Research Ideas and Outcomes :
Review Article
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Corresponding author: Kenneth Alibek (kalbiek@locusfs.com)
Academic editor: Editorial Secretary
Received: 02 Aug 2022 | Accepted: 11 Oct 2022 | Published: 13 Dec 2022
This is an open access article distributed under the terms of the CC0 Public Domain Dedication.
Citation:
Alibek K, Niyazmetova L, Farmer S, Isakov T (2022) Persistent Inflammation Initiated by TORCH Infections and Dysbiotic Microbiome in Autism Spectrum Disorders: A Prospect for Future Interventions. Research Ideas and Outcomes 8: e91179. https://doi.org/10.3897/rio.8.e91179
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Autism spectrum disorders (ASD) are a range of neurodevelopmental conditions that are clinically present early in childhood with the symptoms of social withdrawal and repetitive behavior. Despite an extensive research on ASD, no commonly accepted theory on the disease etiology exists. Hence, we reviewed several scientific publications, including reviews, preclinical and clinical investigations, and published hypotheses to analyze various opinions on the nature and cause of the disorder. Many studies suggest that infections and inflammation during pregnancy play a significant role in genetic and epigenetic changes in the developing fetus, resulting in an autistic phenotype in a child. Still, there is a lack of comprehensive literature about the multitude of autism inducing factors. Therefore, this article reviews and discusses available scientific evidence on the roles of viral, bacterial, fungal, and parasitic infections, overactivation of the immune system, and intestinal microflora in the pathogenesis and clinical manifestation of ASD. The overview of the scientific publications, including our own studies, suggests that TORCH infections, imbalanced microbiome, and persistent inflammation are significantly associated with the disruption of the social domain in ASD children. The ASD-related changes begin prenatally as maternal-to-fetal immune activation triggered by infection. It results in continuous low-grade inflammation and oxidative stress in a fetus, causing germline and somatic genetic changes in the developing brain and the establishment of the dysregulated immune system. These changes and dysregulations result in central and peripheral nervous systems dysfunctions as well as other comorbid conditions found in autistic children.
Autism spectrum disorder, inflammation, TORCH infections, microbiome, wall-free pathogens
Autism Spectrum Disorder (ASD) is a complex neuropsychiatric developmental disorder with a wide range of neurological and psychiatric symptoms including language impairment, repetitive and restricted behavior patterns, limited interests, and disruption of social function (
The current diagnostic statistical manual-5 (DSM-5) incorporated a range of developmental disorders under an umbrella ASD term (
Before diving into the etiopathogenesis of autism, it is crucial to characterize the clinical picture of ASD patients, which includes not only behavioral abnormalities but also various somatic disorders. Comorbidities range from otitis media (
Disease |
Clinical presentation |
GI disturbance |
Diarrhea, constipation, dyspepsia, indigestion, chronic flatulence, intestinal ulcers, etc. |
Allergies |
Asthma, food allergies, atopic dermatitis, etc. |
Autoimmune disorders |
Antibodies against various proteins in the brain |
Endocrine and metabolic problems |
Hypothyroidism, folate and vitamin D deficiencies |
Neurologic |
Disturbed hearing, vision, olfaction, proprioception, etc. |
Persistent infections |
Otitis media, skin infections, pharyngitis, conjunctivitis, etc. |
The idea that people with autism are insensitive to pain is now largely a myth. For example, in an experimental study by (
Autism is a clinically complex disease in which, in addition to classic neuropsychiatric symptoms and signs, many sensory and motor pathologies are described (
Since ASD is primarily a neurodevelopmental disorder, it is intuitive to assume that autistic patients have more brain, spinal cord, and PNS problems. Examples of such issues include various types of headaches, including migraines, as well as epilepsy (
Understanding the possible etiological factors and pathogenetic mechanisms may contribute to recognizing and treating various medical diseases currently associated with autism. For example, children with autism suffer from frequent pain syndrome and such GI symptoms as abdominal pain, bloating, belching, diarrhea or constipation, flatulence, nausea, and reflux (
Endocrine issues are often underdiagnosed in ASD patients due to a multitude of other problems. Additionally, persistent inflammation, abnormal microflora, and restrictive nutrition contribute to the disruption of endocrine health (
Autopsies of ASD patients and brain imaging showed that these children often have substantial disturbances in their brain anatomy compared to neurotypical individuals. For example, it was reported that during the first year of life, autistic children have an enlargement of their brains, which disappears by adolescence, but it is explained by shrinkage of various brain regions rather than return to normal (
There is no doubt that the factors meditating future ASD develop either in early postnatal period or even prenatally. For example, neuroimaging study of 106 infants at high familial risk of ASD and 42 low-risk infants showed that hyper-expansion of the brain’s cortical surface area between 6 and 12 months of age precedes brain volume overgrowth observed from 12 to 24 months (
Abnormal myelination in ASD occurs because oligodendrocytes, the cell responsible for nerve myelination in the CNS, are particularly susceptible to oxidative damage due to insufficient amounts of glutathione and abundance of sphingolipids (
Apart from gross changes in the brains of autistic patient, disruptions of molecular pathways were also examined. The study by (
As seen from the information presented above, inflammation of the CNS is uniformly present in children with autism. Although the exact mechanism of how inflammatory mediators result in ASD is yet to be found, one of the reasons why persistent inflammation induces the development of autistic phenotype is that it alters the morphology of astrocytes and microglia in the hippocampus and the frontal cortex, two essential regions for memory formation, higher-order cognition, and behavior (
