Microbiota-gut-brain axis: interplay between microbiota, barrier function and lymphatic system.

The human gastrointestinal tract, boasting the most diverse microbial community, harbors approximately 100 trillion microorganisms comprising viruses, bacteria, fungi, and archaea. The profound genetic and metabolic capabilities of the gut microbiome underlie its involvement in nearly every facet of human biology, from health maintenance and development to aging and disease. Recent recognition of microbiota - gut - brain axis, referring to the bidirectional communication network between gut microbes and their host, has led to a surge in interdisciplinary research. This review begins with an overview of the current understandings regarding the influence of gut microbes on intestinal and blood-brain barrier integrity. Subsequently, we discuss the mechanisms of the microbiota - gut - brain axis, examining the role of gut microbiota-related neural transmission, metabolites, gut hormones and immunity. We propose the concept of microbiota-mediated multi-barrier modulation in the potential treatment in gastrointestinal and neurological disorders. Furthermore, the role of lymphatic network in the development and maintenance of barrier function is discussed, providing insights into lesser-known conduits of communication between the microbial ecosystem within the gut and the brain. In the final section, we conclude by describing the ongoing frontiers in understanding of the microbiota - gut - brain axis's impact on human health and disease.

The complex interplay between autism spectrum disorder and gut microbiota in children: A comprehensive review.

Autism spectrum disorder (ASD) is characterized by defects in social communication and interaction along with restricted interests and/or repetitive behavior. Children with ASD often also experience gastrointestinal (GI) problems in fact incidence of GI problems in ASD is estimated up to 80 percent. Intestinal microbiota, which is a collection of trillions of microorganisms both beneficial and potentially harmful bacteria living inside the gut, has been considered one of the key elements of gut disorders. The goal of this review is to explore potential link between gut microbiota and ASD in children, based on the recently available data. This review discusses recent advances in this rapidly expanding area of neurodevelopmental disorders, which focuses on what is known about the changes in composition of gut bacteria in children with ASD, exploration of possible mechanisms via which gut microbiota might influence the brain and thus lead to appearance of ASD symptoms, as well as potential treatments that involve modulation of gut flora to improve symptoms in children with ASD, i.e., probiotics, postbiotics or changes in the diet. Of course, it's important to keep in mind inherent difficulties in proving of existence of causal relationships between gut bacteria and ASD. There are significant gaps in understanding of the mechanism of gut-brain axis and the mechanisms that underlie ASD. Standardized approaches for research in this area are needed. This review would provide an overview of this exciting emerging field of research.

Unlocking the mind-gut connection: Impact of human microbiome on cognition.

This perspective explores the current understanding of the gut microbiota's impact on cognitive function in apparently healthy humans and in individuals with metabolic disease. We discuss how alterations in gut microbiota can influence cognitive processes, focusing not only on bacterial composition but also on often overlooked components of the gut microbiota, such as bacteriophages and eukaryotes, as well as microbial functionality. We examine the mechanisms through which gut microbes might communicate with the central nervous system, highlighting the complexity of these interactions. We provide a comprehensive overview of the emerging field of microbiota-gut-brain interactions and its significance for cognitive health. Additionally, we summarize novel therapeutic strategies designed to promote cognitive resilience and reduce the risk of cognitive disorders, focusing on interventions that target the gut microbiota. An in-depth understanding of the microbiome-brain axis is imperative for developing innovative treatments aimed at improving cognitive health.

Difficulty in diagnosing intracranial infection caused by Mycobacterium avium in an AIDS patient: case report and review of the literature.

BACKGROUND: Mycobacterium avium complex (MAC) is an uncommon clinical pathogen, especially in the central nervous system (CNS), and carries a poor prognosis. MAC infections commonly present as immune reconstitution disease (IRD) in HIV patients. Herein, we report a case of intracranial infection caused by MAC in an AIDS patient without disseminated MAC (DMAC) and immune reconstitution inflammatory syndrome (IRIS). CASE PRESENTATION: A 31-year-old HIV-positive male presented us with progressively worsening CNS symptoms, and neuroimaging revealed ring-enhancing lesions. The intracranial lesions worsened after the empirical therapy for toxoplasma encephalitis and fungal infection. Due to the rapid progression of the disease, the patient died. Mycobacterium avium was the only pathogen in brain tissue after cultures and molecular biology tests. CONCLUSION: MAC infection in CNS is challenging to diagnose in HIV patients. Our findings emphasize that obtaining tissue samples and applying molecular biology methods is essential to help diagnose the patient as soon as possible to receive adequate treatment.

