An Alternative Explanation for Alzheimer’s Disease and Parkinson’s Disease Initiation from Specific Antibiotics,Gut Microbiota Dysbiosis and Neurotoxins

The late onset neuropathologies, including Alzheimer’s disease and Parkinson’s disease, have become increasingly prevalent. Their causation has been linked to genetics, gut microbiota dysbiosis (gut dysbiosis), autoimmune diseases, pathogens and exposures to neurotoxins. An alternative explanatory hypothesis is provided for their pathogenesis. Virtually everyone has pervasive daily exposures to neurotoxins, through inhalation, skin contact, direct blood transmission and through the gastrointestinal tract by ingestion. As a result, every individual has substantial and fluctuating neurotoxin blood levels. Two major barriers to neurotoxin entry into the central nervous system are the blood–brain barrier and the intestinal wall, in the absence of gut dysbiosis. Inflammation from gut dysbiosis, induced by antibiotic usage, can increase the intestinal wall permeability for neurotoxins to reach the bloodstream, and also increase the blood–brain barrier permeability to neurotoxins. Gut dysbiosis, including gut dysbiosis caused by antibiotic treatments, is an especially high risk for neurotoxin entry into the brain to cause late onset neuropathologies. Gut dysbiosis has far-reaching immune system and central nervous system effects, and even a transient gut dysbiosis can act in combination with neurotoxins, such as aluminum, mercury, lead, arsenic, cadmium, selenium, manganese, organophosphate pesticides and organochlorines, to reach neurotoxin blood levels that can initiate a late onset neuropathology, depending on an individual’s age and genetic vulnerability.

     

Novel metabolic biomarkers related to sulfur-dependent detoxification pathways in autistic patients of Saudi Arabia

Background  

Xenobiotics are neurotoxins that dramatically alter the health of the child. In addition, an inefficient detoxification system leads to oxidative stress, gut dysbiosis, and immune dysfunction. The consensus among physicians who treat autism with a biomedical approach is that those on the spectrum are burdened with oxidative stress and immune problems. In a trial to understand the role of detoxification in the etiology of autism, selected parameters related to sulfur-dependent detoxification mechanisms in plasma of autistic children from Saudi Arabia will be investigated compared to control subjects.     

The very low birth weight infant microbiome and childhood health

This review describes current understandings about the nature of the very low birth weight infant (VLBW) gut microbiome. VLBW infants often experience disruptive pregnancies and births, and prenatal factors can influence the maturity of the gut and immune system, and disturb microbial balance and succession. Many VLBWs experience rapid vaginal or Caesarean births. After birth these infants often have delays in enteral feeding, and many receive little or no mother's own milk. Furthermore the stressors of neonatal life in the hospital environment, common use of antibiotics, invasive procedures and maternal separation can contribute to dysbiosis. These infants experience gastrointestinal dysfunction, sepsis, transfusions, necrotizing enterocolitis, oxygen toxicity, and other pathophysiological consditions that affect the normal microbiota. The skin is susceptible to dysbiosis, due to its fragility and contact with NICU organisms. Dysbiosis in early life may resolve but little is known about the timing of the development of the signature gut microbiome in VLBWs. Dysbiosis has been associated with a number of physical and behavioral problems, including autism spectrum disorders, allergy and asthma, gastrointestinal disease, obesity, depression, and anxiety. Dysbiosis may be prevented or ameliorated in part by prenatal care, breast milk feeding, skin to skin contact, use of antibiotics only when necessary, and vigilance during infancy and early childhood. Birth Defects Research (Part C) 105:252–264, 2015. © 2015 Wiley Periodicals, Inc.     

