Autism, a disorder influenced by both genetic and environmental factors, presents significant challenges for prevention and treatment. While maternal-infant gut microbiota has been a focus in autism research, preventive strategies targeting maternal gut microbiota remain underexplored. This study demonstrates that prenatal probiotic intake can effectively prevent maternal separation-induced autistic-like behaviors in offspring without altering the embryonic neurodevelopment in mice. Using specific PCR primers and cross-fostering experiments, we traced the vertical transmission of probiotics, primarily via fecal/vaginal contamination. Early probiotic colonization conferred resilience against stress-induced gut pathogenic microbes and Th17-mediated peripheral inflammation while significantly inhibiting hypermyelination and neuroinflammation linked to systemic inflammation. Microbial metabolites like tyrosol and xanthurenic acid alleviated neuroinflammation and hypermyelination in vitro, though the causal relationship among neuroinflammation, hypermyelination, and autism in vivo requires further validation. These findings underscore the importance of the maternal-infant microbiota transmission window in autism prevention and highlight the clinical potential of prenatal probiotic interventions.

Prenatal imprinting to interleukin 17A (IL-17A) triggers behavioral disorders in offspring. However, reported models of maternal immune activation utilizing immunostimulants, lack specificity to elucidate the anatomical compartments of IL-17A's action and the distinct behavioral disturbances it causes. By combining transgenic IL-17A overexpression with maternal deficiency in its receptor, we established a novel model of prenatal imprinting to maternal IL-17A (acronym: PRIMA-17 model). This model allowed us to study prenatal imprinting established exclusively through embryo-restricted IL-17A responses. We demonstrated a transfer of transgenic IL-17A across the placental barrier, which triggered the development of selected behavioral deficits in mouse offspring. More specifically, embryonic responses to IL-17A resulted in communicative impairment in early-life measured by reduced numbers of nest retrieval calls. In adulthood, IL-17A-imprinted offspring displayed an increase in anxiety-like behavior. We advocate our PRIMA-17 model as a useful tool to study neurological deficits in mice.

Humans and other animals contain multitudes of microorganisms including bacteria, fungi, and viruses, which make up a diverse microbiome. Across body sites including skin, gastrointestinal tract, and oral cavity there are distinct microbial niches that are made up of trillions of microorganisms that have co-evolved to inhabit and interact with the host. The microbiome also interacts with the changing environment. This tripartite interaction between the host, microbiome, and environment suggests microbial communities play a key role in the biological processes of the host, such as development and behaviors. Over the past two decades, emerging research continues to reveal how host and microbe interactions impact nervous system signaling and behaviors, and influence neurodevelopmental, neurological, and neurodegenerative disorders. In this review, we will describe the unique features of the maternal microbiome that exist during the perinatal period and discuss evidence for the function of the maternal microbiome in offspring development. Finally, we will discuss how the maternal environment interacts with the microbiome and nervous system development and then postulate how the maternal microbiome can modify early offspring development to have lasting influence on brain health.

The gut microbiota, the complex community of microorganisms that inhabit the gastrointestinal tract, has emerged as a key player in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD). AD is characterized by progressive cognitive decline and neuronal loss, associated with the accumulation of amyloid-β plaques, neurofibrillary tangles, and neuroinflammation in the brain. Increasing evidence suggests that alterations in the composition and function of the gut microbiota, known as dysbiosis, may contribute to the development and progression of AD by modulating neuroinflammation, a chronic and maladaptive immune response in the central nervous system. This review aims to comprehensively analyze the current role of the gut microbiota in regulating neuroinflammation and glial cell function in AD. Its objective is to deepen our understanding of the pathogenesis of AD and to discuss the potential advantages and challenges of using gut microbiota modulation as a novel approach for the diagnosis, treatment, and prevention of AD.

Microbial transmission from mother to infant is important for offspring microbiome formation and health. However, it is unclear whether maternal gut inflammation (MGI) during lactation influences mother-to-infant microbial transmission and offspring microbiota and disease susceptibility. In this study, it is found that MGI during lactation altered the gut microbiota of suckling pups by shaping the maternal microbiota in the gut and mammary glands. MGI-induced changes in the gut microbiota of suckling pups lasted into adulthood, resulting in the exacerbation of acute liver failure (ALF) caused by acetaminophen (APAP) in offspring. Specifically, MGI reduced the abundance of Lactobacillus reuteri (L. reuteri) and its metabolite indole-3-acetic acid (IAA) level in adult offspring. L. reuteri and IAA alleviated ALF in mice by promoting intestinal IL-22 production. Mechanistically, IL-22 limits APAP-induced excessive oxidative stress and ferroptosis by activating STAT3. The intestinal abundances of L. reuteri and IAA are inversely associated with the progression of patients with ALF. Overall, the study reveals the role of MGI in mother-to-infant microbial transmission and disease development in offspring, highlighting potential strategies for intervention in ALF based on the IAA-IL-22-STAT3 axis.

