Potential effects of the most prescribed drugs on the microbiota-gut-brain-axis: A review.

The link between drug-induced dysbiosis and its influence on brain diseases through gut-residing bacteria and their metabolites, named the microbiota-gut-brain axis (MGBA), remains largely unexplored. This review investigates the effects of commonly prescribed drugs (metformin, statins, proton-pump-inhibitors, NSAIDs, and anti-depressants) on the gut microbiota, comparing the findings with altered bacterial populations in major brain diseases (depression, multiple sclerosis, Parkinson's and Alzheimer's). The report aims to explore whether drugs can influence the development and progression of brain diseases via the MGBA. Central findings indicate that all explored drugs induce dysbiosis. These dysbiosis patterns were associated with brain disorders. The influence on brain diseases varied across different bacterial taxa, possibly mediated by direct effects or through bacterial metabolites. Each drug induced both positive and negative changes in the abundance of bacteria, indicating a counterbalancing effect. Moreover, the above-mentioned drugs exhibited similar effects, suggesting that they may counteract or enhance each other's effects on brain diseases when taken together by comorbid patients. In conclusion, the interplay of bacterial species and their abundances may have a greater impact on brain diseases than individual drugs or bacterial strains. Future research is needed to better understand drug-induced dysbiosis and the implications for brain disease pathogenesis, with the potential to develop more effective therapeutic options for patients with brain-related diseases.

Dietary and Non-Dietary Modulators of Cognitive Function.

Manifold internal and external factors may influence brain function in the long run, including genetic predispositions as well as epigenetic and environmental factors [...].

Nutrition and Aging.

This Special Issue focuses on the importance of nutritional interventions for the delay of age-related conditions [...].

Involvement of Intestinal Microbiota in Adult Neurogenesis and the Expression of Brain-Derived Neurotrophic Factor.

Growing evidence suggests a possible involvement of the intestinal microbiota in generating new neurons, but a detailed breakdown of the microbiota composition is lacking. In this report, we systematically reviewed preclinical rodent reports addressing the connection between the composition of the intestinal microbiota and neurogenesis and neurogenesis-affecting neurotrophins in the hippocampus. Various changes in bacterial composition from low taxonomic resolution at the phylum level to high taxonomic resolution at the species level were identified. As for neurogenesis, studies predominantly used doublecortin (DCX) as a marker of newly formed neurons or bromodeoxyuridine (BrdU) as a marker of proliferation. Brain-derived neurotrophic factor (BDNF) was the only neurotrophin found researched in relation to the intestinal microbiota. Phylum Actinobacteria, genus Bifidobacterium and genus Lactobacillus found the strongest positive. In contrast, phylum Firmicutes, phylum Bacteroidetes, and family Enterobacteriaceae, as well as germ-free status, showed the strongest negative correlation towards neurogenesis or BDNF mRNA expression. Age, short-chain fatty acids (SCFA), obesity, and chronic stress were recurring topics in all studies identified. Overall, these findings add to the existing evidence of a connection between microbiota and processes in the brain. To better understand this interaction, further investigation based on analyses of higher taxonomic resolution and clinical studies would be a gain to the matter.

Overlapping Mechanisms of Action of Brain-Active Bacteria and Bacterial Metabolites in the Pathogenesis of Common Brain Diseases.

The involvement of the gut microbiota and the metabolites of colon-residing bacteria in brain disease pathogenesis has been covered in a growing number of studies, but comparative literature is scarce. To fill this gap, we explored the contribution of the microbiota-gut-brain axis to the pathophysiology of seven brain-related diseases (attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, major depressive disorder, and bipolar disorder). In this article, we discussed changes in bacterial abundance and the metabolic implications of these changes on disease development and progression. Our central findings indicate that, mechanistically, all seven diseases are associated with a leaky gut, neuroinflammation, and over-activated microglial cells, to which gut-residing bacteria and their metabolites are important contributors. Patients show a pro-inflammatory shift in their colon microbiota, harbouring more Gram-negative bacteria containing immune-triggering lipopolysaccharides (LPS) in their cell walls. In addition, bacteria with pro-inflammatory properties (Alistipes, Eggerthella, Flavonifractor) are found in higher abundances, whereas lower abundances of anti-inflammatory bacteria (Bifidobacterium, Coprococcus, Eucbacterium, Eubacterium rectale, Faecalibacterium, Faecalibacterium prasunitzii, Lactobacillus, Prevotella, Roseburia) are reported, when compared to healthy controls. On the metabolite level, aberrant levels of short-chain fatty acids (SCFAs) are involved in disease pathogenesis and are mostly found in lower quantities. Moreover, bacterial metabolites such as neurotransmitters (acetylcholine, dopamine, noradrenaline, GABA, glutamate, serotonin) or amino acids (phenylalanine, tryptophan) also play an important role. In the future, defined aberrations in the abundance of bacteria strains and altered bacterial metabolite levels could likely be possible markers for disease diagnostics and follow-ups. Moreover, they could help to identify novel treatment options, underlining the necessity for a deeper understanding of the microbiota-gut-brain axis.

