Aspergillus niger prolyl endopeptidase in celiac disease.

We comment here on the article by Stefanolo et al entitled "Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet", published in the World Journal of Gastroenterology. Celiac disease is a well-recognized systemic autoimmune disorder. In genetically susceptible people, the most evident damage is located in the small intestine, and is caused and worsened by the ingestion of gluten. For that reason, celiac patients adopt a gluten-free diet (GFD), but it has some limitations, and it does not prevent re-exposure to gluten. Research aims to develop adjuvant therapies, and one of the most studied alternatives is supplementation with Aspergillus niger prolyl endopeptidase protease (AN-PEP), which is able to degrade gluten in the stomach, reducing its concentration in the small intestine. The study found a high adherence to the GFD, but did not address AN-PEP as a gluten immunogenic peptide reducer, as it was only tested in patients following a GFD and not in gluten-exposing conditions. This study opens up new research perspectives in this area and shows that further study is needed to clarify the points that are still in doubt.

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.

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.

A Bird's-Eye View of the Pathophysiologic Role of the Human Urobiota in Health and Disease: Can We Modulate It?

For a long time, urine has been considered sterile in physiological conditions, thanks to the particular structure of the urinary tract and the production of uromodulin or Tamm-Horsfall protein (THP) by it. More recently, thanks to the development and use of new technologies, i.e., next-generation sequencing and expanded urine culture, the identification of a microbial community in the urine, the so-called urobiota, became possible. Major phyla detected in the urine are represented by Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Particularly, the female urobiota is largely represented by Lactobacillus spp., which are very active against urinary pathogenic Escherichia (E.) coli (UPEC) strains via the generation of lactic acid and hydrogen peroxide. Gut dysbiosis accounts for recurrent urinary tract infections (UTIs), so-called gut-bladder axis syndrome with the formation of intracellular bacterial communities in the course of acute cystitis. However, other chronic urinary tract infections are caused by bacterial strains of intestinal derivation. Monomicrobial and polymicrobial infections account for the outcome of acute and chronic UTIs, even including prostatitis and chronic pelvic pain. E. coli isolates have been shown to be more invasive and resistant to antibiotics. Probiotics, fecal microbial transplantation, phage therapy, antimicrobial peptides, and immune-mediated therapies, even including vaccines for the treatment of UTIs, will be described.

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.

Might Gut Microbiota Be a Target for a Personalized Therapeutic Approach in Patients Affected by Atherosclerosis Disease?

In recent years, the increasing number of studies on the relationship between the gut microbiota and atherosclerosis have led to significant interest in this subject. The gut microbiota, its metabolites (metabolome), such as TMAO, and gut dysbiosis play an important role in the development of atherosclerosis. Furthermore, inflammation, originating from the intestinal tract, adds yet another mechanism by which the human ecosystem is disrupted, resulting in the manifestation of metabolic diseases and, by extension, cardiovascular diseases. The scientific community must understand and elucidate these mechanisms in depth, to gain a better understanding of the relationship between atherosclerosis and the gut microbiome and to promote the development of new therapeutic targets in the coming years. This review aims to present the knowledge acquired so far, to trigger others to further investigate this intriguing topic.

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.

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.

Neurosensory Alterations and Interleukins Cascade in SARS-CoV-2 Infection - Results from a Retrospective Cohort of COVID-19 Inpatients.

OBJECTIVES: The aim of this study was to relate IL-6 and IL-1ß serum levels with the severity of olfactory disorders and with the type of unperceived odors. METHODS: 82 inpatients (45 men aged 62.3 ± 14.2 and 37 women aged 57.1 ± 12.8) with only smell dysfunctions were divided into two groups. The evaluation of the smell disorder was carried out with a questionnaire to define which sensitivity is most compromised in COVID-19 patients. Cytokine levels were measured with chemiluminescence and ELISA assay. Statistical analyses were performed with the Wilcoxon Rank test, Welch's T-test, and Mann-Whitney test (p < 0.05). RESULTS: Statistically significant differences in IL-6 and IL-1 ß levels were found in moderate disease patients when there was an impairment of trigeminal sensitivity (p <0.05) and trigeminal and olfactory sensitivity. CONCLUSIONS: The results obtained showed that in COVID-19 patients the impairment of trigeminal sensitivity in association with olfactory sensitivity was more prevalent in moderate than in mild forms.

Update on COVID-19 and Effectiveness of a Vaccination Campaign in a Global Context.

The COVID-19 pandemic caused by SARS-CoV-2 remains a significant issue for global health, the economy, and society. When SARS-CoV-2 began to spread, the most recent serious infectious disease of this century around the world, with its high morbidity and mortality rates, it is understandable why such infections have generally been spread in the past, mainly from international travel movements. This perspective review aimed to provide an update for clinicians on the recent developments related to the microbiological perspectives in pandemics, diagnostics, prevention (such as the spread of a virus), vaccination campaigns, treatment options, and health consequences for COVID-19 based on the current literature. In this way, the authors attempt to raise awareness on the transversal nature of these challenges by identifying the main risk/vulnerability factors that the scientific community must face including our current knowledge on the virus capacity of the mechanism of entry into the cells, the current classifications of viral variants, the knowledge of the mathematical model on the spread of viruses (the possible routes of transmission), and the effectiveness of vaccination campaigns in a global context of pandemic, particularly from COVID-19, with a look at new or future vaccines.

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.

Testicular Immunity and Its Connection with the Microbiota. Physiological and Clinical Implications in the Light of Personalized Medicine.

Reproduction is a complex process, which is based on the cooperation between the endocrine-immune system and the microbiota. Testicular immunity is characterized by the so-called immune privilege, a mechanism that avoids autoimmune attacks against proteins expressed by spermatozoa. Testicular microbiota is connected with the gut microbiota, the most prevalent site of commensals inthe body. Both microbiotas take part inthe development of the immune system and protection againstpathogen invasion. Dysbiosis is caused by concurrent pathologies, such as obesity, diabetes, infections and trauma. The substitution of beneficial bacteria with pathogens may lead to destruction of spermatozoa directly or indirectly and, ultimately, to male infertility. Novel therapeutic interventions, i.e., nutritional interventions and supplementation of natural products, such as, probiotics, prebiotics, antioxidants and polyphenols, may lead to the restoration of the otherwise-impaired male reproductive potential, even if experimental and clinical results are not always concordant. In this review, the structure and immune function of the testis will be described with special reference to the blood-testisbarrier. The regulatory role of both the gut and testicular microbiota will be illustrated in health and disease, also emphasizing therapeutic attempts with natural products for the correction of male infertility, in the era of personalized medicine.