The risk factors for type 2 diabetes mellitus (T2DM) have been increasingly researched, but the lack of systematic identification and categorization makes it difficult for clinicians to quickly and accurately access and understand all the risk factors, which are categorized in this paper into five categories: Social determinants, lifestyle, checkable/testable risk factors, history of illness and medication, and other factors, which are discussed in a narrative review. Meanwhile, this paper points out the problems of the current research, helps to improve the systematic categorisation and practicality of T2DM risk factors, and provides a professional research basis for clinical practice and industry decision-making.

The maternal microbiome influences child health. However, its impact on a given offspring's stem cells, which regulate development, remains poorly understood. To investigate the role of the maternal microbiome in conditioning the offspring's stem cells, we manipulated maternal microbiota using Akkermansia muciniphila. Different maternal microbiomes had distinct effects on proliferation and differentiation of neuronal and intestinal stem cells in the offspring, influencing their developmental trajectory, physiology, and long-term health. Transplantation of altered maternal microbiota into germ-free mice transmitted these stem cell phenotypes to the recipients' offspring. The progeny of germ-free mice selectively colonized with Akkermansia did not display these stem cell traits, emphasizing the importance of microbiome diversity. Metabolically more active maternal microbiomes enriched the levels of circulating short-chain fatty acids (SCFAs) and amino acids, leaving distinct transcriptomic imprints on the mTOR pathway of offsprings' stem cells. Blocking mTOR signaling during pregnancy eliminated the maternal-microbiome-mediated effects on stem cells. These results suggest a fundamental role of the maternal microbiome in programming offsprings' stem cells and represent a promising target for interventions.

Gestational diabetes mellitus (GDM) affects over 10% of all pregnancies, both in Korea and worldwide. GDM not only increases the risk of adverse pregnancy outcomes such as preeclampsia, preterm birth, macrosomia, neonatal hypoglycemia, and shoulder dystocia, but it also significantly increases the risk of developing postpartum type 2 diabetes mellitus and cardiovascular disease in the mother. Additionally, GDM is linked to a higher risk of childhood obesity and diabetes in offspring, as well as neurodevelopmental disorders, including autistic spectrum disorder. This review offers a comprehensive summary of clinical epidemiological studies concerning maternal and fetal complications and explores mechanistic investigations that reveal the underlying pathophysiology.

Recent advances in understanding the modulatory functions of gut and gut microbiota on human diseases facilitated our focused attention on the contribution of the gut to the pathophysiological alterations of many extraintestinal organs, including the liver, heart, brain, lungs, kidneys, bone, skin, reproductive, and endocrine systems. In this review, we applied the "gut-X axis" concept to describe the linkages between the gut and other organs and discussed the latest findings related to the "gut-X axis," including the underlying modulatory mechanisms and potential clinical intervention strategies.

Epidemiological studies link exposure to viral infection during pregnancy, including influenza A virus (IAV) infection, with increased incidence of neurodevelopmental disorders (NDDs) in offspring. Models of maternal immune activation (MIA) using viral mimetics demonstrate that activation of maternal intestinal T helper 17 (TH17) cells, which produce effector cytokine interleukin (IL)-17, leads to aberrant fetal brain development, such as neocortical malformations. Fetal microglia and border-associated macrophages (BAMs) also serve as potential cellular mediators of MIA-induced cortical abnormalities. However, neither the inflammation-induced TH17 cell pathway nor fetal brain-resident macrophages have been thoroughly examined in models of live viral infection during pregnancy. Here, we inoculated pregnant mice with two infectious doses of IAV and evaluated peak innate and adaptive immune responses in the dam and fetus. While respiratory IAV infection led to dose-dependent maternal colonic shortening and microbial dysregulation, there was no elevation in intestinal TH17 cells nor IL-17. Systemically, IAV resulted in consistent dose- and time-dependent increases in IL-6 and IFN-γ. Fetal cortical abnormalities and global changes in fetal brain transcripts were observable in the high-but not the moderate-dose IAV group. Profiling of fetal microglia and BAMs revealed dose- and time-dependent differences in the numbers of meningeal but not choroid plexus BAMs, while microglial numbers and proliferative capacity of Iba1+ cells remained constant. Fetal brain-resident macrophages increased phagocytic CD68 expression, also in a dose- and time-dependent fashion. Taken together, our findings indicate that certain features of MIA are conserved between mimetic and live virus models, while others are not. Overall, we provide consistent evidence of an infection severity threshold for downstream maternal inflammation and fetal cortical abnormalities, which recapitulates a key feature of the epidemiological data and further underscores the importance of using live pathogens in NDD modeling to better evaluate the complete immune response and to improve translation to the clinic.

In the United States, autism spectrum disorder (ASD) affects 1 in 33 children and is characterized by atypical social interactions, communication difficulties, and intense, restricted interests. Microbial dysbiosis in the gastrointestinal (GI) tract is frequently observed in individuals with ASD, potentially contributing to behavioral manifestations and correlating with worsening severity. Moreover, dysbiosis may contribute to the increased prevalence of GI comorbidities in the ASD population and exacerbate immune dysregulation, further worsening dysbiosis. Over the past 25 years, research on the impact of microbial manipulation on ASD outcomes has gained substantial interest. Various approaches to microbial manipulation have been preclinically and clinically tested, including antibiotic treatment, dietary modifications, prebiotics, probiotics, and fecal microbiota transplantation. Each method has shown varying degrees of success in reducing the severity of ASD behaviors and/or GI symptoms and varying long-term efficacy. In this review, we discuss these microbiome manipulation methods and their outcomes. We also discuss potential microbiome manipulation early in life, as this is a critical period for neurodevelopment.