Early Life Adversity, Microbiome, and Inflammatory Responses.

Early life adversity has a profound impact on physical and mental health. Because the central nervous and immune systems are not fully mature at birth and continue to mature during the postnatal period, a bidirectional interaction between the central nervous system and the immune system has been hypothesized, with traumatic stressors during childhood being pivotal in priming individuals for later adult psychopathology. Similarly, the microbiome, which regulates both neurodevelopment and immune function, also matures during childhood, rendering this interaction between the brain and the immune system even more complex. In this review, we provide evidence for the role of the immune response and the microbiome in the deleterious effects of early life adversity, both in humans and rodent models.

Medulla oblongata and NCCs are central defenders against Streptococcus agalactiae infection of the tilapia brain.

Various types of professional immune cells first emerge in fish and likely represent the primordial form and functions. Recent advancements revealed the direct connection between the central nervous system and the immune system in the mammalian brain. However, the specifics of brain-immune networks in the fish and the underlying mechanisms of teleost's brain against pathogen infection have not been fully elucidated. In this study, we investigated the distribution of markers representing cerebral cells associated with protection and professional lymphocytes in the seven major components of the Nile tilapia brain through RNA-Seq assay and observed the most dominant abundance in the medulla oblongata. The subsequent challenge test revealed the non-specific cytotoxic cells (NCCs) exhibited the strongest response against streptococcal infection of the brain. The presence of NCCs in the brain was then confirmed using immunofluorescence and the cytotoxic effects usually induced by NCCs under infection were determined as well. Collectively, these findings contribute significantly to comprehending the mechanism of fish neuroimmune interaction and enhancing our understanding of its evolutionary development.

A deep cut into early cryptococcal pathogenesis.

Dissemination from one organ system to another is common to many pathogens and often the key process separating simple illness from fatal infection. The pathogenic Cryptococcus species offer a prime example. Cryptococcal infection is thought to begin in the lungs, as a mild or asymptomatic pneumonia. However, bloodborne dissemination from the lungs to the brain is responsible for the most devastating forms of infection. As with other disseminating infections, the transition likely depends on rare but crucial events, such as the crossing of a tissue barrier. By their nature, these events are difficult to study. Francis et al. (mBio 15:e03078-23, 2024, https://doi.org/10.1128/mbio.03078-23) have addressed this difficulty by developing a powerful imaging pipeline to scan through unprecedented volumes of tissue from mice infected with Cryptococcus at multiple stages of infection. Their observations challenge some of our basic assumptions about cryptococcal pathogenesis, including when and how the organism reaches the bloodstream and the central nervous system.

The gut microbiome in disorders of gut-brain interaction.

Functional gastrointestinal disorders (FGIDs), chronic disorders characterized by either abdominal pain, altered intestinal motility, or their combination, have a worldwide prevalence of more than 40% and impose a high socioeconomic burden with a significant decline in quality of life. Recently, FGIDs have been reclassified as disorders of gut-brain interaction (DGBI), reflecting the key role of the gut-brain bidirectional communication in these disorders and their impact on psychological comorbidities. Although, during the past decades, the field of DGBIs has advanced significantly, the molecular mechanisms underlying DGBIs pathogenesis and pathophysiology, and the role of the gut microbiome in these processes are not fully understood. This review aims to discuss the latest body of literature on the complex microbiota-gut-brain interactions and their implications in the pathogenesis of DGBIs. A better understanding of the existing communication pathways between the gut microbiome and the brain holds promise in developing effective therapeutic interventions for DGBIs.

The critical role of NLRP3 inflammasome activation in Streptococcus suis-induced blood-brain barrier disruption.