Nutrition for Brain Development.

This Special Issue focuses on the fundamental role of nutrition in brain development [...].

The Role of Gut Bacterial Metabolites in Brain Development, Aging and Disease.

In the last decade, emerging evidence has reported correlations between the gut microbiome and human health and disease, including those affecting the brain. We performed a systematic assessment of the available literature focusing on gut bacterial metabolites and their associations with diseases of the central nervous system (CNS). The bacterial metabolites short-chain fatty acids (SCFAs) as well as non-SCFAs like amino acid metabolites (AAMs) and bacterial amyloids are described in particular. We found significantly altered SCFA levels in patients with autism spectrum disorder (ASD), affective disorders, multiple sclerosis (MS) and Parkinson's disease (PD). Non-SCFAs yielded less significantly distinct changes in faecal levels of patients and healthy controls, with the majority of findings were derived from urinary and blood samples. Preclinical studies have implicated different bacterial metabolites with potentially beneficial as well as detrimental mechanisms in brain diseases. Examples include immunomodulation and changes in catecholamine production by histone deacetylase inhibition, anti-inflammatory effects through activity on the aryl hydrocarbon receptor and involvement in protein misfolding. Overall, our findings highlight the existence of altered bacterial metabolites in patients across various brain diseases, as well as potential neuroactive effects by which gut-derived SCFAs, p-cresol, indole derivatives and bacterial amyloids could impact disease development and progression. The findings summarized in this review could lead to further insights into the gut-brain-axis and thus into potential diagnostic, therapeutic or preventive strategies in brain diseases.

The Role of the Gut Microbiota in the Development and Progression of Major Depressive and Bipolar Disorder.

A growing number of studies in rodents indicate a connection between the intestinal microbiota and the brain, but comprehensive human data is scarce. Here, we systematically reviewed human studies examining the connection between the intestinal microbiota and major depressive and bipolar disorder. In this review we discuss various changes in bacterial abundance, particularly on low taxonomic levels, in terms of a connection with the pathophysiology of major depressive and bipolar disorder, their use as a diagnostic and treatment response parameter, their health-promoting potential, as well as novel adjunctive treatment options. The diversity of the intestinal microbiota is mostly decreased in depressed subjects. A consistent elevation of phylum Actinobacteria, family Bifidobacteriaceae, and genus Bacteroides, and a reduction of family Ruminococcaceae, genus Faecalibacterium, and genus Roseburia was reported. Probiotics containing Bifidobacterium and/or Lactobacillus spp. seemed to improve depressive symptoms, and novel approaches with different probiotics and synbiotics showed promising results. Comparing twin studies, we report here that already with an elevated risk of developing depression, microbial changes towards a "depression-like" microbiota were found. Overall, these findings highlight the importance of the microbiota and the necessity for a better understanding of its changes contributing to depressive symptoms, potentially leading to new approaches to alleviate depressive symptoms via alterations of the gut microbiota.

Specific Nutritional Biomarker Profiles in Mild Cognitive Impairment and Subjective Cognitive Decline Are Associated With Clinical Progression: The NUDAD Project.