Pregnancy is a risk factor for increased severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory infections, but the mechanisms underlying this risk are poorly understood. To gain insight into the role of pregnancy in modulating immune responses at baseline and upon SARS-CoV-2 infection, we collected peripheral blood mononuclear cells and plasma from 226 women, including 152 pregnant individuals and 74 non-pregnant women. We find that SARS-CoV-2 infection is associated with altered T cell responses in pregnant women, including a clonal expansion of CD4-expressing CD8+ T cells, diminished interferon responses, and profound suppression of monocyte function. We also identify shifts in cytokine and chemokine levels in the sera of pregnant individuals, including a robust increase of interleukin-27, known to drive T cell exhaustion. Our findings reveal nuanced pregnancy-associated immune responses, which may contribute to the increased susceptibility of pregnant individuals to viral respiratory infection.

The microorganisms colonizing the gastrointestinal tract of animals, collectively referred to as the gut microbiome, affect numerous host behaviors dependent on the central nervous system (CNS). Studies comparing germ-free mice to normally colonized mice have demonstrated influences of the microbiome on anxiety-related behaviors, voluntary activity, and gene expression in the CNS. Additionally, there is epidemiologic evidence supporting an intergenerational influence of the maternal microbiome on neurodevelopment of offspring and behavior later in life. There is limited experimental evidence however directly linking the maternal microbiome to long-term neurodevelopmental outcomes, or knowledge regarding mechanisms responsible for such effects.

Here we show that that the maternal microbiome has a dominant influence on several offspring phenotypes including anxiety-related behavior, voluntary activity, and body weight. Adverse outcomes in offspring were associated with features of the maternal microbiome including bile salt hydrolase activity gene expression (bsh), abundance of certain bile acids, and hepatic expression of Slc10a1. In cross-foster experiments, offspring resembled their birth dam phenotypically, despite faithful colonization in the postnatal period with the surrogate dam microbiome. Genome-wide methylation analysis of hippocampal DNA identified microbiome-associated differences in methylation of 196 loci in total, 176 of which show conserved profiles between mother and offspring. Further, single-cell transcriptional analysis revealed accompanying differences in expression of several differentially methylated genes within certain hippocampal cell clusters, and vascular expression of genes associated with bile acid transport. Inferred cell-to-cell communication in the hippocampus based on coordinated ligand-receptor expression revealed differences in expression of neuropeptides associated with satiety.

Collectively, these data provide proof-of-principle that the maternal gut microbiome has a dominant influence on the neurodevelopment underlying certain offspring behaviors and activities, and selectively affects genome methylation and gene expression in the offspring CNS in conjunction with that neurodevelopment.

Alzheimer's disease (AD) is characterized by progressive cognitive decline and neuronal loss, commonly linked to amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Recent research highlights the gut microbiota as a key player in modulating neuroinflammation, a critical pathological feature of AD. Understanding the role of the gut microbiota in this process is essential for uncovering new therapeutic avenues and gaining deeper insights into AD pathogenesis.

This review provides a comprehensive analysis of how gut microbiota influences neuroinflammation and glial cell function in AD. A systematic literature search was conducted, covering studies from 2014 to 2024, including reviews, clinical trials, and animal studies. Keywords such as "gut microbiota," "Alzheimer's disease," "neuroinflammation," and "blood-brain barrier" were used.

Dysbiosis, or the imbalance in gut microbiota composition, has been implicated in the modulation of key AD-related mechanisms, including neuroinflammation, blood-brain barrier integrity, and neurotransmitter regulation. These disruptions may accelerate the onset and progression of AD. Additionally, therapeutic strategies targeting gut microbiota, such as probiotics, prebiotics, and fecal microbiota transplantation, show promise in modulating AD pathology.

The gut microbiota is a pivotal factor in AD pathogenesis, influencing neuroinflammation and disease progression. Understanding the role of gut microbiota in AD opens avenues for innovative diagnostic, preventive, and therapeutic strategies.

Gut microbiota is involved in intricate and active metabolic processes the host's brain function, especially its role in immune responses, secondary metabolism, and symbiotic connections with the host. Gut microbiota can promote the production of essential metabolites, neurotransmitters, and other neuroactive chemicals that affect the development and treatment of central nervous system diseases. This article introduces the relevant pathways and manners of the communication between the brain and gut, summarizes a comprehensive overview of the current research status of key gut microbiota metabolites that affect the functions of the nervous system, revealing those adverse factors that affect typical communication between the brain-gut axis, and outlining the efforts made by researchers to alleviate these neurological diseases through targeted microbial interventions. The relevant pathways and manners of communication between the brain and gut contribute to the experimental design of new treatment plans and drug development. The factors that may cause changes in gut microbiota and affect metabolites, as well as current intervention methods are summarized, which helps improve gut microbiota brain dialogue, prevent adverse triggering factors from interfering with the gut microbiota system, and minimize neuropathological changes.

