AN EXTENSIVE REVIEW ON EFFECTS OF PSYCHOBIOTIC BASED TREATMENTS IN AUTISTIC SPECTRUM OF DISORDER AND APPLICABILITY OF ZEBRAFISH AS A ROBUST MODEL FOR STUDYING ASD

AN EXTENSIVE REVIEW ON EFFECTS OF PSYCHOBIOTIC BASED TREATMENTS IN AUTISTIC SPECTRUM OF DISORDER AND APPLICABILITY OF ZEBRAFISH AS A ROBUST MODEL FOR STUDYING ASD

Anusha Samanta and Tamalika Chakraborty *

Department of Life Science, Guru Nanak Institute of Pharmaceutical Science and Technology, Kolkata, West Bengal, India.

ABSTRACT: Autism spectrum disorders (ASDs) refer to the group of neuropsychiatric disorders that alter neurodevelopment and mental function and are characterised by an extensive range of symptoms, including hyper-or hyposensitivity, repetitive behaviours, and impairments in social and academic functioning. Untangling the causation of ASD has been complicated, in part because distinct genetic abnormalities can result in both identical and distinctive traits that entirely fall within ASD. ASD can be triggered by hereditary and/or environmental causes. Studies in both experimental and clinical trials have revealed that the gut microbiome is altered in ASD patients. Due to its linkages to nutrition and the reciprocal relationship with the host, these changes affect the composition of the gut microbiota and also the metabolites they create. The gut-brain axis (GBA) mediates how the central nervous system (CNS) associated roles and behaviours are affected by psychobiotics, a unique family of probiotics that enhances not only gastrointestinal (GI) function but also anxiolytic and antidepressant activity. Psychobiotic use can enhance GI processes and ASD-related symptoms. New models for studying ASD have been developed during the past few decades, in-vitro also in-vivo. These models hold great promise for validating few of the formerly identified risk factors for the disorder's onset and for testing novel possible treatments, like the use of psychobiotics to minimise ASD symptoms. The evidence supporting psychobiotics' impact on ASDs is still limited, nevertheless. Future research on the efficiency and mechanism of psychobiotics as treatments for ASDs will be necessary using more effective models e.g., zebrafish.

Keywords: Autism spectrum disorders, Neuropsychiatric disorders, Gut microbiota, Gut-brain axis, Psychobiotics, Zebrafish

INTRODUCTION: A range of diverse neurodevelopmental disorders (NDDs) known as autism spectrum disorders (ASDs) are influenced by both hereditary and environmental factors ¹. Individuals with the presence of social and communication deficits as well as a lack of universal interpersonal skills are considered of having ASDs.

Patients may also experience repetitive or stereotyped forms of behaviour, interests, and/or actions in addition to these symptoms. The 5^th edition of “Diagnostic and Statistical Manual of Mental Disorders” sets forth criteria for the diagnosis of ASDs.

According to that, the NDDs listed below fall under the ASD category: Asperger's disorder, Kanner's autism, pervasive developmental disorder not otherwise specified (PDD-NOS), high functioning autism, atypical autism, early infantile autism, and childhood disintegrative disorder (American Psychiatric Association 2013) ². ASD is, globally, a significant contributor to developmental disability. The “World Health Organization” (WHO) defines the incidence of ASD globally at 0.76% but only accounts for roughly 16% of all children worldwide ³. Its estimated prevalence in the UK is 1% ⁴, and in the US, parent-reported ASD diagnoses in 2016 had an average of 2.5% ⁵. There are around 1.3 billion people living in India, with children below the age of 15 having to make up about one-third of the population. ASD may affect more than 2 million individuals in India, according to estimates. The majority of published research on ASD relies on hospital-based data, hence they lack data on the disorder's estimated prevalence in India. Only a few research have specifically examined its prevalence in community settings. Furthermore, it is challenging to determine the exact occurrence of ASD due to the inconsistent use of properly validated and translated diagnostic methods for autism. Because of a suspension in ASD diagnosis at a young age, the illness is also not fully recognised ⁶.

The development of prospective treatments has been delayed by the difficulty in determining the pleiotropic character and genetic complexity character of ASDs, as well as a variety of putative environmental causes ^{7, 8}. Most prominently, counting Prader-Willi and Angelman syndromes, 1-3% of all cases of autism are associated with duplications of the 15q11-q13 region that are inherited from the mother ⁹. 4–5% of ASD cases had mutations at established ASD sites, like those in Rett and Fragile X syndrome ¹⁰.

Despite being highly heritable illnesses, ASDs are only heritable in about 50% of cases, and even monozygotic twins do not always have identical twins ¹¹. Recent transcriptome investigations have shown that immunological maturation and neural development are both linked to ASD, and enrichment analysis has identified cellular and molecular pathways e.g., synaptic function and WNT signalling ¹². Many genes which regulate the synapse also are revealed primarily in the elated inhibitory neural lineages were discovered in a current whole-exome sequencing analysis of ASDs ¹³. Another recent study links ASD in mice and humans with insufficient myelination brought on by oligodendrocyte dysregulation ¹⁴. Antibiotic use, epigenetic alterations, and the maternal and baby microbiota have entirely been linked to the growth and advancement of ASD pathogenesis.

