived from food wastes, describing the mechanisms of action involved in the antioxidant and anti-inflammatory activities, as well as the modulation of the gut microbiota. The effects of some by-products have also been explored in clinical trials, while others, such as marine by-products, need more investigation for their full exploitation as bioactive compounds in humans.

Current Knowledge about Gastric Microbiota with Special Emphasis on Helicobacter pylori-Related Gastric Conditions.

The gastric milieu, because of its very low acidic pH, is very harsh for bacterial growth. The discovery of Helicobacter pylori (H.p.) has opened a new avenue for studies on the gastric microbiota, thus indicating that the stomach is not a sterile environment. Nowadays, new technologies of bacterial identification have demonstrated the existence of other microorganisms in the gastric habitat, which play an important role in health and disease. This bacterium possesses an arsenal of compounds which enable its survival but, at the same time, damage the gastric mucosa. Toxins, such as cytotoxin-associated gene A, vacuolar cytotoxin A, lipopolysaccharides, and adhesins, determine an inflammatory status of the gastric mucosa which may become chronic, ultimately leading to a gastric carcinoma. In the initial stage, H.p. persistence alters the gastric microbiota with a condition of dysbiosis, predisposing to inflammation. Probiotics and prebiotics exhibit beneficial effects on H.p. infection, and, among them, anti-inflammatory, antioxidant, and antibacterial activities are the major ones. Moreover, the association of probiotics with prebiotics (synbiotics) to conventional anti-H.p. therapy contributes to a more efficacious eradication of the bacterium. Also, polyphenols, largely present in the vegetal kingdom, have been demonstrated to alleviate H.p.-dependent pathologies, even including the inhibition of tumorigenesis. The gastric microbiota composition in health and disease is described. Then, cellular and molecular mechanisms of H.p.-mediated damage are clarified. Finally, the use of probiotics, prebiotics, and polyphenols in experimental models and in patients infected with H.p. is discussed.

Healthy Diets and Lifestyles in the World: Mediterranean and Blue Zone People Live Longer. Special Focus on Gut Microbiota and Some Food Components.

Longevity has been associated with healthy lifestyles, including some dietary regimens, such as the Mediterranean diet (MedDiet) and the Blue Zone (BZ) diets. MedDiet relies on a large consumption of fruit, vegetables, cereals, and extra-virgin olive oil, with less red meat and fat intake. Four major BZ have been recognized in the world, namely, Ogliastra in Sardinia (Italy), Ikaria (Greece), the Peninsula of Nicoya (Costa Rica), and Okinawa (Japan). Extreme longevity in these areas has been associated with correct lifestyles and dietary regimens. Fibers, polyphenols, beta-glucans, and unsaturated fatty acids represent the major constituents of both MedDiet and BZ diets, given their anti-inflammatory and antioxidant activities. Particularly, inhibition of the NF-kB pathway, with a reduced release of pro-inflammatory cytokines, and induction of T regulatory cells, with the production of the anti-inflammatory cytokine, interleukin- 10, are the main mechanisms that prevent or attenuate the "inflammaging." Notably, consistent physical activity, intense social interactions, and an optimistic attitude contribute to longevity in BZD areas. Commonalities and differences between MedDIet and BZ diets will be outlined, with special reference to microbiota and food components, which may contribute to longevity.

Current View on How Human Gut Microbiota Mediate Metabolic and Pharmacological Activity of Panax ginseng. A Scoping Review.

Panax ginseng is one of the most important remedies in ancient Eastern medicine. In the modern Western world, its reputation started to grow towards the end of the XIX century, but the rather approximate understanding of action mechanisms did not provide sufficient information for an appropriate use. Nowadays, Panax ginseng is frequently used in some pathological conditions, but the comprehension of its potential beneficial effects is still incomplete. The purpose of this study is to highlight the most recent knowledge on mechanisms and effects of ginseng active ingredients on the intestinal microbiota. The human microbiota takes part in the immune and metabolic balance and serves as the most important regulator for the control of local pathogens. This delicate role requires a complex interaction and reflects the interconnection with the brain- and the liver-axes. Thus, by exerting their beneficial effects through the intestinal microbiota, the active ingredients of Panax ginseng (glycosides and their metabolites) might help to ameliorate both specific intestinal conditions as well as the whole organism's homeostasis.