Streptococcus suis (S. suis) type 2 (SS2) is an important zoonotic pathogen causing severe neural infections in pigs and causes serious threat to public health. Inflammasome activation plays an important role in the host against microbial infection but the role of inflammasome activation in the blood-brain barrier (BBB) integrity during S. suis infection is rarely studied. This study investigated the mechanism by which S. suis-induced NLRP3 inflammasome activation led to BBB disruption. Our results showed that S. suis infection activated NLRP3 inflammasome in brain microvascular endothelial cells (BMECs) leading to the secretion of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and chemokines (CCL-2 and CXCL-2) as well as the cleavage of Gasdermin D (GSDMD) which were significantly attenuated by inflammasome inhibitor MCC950. Furthermore, S. suis infection significantly downregulated expression of tight junctions (TJs) proteins and trans-endothelial electrical resistance (TEER) while NLRP3 inhibition rescued S. suis-induced degradation of TJs proteins and significantly reduced the number of S. suis crossing BBB in transwell infection model. Moreover, recombinant IL-1ß exacerbated the reduction of TJs proteins in BMECs. In murine S. suis-infection model, MCC950 reduced the bacterial load and the excessive inflammatory response in mice brain. In addition, the integrity of the BBB was protected with increased TJ proteins expression and decreased pathological injury after the inhibition of NLRP3 inflammasome, indicating NLRP3 inflammasome plays a destructive role in meningitis induced by S. suis. Our study expands the understanding on the role of NLRP3 inflammasome in bacterial meningitis, which provide the valuable information for the development of anti-infective agents targeting NLRP3 to treat bacterial meningitis.

Advances in the study of gut microbes in pediatric epilepsy.

Epilepsy a prevalent childhood neurological disorder, arises from chronic brain dysfunction caused by oversynchronized firing of neurons. Frequent seizures often lead to both physical and intellectual damage in children, seriously affecting their growth and development, life and health. Recent research studies have shown that the intestinal microbes in pediatric epilepsy is significantly different from that of healthy children, characterised by changes in the abundance of specific microbe communities and a reduction in diversity. These alterations may influence epileptic seizures through various pathways, including the microbiota-gut-brain axis by modulating neurotransmitters metabolism, affecting gut barrier function and immune responses, and directly impacting brain activity via the vagus nerves. This review highlights the alterations in gut microbes and their metabolites in epileptic children, analyzes their impact on seizures, and explores potential associations.

Relationship between human oral microbiome dysbiosis and neuropsychiatric diseases: An updated overview.

The role of the gut-brain axis in mental health disorders has been extensively studied. As the oral cavity is the starting point of the digestive tract, the role that the oral microbiota plays in mental health disorders has gained recent attention. Oral microbiota can enter the bloodstream and trigger inflammatory responses or translocate to the brain through the trigeminal nerve or olfactory system. Hence, the concept of the oral microbiota-brain axis has emerged. Several hypotheses have been suggested that the oral microbiota can enter the gastrointestinal tract and affect the gut-brain axis; however, literature describing oral-brain communication remains limited. This review summarizes the characteristics of oral microbiota and its mechanisms associated with mental health disorders. Through a comprehensive examination of the relationship between oral microbiota and various neuropsychiatric diseases, such as anxiety, depression, schizophrenia, autism spectrum disorder, epilepsy, Parkinson's disease, and dementia, this review seeks to identify promising avenues of future research.

Cryptococcus neoformans trehalose-6-phosphate synthase (tps1) promotes organ-specific virulence and fungal protection against multiple lines of host defenses.

Trehalose-6-phosphate synthase (TPS1) was identified as a virulence factor for Cryptococcus neoformans and a promising therapeutic target. This study reveals previously unknown roles of TPS1 in evasion of host defenses during pulmonary and disseminated phases of infection. In the pulmonary infection model, TPS1-deleted (tps1Δ) Cryptococci are rapidly cleared by mouse lungs whereas TPS1-sufficent WT (H99) and revertant (tps1Δ:TPS1) strains expand in the lungs and disseminate, causing 100% mortality. Rapid pulmonary clearance of tps1Δ mutant is T-cell independent and relies on its susceptibility to lung resident factors and innate immune factors, exemplified by tps1Δ but not H99 inhibition in a coculture with dispersed lung cells and its rapid clearance coinciding with innate leukocyte infiltration. In the disseminated model of infection, which bypasses initial lung-fungus interactions, tps1Δ strain remains highly attenuated. Specifically, tps1Δ mutant is unable to colonize the lungs from the bloodstream or expand in spleens but is capable of crossing into the brain, where it remains controlled even in the absence of T cells. In contrast, strains H99 and tps1Δ:TPS1 rapidly expand in all studied organs, leading to rapid death of the infected mice. Since the rapid pulmonary clearance of tps1Δ mutant resembles a response to acapsular strains, the effect of tps1 deletion on capsule formation in vitro and in vivo was examined. Tps1Δ cryptococci form capsules but with a substantially reduced size. In conclusion, TPS1 is an important virulence factor, allowing C. neoformans evasion of resident pulmonary and innate defense mechanisms, most likely via its role in cryptococcal capsule formation.