Environmental influence on neurodevelopmental disorders: Potential association of heavy metal exposure and autism

Environmental factors have been severally established to play major roles in the pathogenesis of neurodevelopmental disorders including autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder that is associated with symptoms that reduce the quality of life of affected individuals such as social interaction deficit, cognitive impairment, intellectual disabilities, restricted and repetitive behavioural patterns. ASD pathogenesis has been associated with environmental and genetic factors that alter physiologic processes during development. Here, we review literatures highlighting the environmental impact on neurodevelopmental disorders, and mechanisms by which environmental toxins may influence neurodevelopment. Furthermore, this review discusses reports highlighting neurotoxic metals (specifically, lead, mercury, cadmium, nickel and manganese) as environmental risk factors in the aetiology of ASD. This work, thus suggests that improving the environment could be vital in the management of ASD.     

Does microglial dysfunction play a role in autism and Rett syndrome?

Autism spectrum disorders (ASDs) including classic autism is a group of complex developmental disabilities with core deficits of impaired social interactions, communication difficulties and repetitive behaviors. Although the neurobiology of ASDs has attracted much attention in the last two decades, the role of microglia has been ignored. Existing data are focused on their recognized role in neuroinflammation, which only covers a small part of the pathological repertoire of microglia. This review highlights recent findings on the broader roles of microglia, including their active surveillance of brain microenvironments and regulation of synaptic connectivity, maturation of brain circuitry and neurogenesis. Emerging evidence suggests that microglia respond to pre- and postnatal environmental stimuli through epigenetic interface to change gene expression, thus acting as effectors of experience-dependent synaptic plasticity. Impairments of these microglial functions could substantially contribute to several major etiological factors of autism, such as environmental toxins and cortical underconnectivity. Our recent study on Rett syndrome, a syndromic autistic disorder, provides an example that intrinsic microglial dysfunction due to genetic and epigenetic aberrations could detrimentally affect the developmental trajectory without evoking neuroinflammation. We propose that ASDs provide excellent opportunities to study the influence of microglia on neurodevelopment, and this knowledge could lead to novel therapies.     

Prenatal and postnatal animal models of immune activation: Relevance to a range of neurodevelopmental disorders

Epidemiological evidence has established links between immune activation during the prenatal or early postnatal period and increased risk of developing a range of neurodevelopment disorders in later life. Animal models have been used to great effect to explore the ramifications of immune activation during gestation and neonatal life. A range of behavioral, neurochemical, molecular, and structural outcome measures associated with schizophrenia, autism, cerebral palsy, and epilepsy have been assessed in models of prenatal and postnatal immune activation. However, the epidemiology-driven disease-first approach taken by some studies can be limiting and, despite the wealth of data, there is a lack of consensus in the literature as to the specific dose, timing, and nature of the immunogen that results in replicable and reproducible changes related to a single disease phenotype. In this review, we highlight a number of similarities and differences in models of prenatal and postnatal immune activation currently being used to investigate the origins of schizophrenia, autism, cerebral palsy, epilepsy, and Parkinson's disease. However, we describe a lack of synthesis not only between but also within disease-specific models. Our inability to compare the equivalency dose of immunogen used is identified as a significant yet easily remedied problem. We ask whether early life exposure to infection should be described as a disease-specific or general vulnerability factor for neurodevelopmental disorders and discuss the implications that either classification has on the design, strengths and limitations offuture experiments. ? 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012.     

Altered Heavy Metals and Transketolase Found in Autistic Spectrum Disorder

Autism and autism spectrum disorder (ASD) are developmental brain disorders with complex, obscure, and multifactorial etiology. Our recent clinical survey of patient records from ASD children under the age of 6?years and their age-matched controls revealed evidence of abnormal markers of thiol metabolism, as well as a significant alteration in deposition of several heavy metal species, particularly arsenic, mercury, copper, and iron in hair samples between the groups. Altered thiol metabolism from heavy metal toxicity may be responsible for the biochemical alterations in transketolase, and are mechanisms for oxidative stress production, dysautonomia, and abnormal thiamine homeostasis. It is unknown why the particular metals accumulate, but we suspect that children with ASD may have particular trouble excreting thiol-toxic heavy metal species, many of which exist as divalent cations. Accumulation or altered mercury clearance, as well as concomitant oxidative stress, arising from redox-active metal and arsenic toxicity, offers an intriguing component or possible mechanism for oxidative stress-mediated neurodegeneration in ASD patients. Taken together, these factors may be more important to the etiology of this symptomatically diverse disease spectrum and may offer insights into new treatment approaches and avenues of exploration for this devastating and growing disease.     