Biomolecular Actions by Intestinal Endotoxemia in Metabolic Syndrome.

Metabolic syndrome (MetS) is a combination of metabolic disorders that concurrently act as factors promoting systemic pathologies such as atherosclerosis or diabetes mellitus. It is now believed to encompass six main interacting conditions: visceral fat, imbalance of lipids (dyslipidemia), hypertension, insulin resistance (with or without impairing both glucose tolerance and fasting blood sugar), and inflammation. In the last 10 years, there has been a progressive interest through scientific research investigations conducted in the field of metabolomics, confirming a trend to evaluate the role of the metabolome, particularly the intestinal one. The intestinal microbiota (IM) is crucial due to the diversity of microorganisms and their abundance. Consequently, IM dysbiosis and its derivate toxic metabolites have been correlated with MetS. By intervening in these two factors (dysbiosis and consequently the metabolome), we can potentially prevent or slow down the clinical effects of the MetS process. This, in turn, may mitigate dysregulations of intestinal microbiota axes, such as the lung axis, thereby potentially alleviating the negative impact on respiratory pathology, such as the chronic obstructive pulmonary disease. However, the biomolecular mechanisms through which the IM influences the host's metabolism via a dysbiosis metabolome in both normal and pathological conditions are still unclear. In this study, we seek to provide a description of the knowledge to date of the IM and its metabolome and the factors that influence it. Furthermore, we analyze the interactions between the functions of the IM and the pathophysiology of major metabolic diseases via local and systemic metabolome's relate endotoxemia.

Current Views about the Inflammatory Damage Triggered by Bacterial Superantigens and Experimental Attempts to Neutralize Superantigen-Mediated Toxic Effects with Natural and Biological Products.

Superantigens, i.e., staphylococcal enterotoxins and toxic shock syndrome toxin-1, interact with T cells in a different manner in comparison to conventional antigens. In fact, they activate a larger contingent of T lymphocytes, binding outside the peptide-binding groove of the major histocompatibility complex class II. Involvement of many T cells by superantigens leads to a massive release of pro-inflammatory cytokines, such as interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor-alpha and interferon-gamma. Such a storm of mediators has been shown to account for tissue damage, multiorgan failure and shock. Besides conventional drugs and biotherapeutics, experiments with natural and biological products have been undertaken to attenuate the toxic effects exerted by superantigens. In this review, emphasis will be placed on polyphenols, probiotics, beta-glucans and antimicrobial peptides. In fact, these substances share a common functional denominator, since they skew the immune response toward an anti-inflammatory profile, thus mitigating the cytokine wave evoked by superantigens. However, clinical applications of these products are still scarce, and more trials are needed to validate their usefulness in humans.

Current Views About the Link between SARS-CoV-2 and the Liver: Friends or Foe?

The emergence of the novel coronavirus and the pandemic resulting from its spread have led to significant negative impacts on health, economy, relationships, and others. Particularly in the field of hospital care, the need for a greater number of patients has led to a breakdown of the system. Gastrointestinal manifestations are common in SARS-COV 2 patients, while 10% of those who are sick exhibit symptoms only from gastrointestinal without any manifestation on the part of the respiratory tract. The main manifestations are nausea, vomiting, diarrhoea, and anorexia. It is also interesting to note that biochemical liver disorder is a frequent finding and is associated with a worse prognosis and higher probability admission to intensive care. It was also observed that RNA from the virus was found in the stool several days after the tests came back negative pulmonary secretions, while rectal swab virus detection methods were used with a lower but comparable sensitivity to that of nasal swabs. Gastrointestinal symptoms in SARS-COV 2 infection are common and their search should be part of the initial diagnosis approach and have a connection with the gut microbiota dysbiosis and this can lead to an alteration of the gut/liver axis.

Oral microbiota in human health and disease: A perspective.

