Human Papillomavirus Carcinogenicity and the Need of New Perspectives: Thoughts from a Retrospective Analysis on Human Papillomavirus Outcomes Conducted at the Hospital University of Bari, Apulia, Italy, between 2011 and 2022.

BACKGROUND: The current manuscript's aim was to determine the human papillomavirus (HPV) genotype-specific prevalence and distribution among individuals, males, and females, of different ages in the region of Apulia, Italy, highlighting the possible variables involved in the carcinogenicity mechanism. In addition, we proposed two hypothetical models of HPV's molecular dynamics, intending to clarify the impact of prevention and therapeutic strategies, explicitly modeled by recent survey data. METHODS: We presented clinical data from 9647 participants tested for either high-risk (HR) or low-risk (LR) HPV at the affiliated Bari Policlinic University Hospital of Bari from 2011 to 2022. HPV DNA detection was performed using nested-polymerase chain reaction (PCR) and multiplex real-time PCR assay. Statistical analysis showed significant associations for all genders and ages and both HR- and LR-HPV types. A major number of significant pairwise associations were detected for the higher-risk types and females and lower-risk types and males. RESULTS: The overall prevalence of HPV was 50.5% (n-4.869) vs. 49.5% (n-4.778) of the study population, of which 74.4% (n-3621) were found to be HPV high-risk (HR-HPV) genotypes and 57.7% (n-2.807) low-risk HPV (LR-HPV) genotypes, of which males were 58% and females 49%; the three most prevalent HR-HPV genotypes were HPV 53 (n707-15%), 16 (n704-14%), and 31 (n589-12%), and for LR-HPV, they were 42 (19%), 6 (16%), and 54 (13%); 56% of patients screened for HPV were ≤ 30 years old, 53% were between 31 and 40 years old, 46% were 41-50 and 51-60 years old, and finally, 44% of subjects were >60 years old. CONCLUSIONS: Our study provided comprehensive epidemiological data on HPV prevalence and genotype distribution among 9647 participants, which could serve as a significant reference for clinical practice, and it implied the necessity for more effective screening methods for HPV carcinogenesis covering the use of more specific molecular investigations. Although this is a predominantly descriptive and epidemiological study, the data obtained offer not only a fairly unique trend compared to other studies of different realities and latitudes but also lead us to focus on the HPV infection within two groups of young people and adults and hypothesize the possible involvement of dysbiosis, stem cells, and the retrotransposition mechanism.

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.

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 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.

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.

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.

Alterations of Vaginal Microbiota and Chlamydia trachomatis as Crucial Co-Causative Factors in Cervical Cancer Genesis Procured by HPV.

Chlamydia trachomatis and human papillomavirus (HPV) are the most common pathogens found in sexually transmitted infections (STIs), and both are known to increase the risk of cervical cancer (CC) and infertility. HPV is extremely common worldwide, and scientists use it to distinguish between low-risk and high-risk genotypes. In addition, HPV transmission can occur via simple contact in the genital area. From 50 to 80% of sexually active individuals become infected with both C. trachomatis and HPV viruses during their lifetime, and up to 50% become infected with an HPV oncogenic genotype. The natural history of this coinfection is strongly conditioned by the balance between the host microbiome and immune condition and the infecting agent. Though the infection often regresses, it tends to persist throughout adult life asymptomatically and silently. The partnership between HPV and C. trachomatis is basically due to their similarities: common transmission routes, reciprocal advantages, and the same risk factors. C. trachomatis is a Gram-negative bacteria, similar to HPV, and an intracellular bacterium, which shows a unique biphasic development that helps the latter continue its steady progression into the host throughout the entire life. Indeed, depending on the individual's immune condition, the C. trachomatis infection tends to migrate toward the upper genital tract and spread to the uterus, and the fallopian tubes open up a pathway to HPV invasion. In addition, most HPV and C. trachomatis infections related to the female genital tract are facilitated by the decay of the first line of defense in the vaginal environment, which is constituted by a healthy vaginal microbiome that is characterized by a net equilibrium of all its components. Thus, the aim of this paper was to highlight the complexity and fragility of the vaginal microenvironment and accentuate the fundamental role of all elements and systems involved, including the Lactobacillus strains (Lactobacillus gasseri, Lactobacillus jensenii, Lactobacillus crispatus) and the immune-endocrine system, in preserving it from oncogenic mutation. Therefore, age, diet, and genetic predisposition together with an unspecific, persistent low-grade inflammatory state were found to be implicated in a high frequency and severity grade of disease, potentially resulting in pre-cancerous and cancerous cervical lesions.