The gut microbiota and diet-induced changes in microbiome composition have been linked to various liver diseases, although the specific microbes and mechanisms remain understudied. Alcohol-related liver disease (ALD) is one such disease with limited therapeutic options due to its complex pathogenesis. We demonstrate that a diet rich in soluble dietary fiber increases the abundance of Bacteroides acidifaciens (B. acidifaciens) and alleviates alcohol-induced liver injury in mice. B. acidifaciens treatment alone ameliorates liver injury through a bile salt hydrolase that generates unconjugated bile acids to activate intestinal farnesoid X receptor (FXR) and its downstream target, fibroblast growth factor-15 (FGF15). FGF15 promotes hepatocyte expression of ornithine aminotransferase (OAT), which facilitates the metabolism of accumulated ornithine in the liver into glutamate, thereby providing sufficient glutamate for ammonia detoxification via the glutamine synthesis pathway. Collectively, these findings uncover a potential therapeutic strategy for ALD involving dietary fiber supplementation and B. acidifaciens.

The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children, and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental, and prenatal factors, the molecular etiology of autism is largely unknown. Here, we use untargeted metabolomics to characterize the neonatal metabolome from dried blood spots collected shortly after birth.

We analyze the metabolomic profiles of a subset of a large Danish population-based cohort (iPSYCH2015) consisting of over 1400 newborns, who later are diagnosed with autism and matching controls and in two Swedish population-based cohorts comprising over 7000 adult participants. Mass spectrometry analysis was performed by a timsTOF Pro operated in QTOF mode, using data-dependent acquisition. By applying an untargeted metabolomics approach, we could reproducibly measure over 800 metabolite features.

We detected underlying molecular perturbations across several metabolite classes that precede autism. In particular, the cyclic dipeptide cyclo-leucine-proline (FDR-adjusted p = 0.003) and the carnitine-related 5-aminovaleric acid betaine (5-AVAB) (FDR-adjusted p = 0.03), were associated with an increased probability for autism, independently of known prenatal and genetic risk factors. Analysis of genetic and dietary data in adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy (FDR-adjusted p < 0.05) and with variants near SLC22A4 and SLC22A5 (p < 5.0e - 8), coding for a transmembrane carnitine transporter protein involved in controlling intracellular carnitine levels.

Cyclo-leucine-proline and 5-AVAB are associated with future diagnosis of autism in Danish neonates, both representing novel early biomarkers for autism. 5-AVAB is potentially modifiable and may influence carnitine homeostasis.

Maternal inflammatory response (MIR) during early gestation in mice induces a cascade of physiological and behavioral changes that have been associated with autism spectrum disorder (ASD). In a prior study and the current one, we find that mild MIR results in chronic systemic and neuro-inflammation, mTOR pathway activation, mild brain overgrowth followed by regionally specific volumetric changes, sensory processing dysregulation, and social and repetitive behavior abnormalities. Prior studies of rapamycin treatment in autism models have focused on chronic treatments that might be expected to alter or prevent physical brain changes. Here, we have focused on the acute effects of rapamycin to uncover novel mechanisms of dysfunction and related to mTOR pathway signaling. We find that within 2 hours, rapamycin treatment could rapidly rescue neuronal hyper-excitability, seizure susceptibility, functional network connectivity and brain community structure, and repetitive behaviors and sensory over-responsivity in adult offspring with persistent brain overgrowth. These CNS-mediated effects are also associated with alteration of the expression of several ASD-,ion channel-, and epilepsy-associated genes, in the same time frame. Our findings suggest that mTOR dysregulation in MIR offspring is a key contributor to various levels of brain dysfunction, including neuronal excitability, altered gene expression in multiple cell types, sensory functional network connectivity, and modulation of information flow. However, we demonstrate that the adult MIR brain is also amenable to rapid normalization of these functional changes which results in the rescue of both core and comorbid ASD behaviors in adult animals without requiring long-term physical alterations to the brain. Thus, restoring excitatory/inhibitory imbalance and sensory functional network modularity may be important targets for therapeutically addressing both primary sensory and social behavior phenotypes, and compensatory repetitive behavior phenotypes.

Maternal obesity is associated with an increased risk of psychiatric disorders such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While numerous studies focus on preventive measures targeting the mothers, only a limited number provide practical approaches for addressing the damages once they are already established. We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on hypothalamic inflammation and metabolic disturbances, however, little is known about this relationship on behavioral manifestations and neurochemical imbalances in other brain regions. Therefore, here we tested whether CBD treatment could mitigate anxiety-like and social behavioral alterations, as well as neurochemical disruptions in both male and female offspring of obese dams. Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) from weaning for 3 weeks. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and neurochemical markers were evaluated in the prefrontal cortex (PFC) and hippocampus. CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, followed by rescuing effects on imbalanced neurotransmitter and endocannabinoid concentrations and altered expression of glial markers, CB1, oxytocin and dopamine receptors, with important differences between sexes. Overall, the findings of this study provide insight into the signaling pathways for the therapeutic benefits of CBD on neuroinflammation and neurochemical imbalances caused by perinatal maternal obesity in the PFC and the hippocampus, which translates into the behavioral manifestations, highlighting the sexual dimorphism encompassing both the transgenerational effect of obesity and the endocannabinoid system.