The evolution of medical knowledge about oral microbiota has increased awareness of its important role for the entire human body health. A wide range of microbial species colonizing the oral cavity interact both with each other and with their host through complex pathways. Usually, these interactions lead to a harmonious coexistence (i.e. eubiosis). However, several factors - including diet, poor oral hygiene, tobacco smoking, and certain medications, among others - can disrupt this weak homeostatic balance (i.e. dysbiosis) with potential implications on both oral (i.e. development of caries and periodontal disease) and systemic health. This article is thus aimed at providing an overview on the importance of oral microbiota in mediating several physiological and pathological conditions affecting human health. In this context, strategies based on oral hygiene and diet as well as the role of probiotics supplementation are discussed.

Microbiota revolution: How gut microbes regulate our lives.

The human intestine is a natural environment ecosystem of a complex of diversified and dynamic microorganisms, determined through a process of competition and natural selection during life. Those intestinal microorganisms called microbiota and are involved in a variety of mechanisms of the organism, they interact with the host and therefore are in contact with the organs of the various systems. However, they play a crucial role in maintaining host homeostasis, also influencing its behaviour. Thus, microorganisms perform a series of biological functions important for human well-being. The host provides the microorganisms with the environment and nutrients, simultaneously drawing many benefits such as their contribution to metabolic, trophic, immunological, and other functions. For these reasons it has been reported that its quantitative and qualitative composition can play a protective or harmful role on the host health. Therefore, a dysbiosis can lead to an association of unfavourable factors which lead to a dysregulation of the physiological processes of homeostasis. Thus, it has pre-viously noted that the gut microbiota can participate in the pathogenesis of autoimmune diseases, chronic intestinal inflammation, diabetes mellitus, obesity and atherosclerosis, neurological disorders (e.g., neurological diseases, autism, etc.) colorectal cancer, and more.

An Overview of the Microbiota of the Human Urinary Tract in Health and Disease: Current Issues and Perspectives.

This article is intended to deepen our knowledge to date regarding the functions of the resident microbiota/microbiome in the urinary system for human health and disease. First, we sought to report the general characteristics (composition and stability) of the normal urinary system microbiota in the different anatomical sites in relation to some factors such as the effect of age, gender and diet, analyzing in detail the functions and the composition of the microbiota in the light of current knowledge. Several pieces of evidence suggest the importance of preserving the micro-ecosystem of the urinary system, and in some cases their relationship with diseases is important for maintaining human health is well understood. The female and male reproductive microbiota have mainly been studied over the past decade. In the past, the arrest was thought to have taken place in a sterile environment. Microorganisms of the microbiota form biofilms, three-dimensional structures, that differ in the reproductive organs and interact with both gametes and the embryo as well as with maternal tissues. These biofilms from the reproductive system also interact with others, such as that of the gastrointestinal tract. Reduction in its diversity intestinal microbiota can disrupt estrogen metabolism and affect the reproductive microbiota. It is therefore understood that its quantitative and qualitative identification is important for microbiota, but also the study of the structures formed by the microorganisms. A dysbiosis with local or systemic causes can lead to serious diseases. The role of probiotics in maintaining microbial population harmony (eubiosis) and preventing certain pathologies of the urinary and reproductive system was also investigated. A negative variation in the qualitative and quantitative composition of certain strains of microorganisms (dysbiosis) due to local or systemic causes can even lead to serious diseases. The role of probiotics in maintaining the healthy balance of microorganism populations (eubiosis), and thus in the prevention of certain pathologies of the urinary and reproductive system, has also been studied.

Crosstalk between the Resident Microbiota and the Immune Cells Regulates Female Genital Tract Health.

The female genital tract (FGT) performs several functions related to reproduction, but due to its direct exposure to the external environment, it may suffer microbial infections. Both the upper (uterus and cervix) and lower (vagina) FGT are covered by an epithelium, and contain immune cells (macrophages, dendritic cells, T and B lymphocytes) that afford a robust protection to the host. Its upper and the lower part differ in terms of Lactobacillus spp., which are dominant in the vagina. An alteration of the physiological equilibrium between the local microbiota and immune cells leads to a condition of dysbiosis which, in turn, may account for the outcome of FGT infection. Aerobic vaginitis, bacterial vaginosis, and Chlamydia trachomatis are the most frequent infections, and can lead to severe complications in reproduction and pregnancy. The use of natural products, such as probiotics, polyphenols, and lactoferrin in the course of FGT infections is an issue of current investigation. In spite of positive results, more research is needed to define the most appropriate administration, according to the type of patient.