From Pathogens to Cancer: Are Cancer Cells Evolved Mitochondrial Super Cells?

Life is based on a highly specific combination of atoms, metabolism, and genetics which eventually reflects the chemistry of the Universe which is composed of hydrogen, oxygen, nitrogen, sulfur, phosphorus, and carbon. The interaction of atomic, metabolic, and genetic cycles results in the organization and de-organization of chemical information of that which we consider as living entities, including cancer cells. In order to approach the problem of the origin of cancer it is therefore reasonable to start from the assumption that the sub-molecular level, the atomic structure, should be the considered starting point on which metabolism, genetics, and external insults eventually emanate. Second, it is crucial to characterize which of the entities and parts composing human cells may live a separate life; certainly, this theoretical standpoint would consider mitochondria, an organelle of "bacteria" origin embedded in conditions favorable for the onset of both. This organelle has not only been tolerated by immunity but has also been placed as a central regulator of cell defense. Virus, bacteria, and mitochondria are also similar in the light of genetic and metabolic elements; they share not only equivalent DNA and RNA features but also many basic biological activities. Thus, it is important to finalize that once the cellular integrity has been constantly broken down, the mitochondria like any other virus or bacteria return to their original autonomy to simply survive. The Warburg's law that states the ability of cancers to ferment glucose in the presence of oxygen, indicates mitochondria respiration abnormalities may be the underlying cause of this transformation towards super cancer cells. Though genetic events play a key part in altering biochemical metabolism, inducing aerobic glycolysis, this is not enough to impair mitochondrial function since mitochondrial biogenesis and quality control are constantly upregulated in cancers. While some cancers have mutations in the nuclear-encoded mitochondrial tricarboxylic acid (TCA) cycle, enzymes that produce oncogenic metabolites, there is also a bio-physic pathway for pathogenic mitochondrial genome mutations. The atomic level of all biological activities can be considered the very beginning, marked by the electron abnormal behavior that consequently affects DNA of both cells and mitochondria. Whilst the cell's nucleus DNA after a certain number of errors and defection tends to gradually switch off, the mitochondria DNA starts adopting several escape strategies, switching-on a few important genes that belong back at their original roots as independent beings. The ability to adopt this survival trick, by becoming completely immune to current life-threatening events, is probably the beginning of a differentiation process towards a "super-power cell", the cancer cells that remind many pathogens, including virus, bacteria, and fungi. Thus, here, we present a hypothesis regarding those changes that first begin at the mitochondria atomic level to steadily involve molecular, tissue and organ levels in response to the virus or bacteria constant insults that drive a mitochondria itself to become an "immortal cancer cell". Improved insights into this interplay between these pathogens and mitochondria progression may disclose newly epistemological paradigms as well as innovative procedures in targeting cancer cell progressive invasion.

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.

Evaluation of qualitative and quantitative taste alterations in COVID-19.

A large percentage of coronavirus disease 2019 (COVID-19) patients have taste dysfunction. Interleukin 6 (IL-6) levels in mild and moderate COVID-19 patients with the type (quantitative or qualitative) of taste disorders were compared in this observational study. The 208 COVID-19 patients (118 men and 90 women) revealing only taste dysfunctions as prodromic symptoms were classified as mild and moderate patients. Survey results were used to evaluate the taste disorder. The IL-6 levels were measured using a chemiluminescence assay. Statistical analysis was conducted using the Wilcoxon rank, Welch's, and Mann-Whitney tests. The findings revealed that neither the presence of dysgeusia or phantogeusia nor the perception of sour and salty, differed statistically significantly between moderate and mild patients (P > 0.05). But between moderate and mild patients, there were statistically significant differences in how umami, bitter, sweet, and parageusia were perceived (P < 0.05). There was an impairment of multiple tastes up to ageusia in patients with high IL-6 levels. The findings demonstrated that parageusia and dysfunctions in umami, bitter, and sweet taste perception can be indicators of more severe forms of COVID-19.

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.

Natural Bioactive Compounds against Oxidative Stress: Dietary Polyphenols Strike Back.