Host-microbe interactions: communication in the microbiota-gut-brain axis.

Animals harbor a diverse array of symbiotic micro-organisms that coexist in communities across different body sites. These microbes maintain host homeostasis and respond to environmental insults to impact host physiological processes. Trillions of indigenous microbes reside in the gastrointestinal tract and engage with the host central nervous system (microbiota-gut-brain axis) by modulating immune responses, interacting with gut intrinsic and extrinsic nervous system, and regulating neuromodulators and biochemicals. These gut microbiota to brain signaling pathways are constantly informed by each other and are hypothesized to mediate brain health across the lifespan. In this review, we will examine the crosstalk of gut microbiota to brain communications in neurological pathologies, with an emphasis on microbial metabolites and neuromodulators, and provide a discussion of recent advances that help elucidate the microbiota as a therapeutic target for treating brain and behavioral disorders.

Disseminated cerebral cryptococcoma mimicking glioblastoma - A case report."

We discuss a rare instance of cryptococcoma caused by Cryptococcus gattii in a 55-year-old woman initially treated for suspected COVID bronchopneumonia. The diagnosis posed a challenge due to vague symptoms and unclear imaging findings suggesting malignancy. Postoperative samples confirmed the presence of Cryptococcus gattii through culture of brain tissue and blood. Appropriate therapy was initiated, but despite treatment, it led to a fatal outcome. The case emphasizes the crucial role of microbiologist in early diagnosis of fungal infections of Central Nervous System. Additionally, the delayed diagnosis in immunocompetent individuals highlights the critical need for early recognition and intervention to mitigate potentially fatal outcomes.

The microbiota-gut-brain-immune interface in the pathogenesis of neuroinflammatory diseases: a narrative review of the emerging literature.

Importance: Research is beginning to elucidate the sophisticated mechanisms underlying the microbiota-gut-brain-immune interface, moving from primarily animal models to human studies. Findings support the dynamic relationships between the gut microbiota as an ecosystem (microbiome) within an ecosystem (host) and its intersection with the host immune and nervous systems. Adding this to the effects on epigenetic regulation of gene expression further complicates and strengthens the response. At the heart is inflammation, which manifests in a variety of pathologies including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Multiple Sclerosis (MS). Observations: Generally, the research to date is limited and has focused on bacteria, likely due to the simplicity and cost-effectiveness of 16s rRNA sequencing, despite its lower resolution and inability to determine functional ability/alterations. However, this omits all other microbiota including fungi, viruses, and phages, which are emerging as key members of the human microbiome. Much of the research has been done in pre-clinical models and/or in small human studies in more developed parts of the world. The relationships observed are promising but cannot be considered reliable or generalizable at this time. Specifically, causal relationships cannot be determined currently. More research has been done in Alzheimer's disease, followed by Parkinson's disease, and then little in MS. The data for MS is encouraging despite this. Conclusions and relevance: While the research is still nascent, the microbiota-gut-brain-immune interface may be a missing link, which has hampered our progress on understanding, let alone preventing, managing, or putting into remission neurodegenerative diseases. Relationships must first be established in humans, as animal models have been shown to poorly translate to complex human physiology and environments, especially when investigating the human gut microbiome and its relationships where animal models are often overly simplistic. Only then can robust research be conducted in humans and using mechanistic model systems.

Group B Streptococcus transcriptome when interacting with brain endothelial cells.