Emerging evidence suggests that the gut microbiota and its metabolites regulate neurodevelopment and cognitive functioning via a bi-directional communication system known as the microbiota-gut-brain axis (MGBA).

The MGBA influences brain development and function via the hypothalamic-pituitary axis, the vagal nerve, immune signaling, bacterial production of neurotransmitters, and microbial metabolites like short-chain fatty acids, tryptophan derivatives, and bile acids. Animal studies show fetal neurodevelopment is mediated by maternal microbiota derivatives, immune activation, and diet. Furthermore, manipulation of the microbiota during critical windows of development, like antibiotic exposure and fecal microbiota transplantation, can affect cognitive functioning and behavior in mice. Evidence from human studies, particularly in preterm infants, also suggests that a disrupted gut microbiota colonization may negatively affect neurodevelopment. Early microbial signatures were linked to favorable and adverse neurodevelopmental outcomes.

The link between the gut microbiota and the brain is evident. Future studies, including experimental studies, larger participant cohort studies with longitudinal analyses of microbes, their metabolites, and neurotransmitters, and randomized controlled trials are warranted to further elucidate the mechanisms of the MGBA. Identification of early, predictive microbial markers could pave the way for the development of novel early microbiota-based intervention strategies, such as targeted probiotics, and vaginal or fecal microbiota transplantation, aimed at improving infant neurodevelopment.

To investigate the impact of gut microbiota dysbiosis on neurodevelopment in children.

This study included 338 children aged 0-3 years admitted to our hospital from January to December 2022, The children were divided into a normal neurodevelopment group (169 cases) and a poor neurodevelopment group (169 cases). Basic personal information and clinical data were collected through a detailed questionnaire, and the microbial composition in fecal samples was analyzed using 16S rRNA gene sequencing.

Children in the poor neurodevelopment group showed a significant decrease in gut microbiota diversity compared to those in the normal neurodevelopment group (Shannon index, p < 0.05). The abundance of Bifidobacterium and Veillonella genera significantly decreased (p < 0.05), while the abundance of Streptococcus genus increased significantly (p < 0.05).

There is an association between gut microbiota dysbiosis and poor neurodevelopment in children. The increased abundance of Streptococcus genus and decreased abundance of Bifidobacterium and Veillonella genera in the gut microbiota may be potential risk factors for poor neurodevelopment in preterm infants. Future research should further explore the potential beneficial effects of gut microbiota modulation on neurodevelopment in children.

The intricate relationship between immune dysregulation and neurodevelopmental disorders (NDDs) has been observed across the stages of both prenatal and postnatal development. In this Review, we provide a comprehensive overview of various maternal immune conditions, ranging from infections to chronic inflammatory conditions, that impact the neurodevelopment of the fetus during pregnancy. Furthermore, we examine the presence of immunological phenotypes, such as immune-related markers and coexisting immunological disorders, in individuals with NDDs. By delving into these findings, we shed light on the potential underlying mechanisms responsible for the high occurrence of immune dysregulation alongside NDDs. We also discuss current mouse models of NDDs and their contributions to our understanding of the immune mechanisms underlying these diseases. Additionally, we discuss how neuroimmune interactions contribute to shaping the manifestation of neurological phenotypes in individuals with NDDs while also exploring potential avenues for mitigating these effects.

Crosstalk between gut and brain has long been appreciated in health and disease, and the gut microbiota is a key player in communication between these two distant organs. Yet, the mechanisms through which the microbiota influences development and function of the gut-brain axis remain largely unknown. Barriers present in the gut and brain are specialized cellular interfaces that maintain strict homeostasis of different compartments across this axis. These barriers include the gut epithelial barrier, the blood-brain barrier and the blood-cerebrospinal fluid barrier. Barriers are ideally positioned to receive and communicate gut microbial signals constituting a gateway for gut-microbiota-brain communication. In this Review, we focus on how modulation of these barriers by the gut microbiota can constitute an important channel of communication across the gut-brain axis. Moreover, barrier malfunction upon alterations in gut microbial composition could form the basis of various conditions, including often comorbid neurological and gastrointestinal disorders. Thus, we should focus on unravelling the molecular and cellular basis of this communication and move from simplistic framing as 'leaky gut'. A mechanistic understanding of gut microbiota modulation of barriers, especially during critical windows of development, could be key to understanding the aetiology of gastrointestinal and neurological disorders.