Autism is a multifactorial disorder in which genetic and external risk factors interact to trigger its development. If the search is performed on the SFARI GENE database (https://gene.sfari.org), the results show approximately 700 genes associated with ASD, including copy number variations (CNVs), while some papers report about 1000 candidate autism-related genes (
Gene expression studies have been instrumental in comparing groups of people with ASD and control samples to measure which genes are dysregulated in ASD. Transcriptomic studies are essential as a key link between measuring protein levels and analyzing genetic information. In this field, research concentrates on epigenetic and transcriptional alterations in ASD development. For instance, hypermethylation of specific regions of MECP2 were associated with the behavioral changes observed in ASD (
To summarize the genetics, epigenetics, and transcriptomics data presented above, although above 100 ASD-susceptibility genes have been found, the utility of this information remains elusive. On the other hand, gene expression studies allow to understand thresholds for differential expression of genes, which in turn helps to identify pathologic pathways (
Parental well-being is an essential regulator in the future child’s health not only in terms of inheritance but also in the sense of the autoimmune, metabolic, and inflammatory effects of, especially, maternal health issues on the developing fetus. ASD is not an exception because various endocrine and infectious diseases of the mothers had a strong correlation with autism in their children. For example, the systematic review by (
The effect of maternal diseases on the developing fetus (
Maternal condition during pregnancy |
Effect on fetus |
Pre-eclampsia |
Impaired blood flow to placenta is harmful for fetal brain |
Gestational diabetes |
AGEs damage various organs and tissues |
Obesity |
High pro-inflammatory profile |
Hypothyroidism |
Low level of thyroid hormones causes abnormal brain development and growth retardation |
Autoimmune diseases |
High inflammatory profile |
Chronic stress |
Exposure to cortisol at the wrong time during intrauterine development may disrupt normal brain formation |
Infections |
Persistent inflammatory state and toxic metabolites damage the developing brain and other organs |
Summarizing the information presented in Table
Various maternal infections during pregnancy were found to have a positive correlation with the clinical manifestation of ASD. A 2019 publication in the journal JAMA Psychiatry showed the invovlement of maternal infection in the development of ASD. The article presented the results of a study in which about 1.8 million children born in Sweden were observed from birth for over 40 years (
Other clinical and epidemiological studies also confirmed maternal infection’s role. In the study by (
One of the most interesting discoveries about the role of a mother’s illnesses in children’s autistic phenotype was a wall-free pathogen, also known as L-form. This phenomenon was found both in the intestines of autistic patients and their mothers (
TORCH infections are a group of congenital infections that may cause severe abnormalities in the developing fetus. TORCH stands for Toxoplasmosis, Other (Syphilis, Parvovirus B19, HIV, HBV, and Varicella Zoster), Rubella, CMV, and HSV (
These infections negatively impact brain development in the prenatal period, during which about 57% of crucial differential gene expression in the neocortex occurs (
Severe disorders caused by TORCH infections in the form of a “dysfunctional or even paralyzed immune system” also trigger the process of forming a pathogenic resident microflora in almost all organs and systems of ASD children. The microbiota plays important roles in digestion, nutrient assimilation, vitamin production, and metabolism (
In autism, along with many symptoms associated with the pathology of the nervous system, children with ASD tend to have medical issues related to the GI tract (
The establishment and development of the early gut microbiome in infancy are essential for immune maturation and metabolic programming (
Dysbiosis can be defined a pathological disorder of the microbiota homeostasis caused by an imbalance between the microorganisms present in the natural human microflora, especially in the intestine. For example, it was found that ASD patients have dysbiosis with the abnormal ratio of Firmicutes to Bacteriodetes, the former being reduced while the latter being significantly elevated in their guts (
Gut microbiota is vital for overall intestinal health and the normal functioning of such processes as food digestion, immune system regulation, energy production, and, according to recent data, behavior. It means that microbial dysbiosis, overgrowth of potentially pathogenic microorganisms, poor diversity of the microbiome, or low levels of beneficial bacteria in ASD patients can affect their behavior. Metabolome analysis in autistic children has identified perturbations in multiple metabolic pathways that might be associated with cognitive functions. Recent studies have shown that the intestinal microbiome provides environmental signals that can modify host response to stimuli by modifying the host epigenome, affecting DNA methylation, histone modification, and non-coding RNAs. The most studied microbiota-produced epigenetic modifiers are short-chain fatty acids, although other products of intestinal microbiota might also cause epigenetic alterations in the DNA of the host (
A role of abnormal microflora in autism was shown in the study that found increased Clostridia as well as overgrowth of other spore-forming anaerobes, microaerophilic bacteria, and several Clostridia clusters I/IX and C. bolteae (46-fold increase) within the gastric and duodenal secretions not seen in controls (
Shaping of an infant’s microflora, normal or pathologic, begins when one is born either through vaginal delivery or CS. In children with ASD, this microbiome consists of higher than usual, Staphylococci, Streptococci, Actinomycetes, pathogenic Clostridia, Egertella lenta, Propionibacterium acnes, as well as pathogenic fungi such as Candida, Aspergillus, and other Micromycetes (K. Alibek, MD, unpublished data, 2022). These microbes further contribute to the pathological state of autism by enhancing the chronic inflammation, oxidative stress, and intoxication effects produced by virulence factors or chemical toxins they secrete.