OBJECTIVES: Nutritional insufficiencies have been associated with cognitive impairment. Understanding whether nutritional biomarker levels are associated with clinical progression could help to design dietary intervention trials. This longitudinal study examined a panel of nutritional biomarkers in relation to clinical progression in patients with subjective cognitive decline (SCD) or mild cognitive impairment (MCI). DESIGN, SETTING AND PARTICIPANTS: We included 299 patients without dementia (n = 149 SCD; age 61 ± 10 years, female 44%, n = 150 MCI; age 66 ± 8 years, female 38%). Median (interquartile range) follow-up was 3 (2-5) years. METHODS: We measured 28 nutritional biomarkers in blood and 5 in cerebrospinal fluid (CSF), associated with 3 Alzheimer's disease pathologic processes: vascular change (lipids), synaptic dysfunction (homocysteine-related metabolites), and oxidative stress (minerals and vitamins). Nutritional biomarker associations with clinical progression to MCI/dementia and cognitive decline based on the Mini-Mental State Examination score were evaluated using Cox proportional hazard models and linear mixed models. We used partial least squares Cox models (PLS-Cox) to examine nutritional biomarker profiles associated with clinical progression. RESULTS: In the total group, high high-density lipoprotein (HDL) levels were associated with clinical progression and cognitive decline. In SCD, high folate and low bilirubin levels were associated with cognitive decline. In MCI, low CSF S-adenosylmethionine (SAM) and high theobromine were associated with clinical progression to dementia and high HDL, cholesterol, iron, and 1,25(OH)2 vitamin D were associated with cognitive decline. PLS-Cox showed 1 profile for SCD, characterized by high betaine and folate and low zinc associated with clinical progression. In MCI, a profile with high theobromine and HDL and low triglycerides and a second profile with high plasma SAM and low cholesterol were associated with risk of dementia. CONCLUSION AND IMPLICATIONS: High HDL was most consistently associated with clinical progression. Moreover, different nutritional biomarker profiles for SCD and MCI showed promising associations with clinical progression. Future dietary (intervention) studies could use nutritional biomarker profiles to select patients, taking into account the disease stage.

The Potential Influence of the Bacterial Microbiome on the Development and Progression of ADHD.

The latest research cumulates staggering information about the correlation between the microbiota-gut-brain axis and neurodevelopmental disorders. This review aims to shed light on the potential influence of the microbiome on the development of the most prevalent neurodevelopmental disease, attention-deficit-hyperactive disorder (ADHD). As the etiology and pathophysiology of ADHD are still unclear, finding viable biomarkers and effective treatment still represent a challenge. Therefore, we focused on factors that have been associated with a higher risk of developing ADHD, while simultaneously influencing the microbial composition. We reviewed the effect of a differing microbial makeup on neurotransmitter concentrations important in the pathophysiology of ADHD. Additionally, we deduced factors that correlate with a high prevalence of ADHD, while simultaneously affecting the gut microbiome, such as emergency c-sections, and premature birth as the former leads to a decrease of the gut microbial diversity and the latter causes neuroprotective Lactobacillus levels to be reduced. Also, we assessed nutritional influences, such as breastfeeding, ingestion of short-chain fatty acids (SCFAs) and polyunsaturated fatty acids (PUFAs) on the host's microbiome and development of ADHD. Finally, we discussed the potential significance of Bifidobacterium as a biomarker for ADHD, the importance of preventing premature birth as prophylaxis and nutrition as a prospective therapeutic measurement against ADHD.

The Possible Role of the Microbiota-Gut-Brain-Axis in Autism Spectrum Disorder.

New research points to a possible link between autism spectrum disorder (ASD) and the gut microbiota as many autistic children have co-occurring gastrointestinal problems. This review focuses on specific alterations of gut microbiota mostly observed in autistic patients. Particularly, the mechanisms through which such alterations may trigger the production of the bacterial metabolites, or leaky gut in autistic people are described. Various altered metabolite levels were observed in the blood and urine of autistic children, many of which were of bacterial origin such as short chain fatty acids (SCFAs), indoles and lipopolysaccharides (LPS). A less integrative gut-blood-barrier is abundant in autistic individuals. This explains the leakage of bacterial metabolites into the patients, triggering new body responses or an altered metabolism. Some other co-occurring symptoms such as mitochondrial dysfunction, oxidative stress in cells, altered tight junctions in the blood-brain barrier and structural changes in the cortex, hippocampus, amygdala and cerebellum were also detected. Moreover, this paper suggests that ASD is associated with an unbalanced gut microbiota (dysbiosis). Although the cause-effect relationship between ASD and gut microbiota is not yet well established, the consumption of specific probiotics may represent a side-effect free tool to re-establish gut homeostasis and promote gut health. The diagnostic and therapeutic value of bacterial-derived compounds as new possible biomarkers, associated with perturbation in the phenylalanine metabolism, as well as potential therapeutic strategies will be discussed.

Brain Aging and Gut⁻Brain Axis.

In the last decade, the microbiome in general and the gut microbiome in particular have been associated not only to brain development and function, but also to the pathophysiology of brain aging and to neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), depression, or multiple sclerosis (MS) [...].

The effects of fermentation products of prebiotic fibres on gut barrier and immune functions in vitro.