Due to the physiological alteration during pregnancy, maternal gut microbiota changes following the metabolic processes. Recent studies have revealed that maternal gut microbiota is closely associated with the immune microenvironment in utero during pregnancy and plays a vital role in specific pregnancy complications, including preeclampsia, gestational diabetes, preterm birth and recurrent miscarriages. Some other evidence has also shown that aberrant maternal gut microbiota increases the risk of various diseases in the offspring, such as allergic and neurodevelopmental disorders, through the immune alignment between mother and fetus and the possible intrauterine microbiota. Probiotics and the high-fiber diet are effective inventions to prevent mothers and fetuses from diseases. In this review, we summarize the role of maternal gut microbiota in the development of pregnancy complications and the health condition of future generations from the perspective of immunology, which may provide new therapeutic strategies for the health management of mothers and offspring.

Autism spectrum disorders (ASDs) are recognized as central neurodevelopmental disorders diagnosed by impairments in social interactions, communication and repetitive behaviours. The recognition of ASD as a central nervous system (CNS)-mediated neurobehavioural disorder has led most of the research in ASD to be focused on the CNS. However, gastrointestinal function is also likely to be affected owing to the neural mechanistic nature of ASD and the nervous system in the gastrointestinal tract (enteric nervous system). Thus, it is unsurprising that gastrointestinal disorders, particularly constipation, diarrhoea and abdominal pain, are highly comorbid in individuals with ASD. Gastrointestinal problems have also been repeatedly associated with increased severity of the core symptoms diagnostic of ASD and other centrally mediated comorbid conditions, including psychiatric issues, irritability, rigid-compulsive behaviours and aggression. Despite the high prevalence of gastrointestinal dysfunction in ASD and its associated behavioural comorbidities, the specific links between these two conditions have not been clearly delineated, and current data linking ASD to gastrointestinal dysfunction have not been extensively reviewed. This Review outlines the established and emerging clinical and preclinical evidence that emphasizes the gut as a novel mechanistic and potential therapeutic target for individuals with ASD.

The early-life period is one of microbiome establishment and immune maturation. Early-life exposures are increasingly being recognised to play an important role in IBD risk. The composition of functions of the gut microbiome in the prenatal, perinatal, and postnatal period may be crucial towards development of health or disease, including IBD, later in life. We herein present a comprehensive summary of the interplay between early-life factors and microbiome perturbations, and their association with risk of IBD. In addition, we provide an overview of host and external factors in early life that are known to impact gut microbiome maturation and exposures implicated in IBD risk. Considering the emerging concept of IBD prevention, we propose strategies to minimise maternal and offspring exposure to potentially harmful variables and recommend protective measures during pregnancy and the postpartum period. This holistic view of early-life factors and microbiome signatures among mothers and their offspring will help frame our current understanding of their importance towards IBD pathogenesis and frame the roadmap for preventive strategies.

Pregnancy is a risk factor for increased severity of SARS-CoV-2 and other respiratory infections. The mechanisms underlying this risk have not been well-established, partly due to a limited understanding of how pregnancy shapes immune responses. To gain insight into the role of pregnancy in modulating immune responses at steady state and upon perturbation, we collected peripheral blood mononuclear cells (PBMC), plasma, and stool from 226 women, including 152 pregnant individuals (n = 96 with SARS-CoV-2 infection and n = 56 healthy controls) and 74 non-pregnant women (n = 55 with SARS-CoV-2 and n = 19 healthy controls). We found that SARS-CoV-2 infection was associated with altered T cell responses in pregnant compared to non-pregnant women. Differences included a lower percentage of memory T cells, a distinct clonal expansion of CD4-expressing CD8 + T cells, and the enhanced expression of T cell exhaustion markers, such as programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain-3 (Tim-3), in pregnant women. We identified additional evidence of immune dysfunction in severely and critically ill pregnant women, including a lack of expected elevation in regulatory T cell (Treg) levels, diminished interferon responses, and profound suppression of monocyte function. Consistent with earlier data, we found maternal obesity was also associated with altered immune responses to SARS-CoV-2 infection, including enhanced production of inflammatory cytokines by T cells. Certain gut bacterial species were altered in pregnancy and upon SARS-CoV-2 infection in pregnant individuals compared to non-pregnant women. Shifts in cytokine and chemokine levels were also identified in the sera of pregnant individuals, most notably a robust increase of interleukin-27 (IL-27), a cytokine known to drive T cell exhaustion, in the pregnant uninfected control group compared to all non-pregnant groups. IL-27 levels were also significantly higher in uninfected pregnant controls compared to pregnant SARS-CoV-2-infected individuals. Using two different preclinical mouse models of inflammation-induced fetal demise and respiratory influenza viral infection, we found that enhanced IL-27 protects developing fetuses from maternal inflammation but renders adult female mice vulnerable to viral infection. These combined findings from human and murine studies reveal nuanced pregnancy-associated immune responses, suggesting mechanisms underlying the increased susceptibility of pregnant individuals to viral respiratory infections.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disease characterized by hyperandrogenism, ovulatory dysfunction, and ovarian polycystic changes, which combines with reproductive problems, metabolic disorders, and psychological disorders to exhibit a far-reaching impact on the physical and mental health of women. We reviewed previous research and discovered that psychiatric disorders are more common in PCOS patients and their children, potentially exacerbating the condition and creating a vicious loop. To understand the reasons, relevant articles were collected following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines from PubMed, Web of Science, and Cochrane Library, through December 2022. Evidence suggested that PCOS-related clinical manifestations, hyperandrogenism, insulin resistance, obesity, gut dysbiosis, and other variables may increase the risk of psychiatric disorders in patients. In turn, psychiatric disorders may aggravate the pathologic process of PCOS and increase the difficulty of the treatment. We systematically reported the mechanisms underlying the psychiatric disorders-PCOS interactions, intending to provide potential ways to break the vicious cycle and lay the groundwork for future research. However, research on PCOS and psychiatric disorders were still in initial stages, which limited the scope of this review. More studies are needed to further verify our findings.