Bacterial meningitis is a life-threatening infection of the central nervous system (CNS) that occurs when bacteria are able to cross the blood-brain barrier (BBB) or the meningeal-cerebrospinal fluid barrier (mBCSFB). The BBB and mBCSFB comprise highly specialized brain endothelial cells (BECs) that typically restrict pathogen entry. Group B Streptococcus (GBS or Streptococcus agalactiae) is the leading cause of neonatal meningitis. Until recently, identification of GBS virulence factors has relied on genetic screening approaches. Instead, we here conducted RNA-seq analysis on GBS when interacting with induced pluripotent stem cell-derived BECs (iBECs) to pinpoint virulence-associated genes. Of the 2,068 annotated protein-coding genes of GBS, 430 transcripts displayed significant changes in expression after interacting with BECs. Notably, we found that the majority of differentially expressed GBS transcripts were downregulated (360 genes) during infection of iBECs. Interestingly, codY, encoding a pleiotropic transcriptional repressor in low-G + C Gram-positive bacteria, was identified as being highly downregulated. We conducted qPCR to confirm the codY downregulation observed via RNA-seq during the GBS-iBEC interaction and obtained codY mutants in three different GBS background parental strains. As anticipated from the RNA-seq results, the [Formula: see text]codY strains were more adherent and invasive in two in vitro BEC models. Together, this demonstrates the utility of RNA-seq during the BEC interaction to identify GBS virulence modulators. IMPORTANCE: Group B Streptococcus (GBS) meningitis remains the leading cause of neonatal meningitis. Research work has identified surface factors and two-component systems that contribute to GBS disruption of the blood-brain barrier (BBB). These discoveries often relied on genetic screening approaches. Here, we provide transcriptomic data describing how GBS changes its transcriptome when interacting with brain endothelial cells. Additionally, we have phenotypically validated these data by obtaining mutants of a select regulator that is highly down-regulated during infection and testing on our BBB model. This work provides the research field with a validated data set that can provide an insight into potential pathways that GBS requires to interact with the BBB and open the door to new discoveries.

New methods to unveil host-microbe interaction mechanisms along the microbiota-gut-brain-axis.

Links between the gut microbiota and human health have been supported throughout numerous studies, such as the development of neurological disease disorders. This link is referred to as the "microbiota-gut-brain axis" and is the focus of an emerging field of research. Microbial-derived metabolites and gut and neuro-immunological metabolites regulate this axis in health and many diseases. Indeed, assessing these signals, whether induced by microbial metabolites or neuro-immune mediators, could significantly increase our knowledge of the microbiota-gut-brain axis. However, this will require the development of appropriate techniques and potential models. Methods for studying the induced signals originating from the microbiota remain crucial in this field. This review discusses the methods and techniques available for studies of microbiota-gut-brain interactions. We highlight several much-debated elements of these methodologies, including the widely used in vivo and in vitro models, their implications, and perspectives in the field based on a systematic review of PubMed. Applications of various animal models (zebrafish, mouse, canine, rat, rabbit) to microbiota-gut-brain axis research with practical examples of in vitro methods and innovative approaches to studying gut-brain communications are highlighted. In particular, we extensively discuss the potential of "organ-on-a-chip" devices and their applications in this field. Overall, this review sheds light on the most widely used models and methods, guiding researchers in the rational choice of strategies for studies of microbiota-gut-brain interactions.

From gut microbiota to brain: implications on binge eating disorders.

The prevalence of eating disorders has been increasing over the last 50 years. Binge eating disorder (BED) and bulimia nervosa (BN) are two typical disabling, costly and life-threatening eating disorders that substantially compromise the physical well-being of individuals while undermining their psychological functioning. The distressing and recurrent episodes of binge eating are commonly observed in both BED and BN; however, they diverge as BN often involves the adoption of inappropriate compensatory behaviors aimed at averting weight gain. Normal eating behavior is coordinated by a well-regulated trade-off between intestinal and central ingestive mechanism. Conversely, despite the fact that the etiology of BED and BN remains incompletely resolved, emerging evidence corroborates the notion that dysbiosis of gastrointestinal microbiome and its metabolites, alteration of gut-brain axis, as well as malfunctioning central circuitry regulating motivation, execution and reward all contribute to the pathology of binge eating. In this review, we aim to outline the current state of knowledge pertaining to the potential mechanisms through which each component of the gut-brain axis participates in binge eating behaviors, and provide insight for the development of microbiome-based therapeutic interventions that hold promise in ameliorating patients afflicted with binge eating disorders.