The beneficial effects of prebiotic fibres on human health have been related to their capacities to alter the gut microbiota and modify the growth of beneficial microorganisms. It is long appreciated that bacterial metabolites affect the host's physiology. The inner lining of the intestinal tract is the first level of interaction between the host and bacteria and their metabolites. Therefore, we set out to test the effects of five common dietary fibres (oat ß-glucan 28%; oat ß-glucan 94%; dried chicory root containing inulin 75%; xylo-oligosaccharide; inulin 90%) and maltodextrin, after fermentation by human gut microbiota in vitro, on measures of gut barrier integrity using a Caco-2/HT29-MTX co-culture as well as mucus production and immune parameters using HT29-MTX and HT29 cell models, respectively. Our data show that all fibres, fermentation products increased the tightness of the gut barrier with oat ß-glucan 28% having the largest effect. Fermentation supernatants were tested also in models of the compromised gut barrier (leaky gut). After the addition of ethanol as basolateral stressor, only fermentation supernatant of oat ß-glucan 28%, oat ß-glucan 94% and maltodextrin improved the gut barrier integrity, while oat ß-glucan 28% and dried chicory root containing inulin 75% significantly improved the gut barrier integrity after addition of rhamnolipids as apical stressor. Using the Luminex Technology, we demonstrated an important role of oat ß-glucan fermentation products in modulating cytokine and chemokine productions. Furthermore, treating the goblet cells with effluent from xylo-oligosaccharide fermentation significantly increased mucus production. In summary, our data emphasize the potential positive effects of fermentation supernatant of dietary fibres on gut-related physiological outcomes and show that prebiotic fibres may have promising potential to induce specific gut health benefits.

Correction: The effects of fermentation products of prebiotic fibres on gut barrier and immune functions in vitro.

[This corrects the article DOI: 10.7717/peerj.5288.].

Changes of Colonic Bacterial Composition in Parkinson's Disease and Other Neurodegenerative Diseases.

In recent years evidence has emerged that neurodegenerative diseases (NDs) are strongly associated with the microbiome composition in the gut. Parkinson's disease (PD) is the most intensively studied neurodegenerative disease in this context. In this review, we performed a systematic evaluation of the published literature comparing changes in colonic microbiome in PD to the ones observed in other NDs including Alzheimer's disease (AD), multiple system atrophy (MSA), multiple sclerosis (MS), neuromyelitis optica (NMO) and amyotrophic lateral sclerosis (ALS). To enhance the comparability of different studies, only human case-control studies were included. Several studies showed an increase of Lactobacillus, Bifidobacterium, Verrucomicrobiaceae and Akkermansia in PD. A decrease of Faecalibacterium spp., Coprococcus spp., Blautia spp., Prevotella spp. and Prevotellaceae was observed in PD. On a low taxonomic resolution, like the phylum level, the changes are not disease-specific and are inconsistent. However, on a higher taxonomic resolution like genus or species level, a minor overlap was observed between PD and MSA, both alpha synucleinopathies. We show that standardization of sample collection and analysis is necessary for ensuring the reproducibility and comparability of data. We also provide evidence that assessing the microbiota composition at high taxonomic resolution reveals changes in relative abundance that may be specific to or characteristic of one disease or disease group, and might evolve discriminative power. The interactions between bacterial species and strains and the co-abundances must be investigated before assumptions about the effects of specific bacteria on the host can be made with certainty.

The role of the microbiome for human health: from basic science to clinical applications.

The 2017 annual symposium organized by the University Medical Center Groningen in The Netherlands focused on the role of the gut microbiome in human health and disease. Experts from academia and industry examined interactions of prebiotics, probiotics, or vitamins with the gut microbiome in health and disease, the development of the microbiome in early-life and the role of the microbiome on the gut-brain axis. The gut microbiota changes dramatically during pregnancy and intrinsic factors (such as stress), in addition to extrinsic factors (such as diet, and drugs) influence the composition and activity of the gut microbiome throughout life. Microbial metabolites, e.g. short-chain fatty acids affect gut-brain signaling and the immune response. The gut microbiota has a regulatory role on anxiety, mood, cognition and pain which is exerted via the gut-brain axis. Ingestion of prebiotics or probiotics has been used to treat a range of conditions including constipation, allergic reactions and infections in infancy, and IBS. Fecal microbiota transplantation (FMT) highly effective for treating recurrent Clostridium difficile infections. The gut microbiome affects virtually all aspects of human health, but the degree of scientific evidence, the models and technologies and the understanding of mechanisms of action vary considerably from one benefit area to the other. For a clinical practice to be broadly accepted, the mode of action, the therapeutic window, and potential side effects need to thoroughly be investigated. This calls for further coordinated state-of-the art research to better understand and document the human gut microbiome's effects on human health.

Relationship between the gut microbiome and brain function.