The gut-brain axis is gaining more attention in neurodevelopmental disorders, especially autism spectrum disorder (ASD). Many factors can influence microbiota in early life, including host genetics and perinatal events (infections, mode of birth/delivery, medications, nutritional supply, and environmental stressors). The gut microbiome can influence blood-brain barrier (BBB) permeability, drug bioavailability, and social behaviors. Developing microbiota-based interventions such as probiotics, gastrointestinal (GI) microbiota transplantation, or metabolite supplementation may offer an exciting approach to treating ASD. This review highlights that RNA sequencing, metabolomics, and transcriptomics data are needed to understand how microbial modulators can influence ASD pathophysiology. Due to the substantial clinical heterogeneity of ASD, medical caretakers may be unlikely to develop a broad and effective general gut microbiota modulator. However, dietary modulation followed by administration of microbiota modulators is a promising option for treating ASD-related behavioral and gastrointestinal symptoms. Future work should focus on the accuracy of biomarker tests and developing specific psychobiotic agents tailored towards the gut microbiota seen in ASD patients, which may include developing individualized treatment options.

Investigations into the association of antepartum maternal infections with the pathogenesis of biliary atresia (BA) in human offspring are insufficient.

To examine the association between prenatal infections in mothers and the development of BA in their offspring.

This population-based case-control study obtained administrative data from the Taiwan National Health Insurance Research Database with linkage to the Taiwan Maternal and Child Health Database, capturing demographic and medical information on nearly all 23 million of the Taiwan population. The cohort comprised 2 905 978 singleton live births among mother-infant dyads between January 1, 2004, and December 31, 2020, in Taiwan. The case group of infants with BA was identified from use of International Classification of Diseases diagnostic codes for BA and subsequent Kasai procedure or liver transplant. The control group was randomly selected from infants without BA, representing approximately 1 in 1000 study population. Data analyses were performed from May 1 to October 31, 2023.

Prenatal maternal infections, including intestinal infection, influenza, upper airway infection, pneumonia, soft-tissue infection, and genitourinary tract infection.

The main outcome was exposure to prenatal maternal infections. Inverse probability weighting analysis was performed by building a logistic regression model to estimate the probability of the exposure observed for a particular infant and using the estimated probability as a weight in subsequent analyses. The weighted odds ratio (OR) estimated by logistic regressions was then used to assess the risk of BA in offspring after prenatal maternal infections.

Among the mother-infant dyads included, 447 infants with BA were cases (232 females [51.9%]) and 2912 infants without BA were controls (1514 males [52.0%]). The mean (SD) maternal age at childbirth was 30.7 (4.9) years. Offspring exposed to prenatal intestinal infection (weighted OR, 1.46; 95% CI, 1.17-1.82) and genitourinary tract infection (weighted OR, 1.22; 95% CI, 1.05-1.41) in mothers exhibited a significantly higher risk of BA. Furthermore, maternal intestinal infection (weighted OR, 6.05; 95% CI, 3.80-9.63) and genitourinary tract infection (weighted OR, 1.55; 95% CI, 1.13-2.11) that occurred during the third trimester were associated with an increased risk of BA in offspring.

Results of this case-control study indicate an association between prenatal intestinal infection and genitourinary tract infection in mothers and BA occurrence in their offspring. Further studies are warranted to explore the underlying mechanisms of this association.

Pregnancy is a finely tuned process, with the health and well-being of the developing fetus determined by the metabolic status and dietary intake of the mother. The maternal gut microbiome is remodeled during pregnancy, and this, coupled with the maternal nutrient intake during gestation shapes the production of metabolites that can cross the placenta and affect fetal development. As posited by the Developmental Origins of Health and Disease Hypothesis, such environmental influences can have major effects on the developing organ systems. When occurring at particularly sensitive gestational time points, these developmental programming events can have long lasting effects on offspring adaptation to the postnatal environment, and major health implications later in life. This review will summarize current knowledge on how pregnancy and maternal dietary intake intrinsically and extrinsically modify maternal gut microbiota composition and metabolite production. Further, we will assess how these factors shape the fetal landscape and ultimately contribute to offspring health. DOHaD, fetal development, metabolites, microbiome, nutrition, pregnancy, short-chain fatty acids.