The Crosstalk between Gut Microbiota and Nervous System: A Bidirectional Interaction between Microorganisms and Metabolome.

Several studies have shown that the gut microbiota influences behavior and, in turn, changes in the immune system associated with symptoms of depression or anxiety disorder may be mirrored by corresponding changes in the gut microbiota. Although the composition/function of the intestinal microbiota appears to affect the central nervous system (CNS) activities through multiple mechanisms, accurate epidemiological evidence that clearly explains the connection between the CNS pathology and the intestinal dysbiosis is not yet available. The enteric nervous system (ENS) is a separate branch of the autonomic nervous system (ANS) and the largest part of the peripheral nervous system (PNS). It is composed of a vast and complex network of neurons which communicate via several neuromodulators and neurotransmitters, like those found in the CNS. Interestingly, despite its tight connections to both the PNS and ANS, the ENS is also capable of some independent activities. This concept, together with the suggested role played by intestinal microorganisms and the metabolome in the onset and progression of CNS neurological (neurodegenerative, autoimmune) and psychopathological (depression, anxiety disorders, autism) diseases, explains the large number of investigations exploring the functional role and the physiopathological implications of the gut microbiota/brain axis.

Ancient herbal therapy: A brief history of Panax ginseng.

Ginseng was the most revered of the herbs in ancient times in China, Korea, Japan, America. Ginseng was discovered over 5000 years ago in the mountains of Manchuria, China. References to ginseng are found in books dating back more than two millennia. It is revered by the Chinese people as it is considered a herb for everything use and therefore for a wide range of diseases (currently its Latin name derived from the Greek panacea, meanings, that is, for everything). So, it was used exclusively by the Chinese Emperor's, and they were willing to pay the price without problems. Increasing its fame, ginseng brought a flourishing international trade that allowed Korea to supply China with silk and medicines in exchange for wild ginseng and later along with what grows in America.

About Functional Foods: The Probiotics and Prebiotics State of Art.

Poor diet, obesity and a sedentary lifestyle have a significant impact on natural microbiota disorders; specifically, the intestinal one. This in turn can lead to a multitude of organ dysfunctions. The gut microbiota contains more than 500 species of bacteria and constitutes 95% of the total number of cells in the human body, thus contributing significantly to the host's resistance to infectious diseases. Nowadays, consumers have turned to purchased foods, especially those containing probiotic bacteria or prebiotics, that constitute some of the functional food market, which is constantly expanding. Indeed, there are many products available that incorporate probiotics, such as yogurt, cheese, juices, jams, cookies, salami sausages, mayonnaise, nutritional supplements, etc. The probiotics are microorganisms that, when taken in sufficient amounts, contribute positively to the health of the host and are the focus of interest for both scientific studies and commercial companies. Thus, in the last decade, the introduction of DNA sequencing technologies with subsequent bioinformatics processing contributes to the in-depth characterization of the vast biodiversity of the gut microbiota, their composition, their connection with the physiological function-known as homeostasis-of the human organism, and their involvement in several diseases. Therefore, in this study, we highlighted the extensive investigation of current scientific research for the association of those types of functional foods containing probiotics and prebiotics in the diet and the composition of the intestinal microbiota. As a result, this study can form the foundation for a new research path based on reliable data from the literature, acting a guide in the continuous effort to monitor the rapid developments in this field.

Non-Surgical Therapy and Oral Microbiota Features in Peri-Implant Complications: A Brief Narrative Review.

The therapeutic discretion in cases of peri-implantitis should take into account the limits and advantages of specific therapeutic itineraries tailored according to each clinical case and each individual patient. This type of oral pathology emphasizes the complex classification and diagnostic issues coupled with the need for targeted treatments, in light of the oral peri-implant microbiota changes. This review highlights the current indications for the non-surgical treatment of peri-implantitis, describing the specific therapeutic efficacy of different approaches and discussing the more appropriate application of single non-invasive therapies The non-surgical treatment choice with antiseptics or antibiotics (single or combined, local, or systemic) for short courses should be considered on a case-by-case basis to minimize the incidence of side effects and concomitantly avoid disease progression.