Chronic Functional Bowel Syndrome Enhances Gut-Brain Axis Dysfunction,Neuroinflammation, Cognitive Impairment,and Vulnerability to Dementia

The irritable bowel syndrome (IBS) is a common chronic functional gastrointestinal disorder world wide that lasts for decades. The human gut harbors a diverse population of microbial organisms which is symbiotic and important for well being. However, studies on conventional, germ-free, and obese animals have shown that alteration in normal commensal gut microbiota and an increase in pathogenic microbiota—termed “dysbiosis”, impact gut function, homeostasis, and health. Diarrhea, constipation, visceral hypersensitivity, and abdominal pain arise in IBS from the gut-induced dysfunctional metabolic, immune, and neuro-immune communication. Dysbiosis in IBS is associated with gut inflammation. Gut-related inflammation is pivotal in promoting endotoxemia, systemic inflammation, and neuroinflammation. A significant proportion of IBS patients chronically consume alcohol, non-steroidal anti-inflammatories, and fatty diet; they may also suffer from co-morbid respiratory, neuromuscular, psychological, sleep, and neurological disorders. The above pathophysiological substrate is underpinned by dysbiosis, and dysfunctional bidirectional “Gut-Brain Axis” pathways. Pathogenic gut microbiota-related systemic inflammation (due to increased lipopolysaccharide and pro-inflammatory cytokines, and barrier dysfunction), may trigger neuroinflammation enhancing dysfunctional brain regions including hippocampus and cerebellum. These as well as dysfunctional vago-vagal gut-brain axis may promote cognitive impairment. Indeed, inflammation is characteristic of a broad spectrum of neurodegenerative diseases that manifest demntia. It is argued that an awareness of pathophysiological impact of IBS and implementation of appropriate therapeutic measures may prevent cognitive impairment and minimize vulnerability to dementia.     

Fetal Exposure to Environmental Neurotoxins in Taiwan

Mercury (Hg), lead (Pb), cadmium (Cd), and arsenic (As) are recognized neurotoxins in children that particularly affect neurodevelopment and intellectual performance. Based on the hypothesis that the fetal basis of adult disease is fetal toxic exposure that results in adverse outcomes in adulthood, we explored the concentrations of key neurotoxins (i.e., Hg, Pb, Cd, and As) in meconium to identify the risk factors associated with these concentrations. From January 2007 to December 2009, 545 mother-infant pairs were recruited. The geometric mean concentrations of Pb and As in the meconium of babies of foreign-born mothers (22.9 and 38.1 µg/kg dry weight, respectively) were significantly greater than those of babies of Taiwan-born mothers (17.5 and 33.0 µg/kg dry weight, respectively). Maternal age (≥30 y), maternal education, use of traditional Chinese herbs during pregnancy, and fish cutlet consumption (≥3 meals/wk) were risk factors associated with concentrations of key prenatal neurotoxins. The Taiwan government should focus more attention on providing intervention programs for immigrant mothers to help protect the health of unborn babies. Further investigation on how multiple neurotoxins influence prenatal neurodevelopment is warranted.     

Etiology of Developmental Disorders: Good Science, Bad Science, and Pseudoscience

Developmental disorders originate in infancy or early childhood, are associated with presumed or observed organic abnormalities, and have serious long-term physical and/or psychological sequelae. Of particular interest here are two such disorders, mental retardation and autism. Purported causes range from genetics, early prenatal and/or postnatal exposure to toxins (including heavy metals), and recently, vaccinations. Single factors have often been claimed to be the cause of a developmental disorder, without regard to possible exacerbating or alleviating roles of other factors, including socioeconomic status. Unfortunately, professional and popular literature on both claimed causes and effective treatments has often been characterized by research and theorizing that is seriously flawed (bad science) or actively misrepresented (pseudoscience). The present paper critically reviews selected research on a few controversial issues concerning developmental disorders, particular mental retardation and autism, and emphasizes the role of low socioeconomic status.     