Pregnancy dramatically changes maternal metabolism and the microbiome. Low-grade inflammation can cause maternal complications and fetal abnormalities. The objective of this open-label, randomized, controlled study was to evaluate the efficacy and safety of orally administered Chlorella, a green alga that is commercially available as a dietary supplement with rich nutrients and dietary fiber for pregnant women with low-grade inflammation. Patients with C-reactive protein levels >0.05 mg/dL (16 weeks gestation, n = 22) were enrolled and randomly allocated to the Chlorella group (n = 10) or control group (n = 12). We conducted blood biochemical tests at 25, 30, and 35 weeks gestation and evaluated the evacuation status (symptoms depending on the Rome IV C2 criteria and laxative usage), side effects, and complications throughout the investigation. We also monitored the status of the offspring. The Chlorella group (n = 0) showed a significantly lower rate of constipation than the control group (n = 8). This study demonstrated the beneficial effects and safety of Chlorella supplementation in pregnant women, which prevented constipation and unnecessary laxative administration.

Autism spectrum disorders (ASD) are complex human neurodiversities increasing in prevalence within the human population. In search of therapeutics to improve quality-of-life for ASD patients, the gut microbiome (GM) has become a promising target as a growing body of work supports roles for the complex community of microorganisms in influencing host behavior via the gut-brain-axis. However, whether naturally-occurring microbial diversity within the host GM affects these behaviors is often overlooked. Here, we applied a model of population-level differences in the GM to a classic ASD model - the BTBR T+ Itpr3tf/J mouse - to assess how complex GMs affect host behavior. Leveraging the naturally occurring differences between supplier-origin GMs, our data demonstrate that differing, complex GMs selectively effect host ASD-related behavior - especially neonatal ultrasonic communication - and reveal a male-specific effect on behavior not typically observed in this strain. We then identified that the body weight of BTBR mice is influenced by the postnatal GM which was potentially mediated by microbiome-dependent effects on energy harvest in the gut. These data provide insight into how variability within the GM affects host behavior and growth, thereby emphasizing the need to incorporate microbial diversity within the host GM as an experimental factor in biomedical research.

Microbiota have an important function in shaping and priming neonatal immunity, although the cellular and molecular mechanisms underlying these effects remain obscure. Here we report that prenatal antibiotic exposure causes significant elevation of group 2 innate lymphoid cells (ILC2s) in neonatal lungs, in both cell numbers and functionality. Downregulation of type 1 interferon signaling in ILC2s due to diminished production of microbiota-derived butyrate represents the underlying mechanism. Mice lacking butyrate receptor GPR41 (Gpr41-/-) or type 1 interferon receptor IFNAR1 (Ifnar1-/-) recapitulate the phenotype of neonatal ILC2s upon maternal antibiotic exposure. Furthermore, prenatal antibiotic exposure induces epigenetic changes in ILC2s and has a long-lasting deteriorative effect on allergic airway inflammation in adult offspring. Prenatal supplementation of butyrate ameliorates airway inflammation in adult mice born to antibiotic-exposed dams. These observations demonstrate an essential role for the microbiota in the control of type 2 innate immunity at the neonatal stage, which suggests a therapeutic window for treating asthma in early life.

The intricacy of diseases, shaped by intrinsic processes like immune system exhaustion and hyperactivation, highlights the potential of immune renormalization as a promising strategy in disease treatment. In recent years, our primary focus has centered on γδ T cell-based immunotherapy, particularly pioneering the use of allogeneic Vδ2+ γδ T cells for treating late-stage solid tumors and tuberculosis patients. However, we recognize untapped potential and optimization opportunities to fully harness γδ T cell effector functions in immunotherapy. This review aims to thoroughly examine γδ T cell immunology and its role in diseases. Initially, we elucidate functional differences between γδ T cells and their αβ T cell counterparts. We also provide an overview of major milestones in γδ T cell research since their discovery in 1984. Furthermore, we delve into the intricate biological processes governing their origin, development, fate decisions, and T cell receptor (TCR) rearrangement within the thymus. By examining the mechanisms underlying the anti-tumor functions of distinct γδ T cell subtypes based on γδTCR structure or cytokine release, we emphasize the importance of accurate subtyping in understanding γδ T cell function. We also explore the microenvironment-dependent functions of γδ T cell subsets, particularly in infectious diseases, autoimmune conditions, hematological malignancies, and solid tumors. Finally, we propose future strategies for utilizing allogeneic γδ T cells in tumor immunotherapy. Through this comprehensive review, we aim to provide readers with a holistic understanding of the molecular fundamentals and translational research frontiers of γδ T cells, ultimately contributing to further advancements in harnessing the therapeutic potential of γδ T cells.

Interleukin-17 (IL-17), a cytokine characteristically secreted by T helper 17 (Th17) cells, has attracted increasing attention in recent years because of its importance in the pathogenesis of many autoimmune or chronic inflammatory diseases. Recent studies have shown that neurological diseases and mental disorders are closely related to immune function, and varying degrees of immune dysregulation may disrupt normal expression of immune molecules at critical stages of neural development. Starting from relevant mechanisms affecting immune regulation, this article reviews the research progress of IL-17 in a selected group of neurological diseases and mental disorders (autism spectrum disorder, Alzheimer's disease, epilepsy, and depression) from the perspective of neuroinflammation and the microbiota-gut-brain axis, summarizes the commonalities, and provides a prospective outlook of target application in disease treatment.