The research also shows that autistic children having an overgrowth of the spore-forming Clostridium filum in their intestines developed a regressive form of ASD, in addition to having severe GI symptoms (
Another GI problem often seen in ASD patients is small intestinal bacterial overgrowth (SIBO), which is presented by bloating, distention, diarrhea, and abdominal pain after eating carbohydrate-rich meals, legumes, grains, or excess fiber (
When discussing pathogenic microflora in ASD patients, it is crucial to elaborate on why anti-microbial therapies fail to produce the desired effect soon after the completion of these therapies. It appears that biofilms play a critical role in this problem. Biofilm is a complex structure of microbiome having different bacterial colonies or single type of cells in a group, adhering to a surface. These cells are dispersed in extracellular polymeric substances, a matrix composed of eDNA, proteins, and polysaccharides, which showed high resistance to antibiotics (
As discussed earlier in this paper, children with ASD struggle with immune dysfunction, among other things. Indeed, immune system dysregulation makes these children susceptible to damage from opportunistic pathogens. Furthermore, they become prone to develop autoimmune disorders that, by definition, produce harm to various tissues and organs of a child who was already born with some structural abnormalities of some organs due to the undesired prenatal exposure to toxic or infectious agents. These problems include allergic reactions, contact dermatitis, chronic inflammation, and persistent infections like otitis media, as well as GI and GU infections (
Cytomegalovirus (CMV) belongs to the family of human herpesviruses and infects approximately 60-90% of the world population (
CMV encodes numerous proteins and miRNAs that allow the virus to replicate and disseminate in the body, evading the immune system and resulting in detrimental health outcomes (
The Epstein-Barr virus (EBV) is a highly successful human herpes virus that infects more than 90% of people globally at some point in their lives (
Although symptomatic EBV infection is rare in infants, it can sometimes can cause such neurologic disorders as meningitis, encephalitis, transverse myelitis, Guillain-Barré syndrome, cerebellar ataxia, sleep disorders, and psychoses (
Congenital rubella syndrome (CRS) is an infant disease that stems from maternal infection with rubella virus (
All the examples presented above show that a large variety of pathogens can play a role in the initiation, promotion, or worsening of the course of ASD. And there is a high probability that several cases of ASD could result not from a single infectious pathology but poly-infection. Many autistic patients’ post-mortem samples had a burden of infections, having 2-3 infections, including the various herpes viruses, including HHV-6 and CMV, while the samples of healthy controls had no more than one virus (
Autism spectrum disorders are a range of neurodevelopmental problems that often present clinically as repetitive behavior, restricted interests, and a lack of capacity for regular social interaction. The inflammatory and infectious nature of this disease is now a predominant theory about the etiology of this disorder, whereas other hypotheses related to unempathetic parents and heavy metals exposure are no longer valid. Inflammation in a fetus can be caused by various factors, ranging from TORCH infections to wall-free pathogens from the mother. Another critical contributor to immune, humoral, and nervous system dysfunction in ASD patients is the predominance of pathogenic microflora. All these factors trigger sustained systemic inflammation and oxidative stress that cause mutations, abnormal epigenetic alterations, and tissue necrosis in various organs, particularly in the brain. Necrosis and inflammation produce brain edema and subsequent shrinkage, resulting in irreversible changes in anatomy and physiology, producing distinct autistic phenotype. Overall, the results and findings of the studies discussed in this paper suggest that future methods for improving the symptoms can be based on prophylaxis and treatment of maternal infections during and even before pregnancy. In ASD children, complex anti-microbial and anti-inflammatory therapy not only can improve somatic symptoms but also enhance the efficiency of treatment methods that target behavioral problems in these patients.
We are grateful to Andrew Lefkowitz, CEO and chairman of FLAASK, LLC, for his financial, administrative, and moral support provided for this work.
The study was funded by FLAASK, LLC.
This article does not contain any studies with human participants or animals performed by any of the authors.
All authors equally contributed to writing and editing this article.
The authors declare that they have no conflict of interest.