It has become increasingly evident in recent years that the gut microbiome and the brain communicate in a bidirectional manner, with each possibly affecting the other's functions. Substantial research has aimed to understand the mechanisms of this interaction and to outline strategies for preventing or treating nervous system-related disturbances. This review explores the evidence demonstrating how the gut microbiome may affect brain function in adults, thereby having an impact on stress, anxiety, depression, and cognition. In vitro, in vivo, and human studies reporting an association between a change in the gut microbiome and functional changes in the brain are highlighted, as are studies outlining the mechanisms by which the brain affects the microbiome and the gastrointestinal tract. Possible modes of action to explain how the gut microbiome and the brain functionally affect each other are proposed. Supplemental probiotics to combat brain-related dysfunction offer a promising approach, provided future research elucidates their mode of action and possible side effects. Further studies are warranted to establish how pre- and probiotic interventions may help to balance brain function in healthy and diseased individuals.

Toll-Like Receptors: Regulators of the Immune Response in the Human Gut.

Toll-like receptors (TLRs) are powerful molecular regulators by which the immune system may "sense" the environment and protect the host from pathogens or endogenous threats. In mammalian cells, several TLRs were identified with a tissue and cell type-specific distribution. Understanding the functions of specific TLRs is crucial for the development and discovery of compounds useful to maintaining or re-establishing homeostasis in the gastrointestinal tract (GIT). Due to their relevance in regulating the inflammatory response in the GIT, we will focus here on TLR2, TLR4, and TLR5. In particular, we describe (a) the molecular pathways activated by the stimulation of these receptors with their known bacterial ligands; (b) the non-bacterial ligands known to interact directly with TLR2 and TLR4 and their soluble forms. The scope of this minireview is to highlight the importance of bacterial and non-bacterial compounds in affecting the gut immune functions via the activation of the TLRs.

Poor cognitive ageing: Vulnerabilities, mechanisms and the impact of nutritional interventions.

BACKGROUND: Ageing is a highly complex process marked by a temporal cascade of events, which promote alterations in the normal functioning of an individual organism. The triggers of normal brain ageing are not well understood, even less so the factors which initiate and steer the neuronal degeneration, which underpin disorders such as dementia. A wealth of data on how nutrients and diets may support cognitive function and preserve brain health are available, yet the molecular mechanisms underlying their biological action in both normal ageing, age-related cognitive decline, and in the development of neurodegenerative disorders have not been clearly elucidated. OBJECTIVES: This review aims to summarise the current state of knowledge of vulnerabilities that predispose towards dysfunctional brain ageing, highlight potential protective mechanisms, and discuss dietary interventions that may be used as therapies. A special focus of this paper is on the impact of nutrition on neuroprotection and the underlying molecular mechanisms, and this focus reflects the discussions held during the 2nd workshop 'Nutrition for the Ageing Brain: Functional Aspects and Mechanisms' in Copenhagen in June 2016. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe). CONCLUSION: Coupling studies of cognitive ageing with studies investigating the effect of nutrition and dietary interventions as strategies targeting specific mechanisms, such as neurogenesis, protein clearance, inflammation, and non-coding and microRNAs is of high value. Future research on the impact of nutrition on cognitive ageing will need to adopt a longitudinal approach and multimodal nutritional interventions will likely need to be imposed in early-life to observe significant impact in older age.

Probiotics and the Gut Immune System: Indirect Regulation.

The gastrointestinal tract (GIT) represents the largest interface between the human organism and the external environment. In the lumen and upper part of the mucus layer, this organ hosts an enormous number of microorganisms whose composition affects the functions of the epithelial barrier and the gut immune system. Consequentially, the microorganisms in the GIT influence the health status of the organism. Probiotics are living microorganisms which, in specific conditions, confer a health benefit to the host. Among others, probiotics have immunomodulatory properties that usually act directly by (a) increasing the activity of macrophages or natural killer cells, (b) modulating the secretion of immunoglobulins or cytokines, or indirectly by (c) enhancing the gut epithelial barrier, (d) altering the mucus secretion, and (e) competitive exclusion of other (pathogenic) bacteria. This review focuses on specific bacteria strains with indirect immunomodulatory properties. Particularly, we describe here the mechanisms through which specific probiotics enhance the gut epithelial barrier and modulate mucus production. Moreover, we describe the antimicrobial properties of specific bacteria strains. Recent data suggest that multiple pathologies are associated with an unbalanced gut microflora (dysbiosis). Although the cause-effect relationship between pathology and gut microflora is not yet well established, consumption of specific probiotics may represent a powerful tool to re-establish gut homeostasis and promote gut health.