Neuropathy in COVID-19 associated with dysbiosis-related inflammation

Although COVID-19 affects mainly lungs with a hyperactive and imbalanced immune response, gastrointestinal and neurological symptoms such as diarrhea and neuropathic pains have been described as well in patients with COVID-19. Studies indicate that gut–lung axis maintains host homeostasis and disease development with the association of immune system, and gut microbiota is involved in the COVID-19 severity in patients with extrapulmonary conditions. Gut microbiota dysbiosis impairs the gut permeability resulting in translocation of gut microbes and their metabolites into the circulatory system and induce systemic inflammation which, in turn, can affect distal organs such as the brain. Moreover, gut microbiota maintains the availability of tryptophan for kynurenine pathway, which is important for both central nervous and gastrointestinal system in regulating inflammation. SARS-CoV-2 infection disturbs the gut microbiota and leads to immune dysfunction with generalized inflammation. It has been known that cytokines and microbial products crossing the blood-brain barrier induce the neuroinflammation, which contributes to the pathophysiology of neurodegenerative diseases including neuropathies. Therefore, we believe that both gut–lung and gut–brain axes are involved in COVID-19 severity and extrapulmonary complications. Furthermore, gut microbial dysbiosis could be the reason of the neurologic complications seen in severe COVID-19 patients with the association of dysbiosis-related neuroinflammation. This review will provide valuable insights into the role of gut microbiota dysbiosis and dysbiosis-related inflammation on the neuropathy in COVID-19 patients and the disease severity.     

MRI study of minor physical anomaly in childhood autism implicates aberrant neurodevelopment in infancy

Background

MPAs (minor physical anomalies) frequently occur in neurodevelopmental disorders because both face and brain are derived from neuroectoderm in the first trimester. Conventionally, MPAs are measured by evaluation of external appearance. Using MRI can help overcome inherent observer bias, facilitate multi-centre data acquisition, and explore how MPAs relate to brain dysmorphology in the same individual. Optical MPAs exhibit a tightly synchronized trajectory through fetal, postnatal and adult life. As head size enlarges with age, inter-orbital distance increases, and is mostly completed before age 3 years. We hypothesized that optical MPAs might afford a retrospective ‘window’ to early neurodevelopment; specifically, inter-orbital distance increase may represent a biomarker for early brain dysmaturation in autism.

Methods

We recruited 91 children aged 7–16; 36 with an autism spectrum disorder and 55 age- and gender-matched typically developing controls. All children had normal IQ. Inter-orbital distance was measured on T1-weighted MRI scans. This value was entered into a voxel-by-voxel linear regression analysis with grey matter segmented from a bimodal MRI data-set. Age and total brain tissue volume were entered as covariates.

Results

Intra-class coefficient for measurement of the inter-orbital distance was 0.95. Inter-orbital distance was significantly increased in the autism group (p = 0.03, 2-tailed). The autism group showed a significant relationship between inter-orbital distance grey matter volume of bilateral amygdalae extending to the unci and inferior temporal poles.

Conclusions

Greater inter-orbital distance in the autism group compared with healthy controls is consistent with infant head size expansion in autism. Inter-orbital distance positively correlated with volume of medial temporal lobe structures, suggesting a link to “social brain” dysmorphology in the autism group. We suggest these data support the role of optical MPAs as a “fossil record” of early aberrant neurodevelopment, and potential biomarker for brain dysmaturation in autism.     