Ceramic Materials for Biomedical Applications: An Overview on Properties and Fabrication Processes.

A growing interest in creating advanced biomaterials with specific physical and chemical properties is currently being observed. These high-standard materials must be capable to integrate into biological environments such as the oral cavity or other anatomical regions in the human body. Given these requirements, ceramic biomaterials offer a feasible solution in terms of mechanical strength, biological functionality, and biocompatibility. In this review, the fundamental physical, chemical, and mechanical properties of the main ceramic biomaterials and ceramic nanocomposites are drawn, along with some primary related applications in biomedical fields, such as orthopedics, dentistry, and regenerative medicine. Furthermore, an in-depth focus on bone-tissue engineering and biomimetic ceramic scaffold design and fabrication is presented.

Microbial and Host Metabolites at the Backstage of Fever: Current Knowledge about the Co-Ordinate Action of Receptors and Molecules Underlying Pathophysiology and Clinical Implications.

Fever represents an elevation of body temperature, that exerts a protective effect against pathogens. Innate immune cells and neurons are implicated in the regulation of body temperature. Pathogen-associated molecular patterns, i.e., lipopolysaccharides from Gram-negative bacteria and peptidoglycan and lipoteichoic acid from Gram-positive bacteria are exogenous pyrogens, that bind to Toll-like receptors on immune and non-immune cells. The subsequent release of pro-inflammatory cytokines [interleukin-1 (IL-1), IL-6 and Tumor necrosis factor-alpha] and their passage through the brain trigger the febrile response. In fact, neurons of the pre-optic area produce prostaglandin E2 (PGE2), that, in turn, bind to the PGE2 receptors; thus, generating fever. Apart from classical non-steroidal anti-inflammatory drugs, i.e., aspirin and acetaminophen, various botanicals are currently used as antipyretic agents and, therefore, their mechanisms of action will be elucidated.

Subversion of the Oral Microbiota and Induction of Immune-Mediated Systemic Inflammation with Special Reference to Periodontitis: Current Knowledge and Perspectives.

Under steady-state circumstances, the oral microbiota is in equilibrium with host tissues, thus contributing to local and systemic health. Any interruption of such equilibrium leads to a condition of dysbiosis with the proliferation of oral pathogens able to cause gingivitis and periodontal disease. The mechanisms of periodontitis will be described, mostly emphasizing the noxious effects exerted by oral pathogens on the periodontium either directly or indirectly via the release of an array of mediators, even including pro-inflammatory cytokines, chemokines, and enzymes. The persistence of local inflammation ultimately leads to systemic inflammation; therefore, the link between periodontitis and obesity, diabetes and cardiovascular disease will be elucidated. Some natural compounds, such as polyphenols, prebiotics, and probiotics, will be discussed for their ability to exert anti-inflammatory and anti-oxidant activities in the context of the inflamed buccal cavity and systemically, as well as for their modulation of the altered gum-gut microbiota.

Biomolecular Mechanisms of Autoimmune Diseases and Their Relationship with the Resident Microbiota: Friend or Foe?

The use of innovative approaches to elucidate the pathophysiological mechanisms of autoimmune diseases, as well as to further study of the factors which can have either a positive or negative effect on the course of the disease, is essential. In this line, the development of new molecular techniques and the creation of the Human Genome Program have allowed access to many more solutions to the difficulties that exist in the identification and characterization of the microbiome, as well as changes due to various factors. Such innovative technologies can rekindle older hypotheses, such as molecular mimicry, allowing us to move from hypothesis to theory and from correlation to causality, particularly regarding autoimmune diseases and dysbiosis of the microbiota. For example, Prevotella copri appears to have a strong association with rheumatoid arthritis; it is expected that this will be confirmed by several scientists, which, in turn, will make it possible to identify other mechanisms that may contribute to the pathophysiology of the disease. This article seeks to identify new clues regarding similar correlations between autoimmune activity and the human microbiota, particularly in relation to qualitative and quantitative microbial variations therein.