BACKGROUND: Age-related neurodegenerative diseases (NDs) pose a formidable challenge to healthcare systems worldwide due to their complex pathogenesis, significant morbidity, and mortality. Scope and Approach: This comprehensive review aims to elucidate the central role of the microbiotagut- brain axis (MGBA) in ND pathogenesis. Specifically, it delves into the perturbations within the gut microbiota and its metabolomic landscape, as well as the structural and functional transformations of the gastrointestinal and blood-brain barrier interfaces in ND patients. Additionally, it provides a comprehensive overview of the recent advancements in medicinal and dietary interventions tailored to modulate the MGBA for ND therapy. CONCLUSION: Accumulating evidence underscores the pivotal role of the gut microbiota in ND pathogenesis through the MGBA. Dysbiosis of the gut microbiota and associated metabolites instigate structural modifications and augmented permeability of both the gastrointestinal barrier and the blood-brain barrier (BBB). These alterations facilitate the transit of microbial molecules from the gut to the brain via neural, endocrine, and immune pathways, potentially contributing to the etiology of NDs. Numerous investigational strategies, encompassing prebiotic and probiotic interventions, pharmaceutical trials, and dietary adaptations, are actively explored to harness the microbiota for ND treatment. This work endeavors to enhance our comprehension of the intricate mechanisms underpinning ND pathogenesis, offering valuable insights for the development of innovative therapeutic modalities targeting these debilitating disorders.

• Keywords
• Neurodegenerative diseases, blood-brain barrier, dietary adaptations., gut microbiota, microbiota-gut-brain axis, therapy,
• MeSH
• Dysbiosis metabolism   MeSH
• Blood-Brain Barrier metabolism   MeSH
• Humans MeSH
• Brain * metabolism   MeSH
• Neurodegenerative Diseases * microbiology   metabolism   MeSH
• Brain-Gut Axis * physiology   MeSH
• Probiotics MeSH
• Aging * MeSH
• Gastrointestinal Microbiome * physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

The gradual decrease in the prevalence of serious infectious diseases over the last century has been followed by increase in so called "modern" diseases, including allergies, chronic inflammatory conditions, psychiatric, and metabolic disorders. Between 2019 and 2022, public awareness of the threat of infectious diseases in humans was renewed by the global pandemic of a new type of a coronavirus, the SARS-COV-2. This public interest opened improved possibilities to test hypotheses on the factors associated with inter-individual variation in susceptibility to infectious and "modern" diseases. Based on the Hygiene hypothesis and Biodiversity hypothesis, we predicted that contacts with natural environment and wildlife in childhood and/or in adulthood can improve general health and decrease the risks of severe COVID-19 progression or prevalence of the "modern" diseases, namely the allergies. Here we report the results of an online, self-evaluating questionnaire survey conducted in the Czech Republic, where we contrasted selected health issues, and linked them to the living environment, including the level of contacts with biodiversity. In a sample of 1188 respondents, we revealed a significant association of time spent in nature or contacts with biodiversity with physical and mental health, or incidence of allergies. This is unlike the COVID-19 progression, which was related to age, physical health, smoking, allergies, and interaction of age with smoking, but not to contacts with the natural environmental diversity. Our findings regarding to physical and mental health and allergies are in agreement with the Biodiversity hypothesis of allergy and, linking human and environmental health, they urge for One Health approach application.

• Keywords
• Allergies, Biodiversity antigen richness, Civilization diseases, Contacts with nature, Infectious diseases, Wildlife,
• MeSH
• Hypersensitivity epidemiology   MeSH
• Biodiversity * MeSH
• COVID-19 * epidemiology   MeSH
• Adult MeSH
• Mental Health MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Pandemics MeSH
• Surveys and Questionnaires MeSH
• SARS-CoV-2 * isolation & purification   pathogenicity   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic epidemiology   MeSH