Mast cell activation and autism

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by varying degrees of dysfunctional communication and social interactions, repetitive and stereotypic behaviors, as well as learning and sensory deficits. Despite the impressive rise in the prevalence of autism during the last two decades, there are few if any clues for its pathogenesis, early detection or treatment. Increasing evidence indicates high brain expression of pro-inflammatory cytokines and the presence of circulating antibodies against brain proteins. A number of papers, mostly based on parental reporting on their children's health problems, suggest that ASD children may present with “allergic-like” problems in the absence of elevated serum IgE and chronic urticaria. These findings suggest non-allergic mast cell activation, probably in response to environmental and stress triggers that could contribute to inflammation. In utero inflammation can lead to preterm labor and has itself been strongly associated with adverse neurodevelopmental outcomes. Premature babies have about four times higher risk of developing ASD and are also more vulnerable to infections, while delayed development of their gut-blood-brain barriers makes exposure to potential neurotoxins likely. Perinatal mast cell activation by infectious, stress-related, environmental or allergic triggers can lead to release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in a subgroup of ASD patients. This article is part of a Special Issue entitled: Mast cells in inflammation.     

Prenatal Exposure to a Common Organophosphate Insecticide Delays Motor Development in a Mouse Model of Idiopathic Autism

Autism spectrum disorders are characterized by impaired social and communicative skills and repetitive behaviors. Emerging evidence supported the hypothesis that these neurodevelopmental disorders may result from a combination of genetic susceptibility and exposure to environmental toxins in early developmental phases. This study assessed the effects of prenatal exposure to chlorpyrifos (CPF), a widely diffused organophosphate insecticide endowed with developmental neurotoxicity at sub-toxic doses, in the BTBR T+tf/J mouse strain, a validated model of idiopathic autism that displays several behavioral traits relevant to the autism spectrum. To this aim, pregnant BTBR mice were administered from gestational day 14 to 17 with either vehicle or CPF at a dose of 6 mg/kg/bw by oral gavages. Offspring of both sexes underwent assessment of early developmental milestones, including somatic growth, motor behavior and ultrasound vocalization. To evaluate the potential long-term effects of CPF, two different social behavior patterns typically altered in the BTBR strain (free social interaction with a same-sex companion in females, or interaction with a sexually receptive female in males) were also examined in the two sexes at adulthood. Our findings indicate significant effects of CPF on somatic growth and neonatal motor patterns. CPF treated pups showed reduced weight gain, delayed motor maturation (i.e., persistency of immature patterns such as pivoting at the expenses of coordinated locomotion) and a trend to enhanced ultrasound vocalization. At adulthood, CPF associated alterations were found in males only: the altered pattern of investigation of a sexual partner, previously described in BTBR mice, was enhanced in CPF males, and associated to increased ultrasonic vocalization rate. These findings strengthen the need of future studies to evaluate the role of environmental chemicals in the etiology of neurodevelopment disorders.     

Convergent synaptic and circuit substrates underlying autism genetic risks

There has been a surge of diagnosis of autism spectrum disorders （ASD） over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.     

Immune system gene dysregulation in autism and schizophrenia

Gene*environment interactions play critical roles in the emergence of autism and schizophrenia pathophysiology. In both disorders, recent genetic association studies have provided evidence for disease-linked variation in immune system genes and postmortem gene expression studies have shown extensive chronic immune abnormalities in brains of diseased subjects. Furthermore, peripheral biomarker studies revealed that both innate and adaptive immune systems are dysregulated. In both disorders symptoms of the disease correlate with the immune system dysfunction; yet, in autism this process appears to be chronic and sustained, while in schizophrenia it is exacerbated during acute episodes. Furthermore, since immune abnormalities endure into adulthood and anti-inflammatory agents appear to be beneficial, it is likely that these immune changes actively contribute to disease symptoms. Modeling these changes in animals provided further evidence that prenatal maternal immune activation alters neurodevelopment and leads to behavioral changes that are relevant for autism and schizophrenia. The converging evidence strongly argues that neurodevelopmental immune insults and genetic background critically interact and result in increased risk for either autism or schizophrenia. Further research in these areas may improve prenatal health screening in genetically at-risk families and may also lead to new preventive and/or therapeutic strategies. ? 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012.     