Oxidative stress is a major cellular and metabolic burden that can really alter cell life and become the base for disease onset and development. Many widespread pathologies can develop from an unresolved oxidative stress situation; thus, addressing this state is paramount for human health. Our antioxidant enzymes sometimes are not just enough. Fortifying our defense and the antioxidant and anti-inflammatory system can make a difference in our health: if this is attainable with our dietary habits, it could be a dream come true. Polyphenols are a fantastic tool indeed in the fight against oxidative stress: they are easy to obtain, with little cost, no side effects, and have a multitude of metabolic actions. This perspective review would shed light on polyphenol's metabolic and molecular action regarding oxidative stress to help preserve our health.

Role of Candida albicans in Oral Carcinogenesis.

Oral carcinogenesis is also dependent on the balance of the oral microbiota. Candida albicans is a member oral microbiota that acts as an opportunistic pathogen along with changes in the epithelium that can predispose to premalignancy and/or malignancy. This systematic review uses the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to analyze the role of Candida albicans in the process of oral carcinogenesis. Eleven articles qualified inclusion criteria, matched keywords, and provided adequate information about the carcinogenesis parameters of Candida albicans in oral cancer. Candida albicans in oral carcinogenesis can be seen as significant virulent factors for patients with oral squamous cell carcinoma (OSCC) or potentially malignant disorder (OPMD) with normal adjacent mucosa. Candida albicans have a role in the process of oral carcinogenesis concerning morphological phenotype changes in cell structure and genotype and contribute to the formation of carcinogenic substances that can affect cell development towards malignancy.

Characteristics of Hepatitis B Virus Genotype and Sub-Genotype in Hepatocellular Cancer Patients in Vietnam.

Untreated chronic hepatitis B virus (HBV) infection can lead to chronic liver disease and may progress to cirrhosis or hepatocellular carcinoma (HCC). HBV infection has been prevalent in Vietnam, but there is little information available on the genotypes, sub-genotypes, and mutations of HBV in patients with HBV-related HCC confirmed by histopathological diagnosis. We studied the molecular characteristics of HBV and its genetic variants in Vietnamese HCC patients after liver tumor resection. We conducted a descriptive cross-sectional study on 107 HBV-related HCC hospitalized patients from October 2018 to April 2019. The specimens collected included EDTA anticoagulant blood and liver tissues. Extracted HBV DNA was subjected to whole genome sequencing by the Sanger method. We discovered 62 individuals (57.9%) with genotype B and 45 patients (42.1%) with genotype C, with only sub-genotypes B4 and C1. Among the mutations, the double mutation, A1762T-G1764A, had the most significant frequency (73/107 samples; 68.2%) and was higher in genotype C than in genotype B (p < 0.001). The most common genotypes found in HCC patients in this investigation were B and C, with sub-genotypes B4 and C1 for each. The prevalence of genotype B4 was greater in HBV-infected Vietnamese HCC patients.

Antibiotic Resistance to Mycobacterium tuberculosis and Potential Use of Natural and Biological Products as Alternative Anti-Mycobacterial Agents.

BACKGROUND: Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis (Mtb). TB treatment is based on the administration of three major antibiotics: isoniazid, rifampicin, and pyrazinamide. However, multi-drug resistant (MDR) Mtb strains are increasing around the world, thus, allowing TB to spread around the world. The stringent response is demonstrated by Mtb strains in order to survive under hostile circumstances, even including exposure to antibiotics. The stringent response is mediated by alarmones, which regulate bacterial replication, transcription and translation. Moreover, the Mtb cell wall contributes to the mechanism of antibiotic resistance along with efflux pump activation and biofilm formation. Immunity over the course of TB is managed by M1-macrophages and M2-macrophages, which regulate the immune response against Mtb infection, with the former exerting inflammatory reactions and the latter promoting an anti-inflammatory profile. T helper 1 cells via secretion of interferon (IFN)-gamma, play a protective role in the course of TB, while T regulatory cells secreting interleukin 10, are anti-inflammatory. Alternative therapeutic options against TB require further discussion. In view of the increasing number of MDR Mtb strains, attempts to replace antibiotics with natural and biological products have been object of intensive investigation. Therefore, in this review the anti-Mtb effects exerted by probiotics, polyphenols, antimicrobial peptides and IFN-gamma will be discussed. All the above cited compounds are endowed either with direct antibacterial activity or with anti-inflammatory and immunomodulating characteristics.

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.