Microbiota plays a role in shaping the HPA-axis response to psychological stressors. To examine the role of microbiota in response to acute immune stressor, we stimulated the adaptive immune system by anti-CD3 antibody injection and investigated the expression of adrenal steroidogenic enzymes and profiling of plasma corticosteroids and their metabolites in specific pathogen-free (SPF) and germ-free (GF) mice. Using UHPLC-MS/MS, we showed that 4 hours after immune challenge the plasma levels of pregnenolone, progesterone, 11-deoxycorticosterone, corticosterone (CORT), 11-dehydroCORT and their 3α/β-, 5α-, and 20α-reduced metabolites were increased in SPF mice, but in their GF counterparts, only CORT was increased. Neither immune stress nor microbiota changed the mRNA and protein levels of enzymes of adrenal steroidogenesis. In contrast, immune stress resulted in downregulated expression of steroidogenic genes (Star, Cyp11a1, Hsd3b1, Hsd3b6) and upregulated expression of genes of the 3α-hydroxysteroid oxidoreductase pathway (Akr1c21, Dhrs9) in the testes of SPF mice. In the liver, immune stress downregulated the expression of genes encoding enzymes with 3β-hydroxysteroid dehydrogenase (HSD) (Hsd3b2, Hsd3b3, Hsd3b4, Hsd3b5), 3α-HSD (Akr1c14), 20α-HSD (Akr1c6, Hsd17b1, Hsd17b2) and 5α-reductase (Srd5a1) activities, except for Dhrs9, which was upregulated. In the colon, microbiota downregulated Cyp11a1 and modulated the response of Hsd11b1 and Hsd11b2 expression to immune stress. These data underline the role of microbiota in shaping the response to immune stressor. Microbiota modulates the stress-induced increase in C21 steroids, including those that are neuroactive that could play a role in alteration of HPA axis response to stress in GF animals.

• Keywords
• anti-CD3, germ-free, gut microbiota, immune stress, mice, steroidogenic genes, steroids,
• MeSH
• Cholesterol Side-Chain Cleavage Enzyme genetics   metabolism   MeSH
• Corticosterone metabolism   MeSH
• Microbiota * MeSH
• Mice MeSH
• Steroids metabolism   MeSH
• Pituitary-Adrenal System metabolism   MeSH
• Hypothalamo-Hypophyseal System * metabolism   MeSH
• Tandem Mass Spectrometry MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cholesterol Side-Chain Cleavage Enzyme MeSH
• Corticosterone MeSH
• Steroids MeSH

Glucocorticoids (GCs) are hormones that are released in response to stressors and exhibit many activities, including immunomodulatory and anti-inflammatory activities. They are primarily synthesized in the adrenal gland but are also produced in peripheral tissues via regeneration of adrenal 11-oxo metabolites or by de novo synthesis from cholesterol. The present study investigated the influence of the microbiota on de novo steroidogenesis and regeneration of corticosterone in the intestine of germ-free (GF) and specific pathogen-free mice challenged with a physical stressor (anti-CD3 antibody i.p. injection). In the small intestine, acute immune stress resulted in increased mRNA levels of the proinflammatory cytokines IL1β, IL6 and Tnfα and genes involved in de novo steroidogenesis (Stard3 and Cyp11a1), as well as in regeneration of active GCs from their 11-oxo metabolites (Hsd11b1). GF mice showed a generally reduced transcriptional response to immune stress, which was accompanied by decreased intestinal corticosterone production and reduced expression of the GC-sensitive marker Fkbp5. In contrast, the interaction between stress and the microbiota was not detected at the level of plasma corticosterone or the transcriptional response of adrenal steroidogenic enzymes. The results indicate a differential immune stress-induced intestinal response to proinflammatory stimuli and local corticosterone production driven by the gut microbiota.

• Keywords
• 11β-hydroxysteroid dehydrogenase, anti-CD3 antibody, extra-adrenal steroidogenesis, glucocorticoids, intestine, microbiome,
• MeSH
• 11-beta-Hydroxysteroid Dehydrogenases genetics   metabolism   MeSH
• Corticosterone metabolism   MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Mice MeSH
• Steroids metabolism   MeSH
• Gastrointestinal Microbiome physiology   MeSH
• Tandem Mass Spectrometry MeSH
• Intestine, Small metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 11-beta-Hydroxysteroid Dehydrogenases MeSH
• Corticosterone MeSH
• Steroids MeSH