Decreased Enterobacteriaceae translocation due to gut microbiota remodeling mediates the alleviation of premature aging by a high-fat diet

Aging-associated microbial dysbiosis exacerbates various disorders and dysfunctions, and is a major contributor to morbidity and mortality in the elderly, but the underlying cause of this aging-related syndrome is confusing. SIRT6 knockout (SIRT6 KO) mice undergo premature aging and succumb to death by 4 weeks, and are therefore useful as a premature aging research model. Here, fecal microbiota transplantation from SIRT6 KO mice into wild-type (WT) mice phenocopies the gut dysbiosis and premature aging observed in SIRT6 KO mice. Conversely, an expanded lifespan was observed in SIRT6 KO mice when transplanted with microbiota from WT mice. Antibiotic cocktail treatment attenuated inflammation and cell senescence in KO mice, directly suggesting that gut dysbiosis contributes to the premature aging of SIRT6 KO mice. Increased Enterobacteriaceae translocation, driven by the overgrowth of Escherichia coli, is the likely mechanism for the premature aging effects of microbiome dysregulation, which could be reversed by a high-fat diet. Our results provide a mechanism for the causal link between gut dysbiosis and aging, and support a beneficial effect of a high-fat diet for correcting gut dysbiosis and alleviating premature aging. This study provides a rationale for the integration of microbiome-based high-fat diets into therapeutic interventions against aging-associated diseases.     

Perturbateurs endocriniens et troubles du comportement

Prenatal environmental events that disturb neurodevelopment are suspected to increase the risk of psychiatric disorders. Estrogenic hormones such as diethylstilbestrol (DES) and environmental monomers like Bisphenol A (BPA) have the potential to disturb the development of the foetus and especially its brain. We reviewed the epidemiological studies investigating a possible association between prenatal DES or BPA exposure and risk of psychiatric disorders and discussed the hypothetical biological mechanisms linking this prenatal exposure with psychiatric disorders. The principal methodological issues that could represent confounding factors and may explain conflicting results are discussed. Interestingly, prenatal exposure to DES and BPA has been linked to epigenetic alterations associated with urogenital lesions observed in the exposed offspring, supporting the hypothesis that this environmental factor can indeed alter epigenetic regulations. Following the same line of thinking, these endocrine disruptors may modify the epigenetic mechanisms involved in neurodevelopment and, in turn, increase the occurrence of psychiatric disorders.     

Intestinal Pathology and Gut Microbiota Alterations in a Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Mouse Model of Parkinson’s Disease

Patients with Parkinson’s disease (PD) often have non-motor symptoms related to gastrointestinal (GI) dysfunction, such as constipation and delayed gastric emptying, which manifest prior to the motor symptoms of PD. Increasing evidence indicates that changes in the composition of the gut microbiota may be related to the pathogenesis of PD. However, it is unclear how GI dysfunction occurs and how gut microbial dysbiosis is caused. We investigated whether a neurotoxin model of PD induced by chronic low doses of MPTP is capable of reproducing the clinical intestinal pathology of PD, as well as whether gut microbial dysbiosis accompanies this pathology. C57BL/6 male mice were administered 18 mg/kg MPTP twice per week for 5 weeks via intraperitoneal injection. GI function was assessed by measuring the 1-h stool frequency and fecal water content; motor function was assessed by pole tests; and tyrosine hydroxylase and alpha-synuclein expression were analyzed. Furthermore, the inflammation, intestinal barrier and composition of the gut microbiota were measured. We found that MPTP caused GI dysfunction and intestinal pathology prior to motor dysfunction. The composition of the gut microbiota was changed; in particular, the change in the abundance of Lachnospiraceae, Erysipelotrichaceae, Prevotellaceae, Clostridiales, Erysipelotrichales and Proteobacteria was significant. These results indicate that a chronic low-dose MPTP model can be used to evaluate the progression of intestinal pathology and gut microbiota dysbiosis in the early stage of PD, which may provide new insights into the pathogenesis of PD.