Recent studies have exposed that ASD sufferers are known to experience digestive issues and different microbiome taxonomic patterns from neurotypical (NT) people ¹⁵. The “gut-brain axis” is thought to be a two-way transmission channel involving the brain and the gut. Still, this idea might be broadened to make the community of microorganisms a crucial component of this triangle ¹⁶. Antibiotic use influenced the enteric nervous system (ENS) also the central nervous system (CNS), and exposure to infections altered gut-brain symptoms as well as immune activation. In the opposite circumstance, microbiota-targeting antibiotics have been used to successfully treat hepatic encephalopathy ¹⁷. The neuroendocrine, neuroimmune, and autonomic nervous systems all perform a role in the connection or transmission between the microbiota in the stomach also the brain ¹⁸.

Around 9 to 84% of people with ASD report having GI issues as a comorbidity¹⁹. These include diarrhoea (19%) and constipation (20%), both of which are more common in children having ASD than in their healthy brothers or sisters (42 vs. 23%, correspondingly) ²⁰. The data connecting the gut microbiota either directly or indirectly to the symptoms of ASD suggests that this may occur in part due to its impact on the host metabolism also its defence mechanism ^{21, 22}. One of the diseases associated with ASD patients is leaky gut or increased intestinal epithelial permeability ²³.

Compared to the control batch (4.8%), patients with ASD (36.7%) also their family members (21.2%) demonstrated greater percentages of aberrant intestinal epithelial permeability ²⁴. Increased permeability makes it possible for toxins also bacterial by-products to go into circulation, which ultimately affects brain function with lowers social behavioural scores ¹⁸. Recent research indicates strong links between the gut microbiota also the aetiology of ASD, with bacterially obtained metabolites from the GI tract linked to changes in host neurodevelopment along with neural-specific mRNA processing, even though our understanding of the relationship between the microbiome and ASD is still limited ^{25, 26}.

Probiotics Affecting Gut-Brain Axis –Psychobiotics in Mental Health: The sum of bacteria in the human digestive tract, 10¹⁴, stands 100 times above the total number of cells in the body. Numerous physiological systems, such as energy balance, ENS activation, and immunomodulation, have been demonstrated to be influenced by gut bacteria or an individual's microbiota profile influenced by d Diet, genetics, sex, age, and other variables ²⁷. The relationship among gut dysbiosis along with functional gutdisorders and CNS disorders provides implications for the microbiota-gut-brain axis (MGBA) connection ^{28, 29}. The idea compared to specific pathogen-free (SPF) controls of MGBA was established by the reduced social behaviours of germ-free (GF) animals. Another indication of the significance of gut flora to CNS functioning is the improvement of social impairments in GF mice following the transplantation of a typical microbiome ³⁰.

A unique class of probiotics known as "psychobiotics" suggests potential uses in the therapeutics of psychiatric disorders by regulating gamma-aminobutyric acid (GABA), brain-derived neurotrophic factor(BDNF),glutamate, and serotonin, that perform crucial parts in managing the neuronal excitatory-inhibitory stability, cognitive abilities, mood, learning as well as memory processes ^{31, 32, 33}. Immunoregulatory, neuroendocrine, and vagus pathways have all been proposed as potential channels of transmission among the brain and gut microbiota ³⁴. Some Lactobacillus and Bifidobacterium strains, including Lactobacillus plantarum, Bifidobacterium dentium, and Lactobacillus brevis create serotonin and GABA, while other Lactobacillus strains, including L. plantarum and L. odontolyticus, produce acetylcholine ^{35, 36, 37, 38}. It has recently been discovered that bacteria can control the synthesis of serotonin in the gut as enterochromaffin cells in the stomach stimulate serotonin production when exposed to spore-forming bacteria from the gut microbiota ³⁹. Erythrogenic cytokines can be decreased by probiotics e.g., Lactobacillus, Bifidobacterium, and Enterococcus ⁴⁰. Probiotics have been revealed to have anti-immunoregulatory effects that activate the T regulatory cell population and IL-10 production ⁴¹.

Additionally, probiotics interact with GI epithelial enteroendocrine cells (EECs) for the formation of neuropeptides also neurotransmitters like substance P, neuropeptide Y (NPY), serotonin, peptide YY (PYY), glucagon-like peptide-1 and -2 (GLP-1 and GLP-2) and cholecystokinin ^{42, 43}. ENS neurons and gut EECs are the primary sources of serotonin, which is associated with the control of GI secretion and motility ⁴⁴. In Table 1, some pieces of evidence of psychobiotics having psychotropic reactions to stress, anxiety and also depression has been shown. Regarding the potential uses of psychobiotics, the investigations have yielded some encouraging data, however, there is still unavailability of human data. In this area, additional clinical research is indispensable.

TABLE 1: EXAMPLES OF SOME RECENTLY OBSERVED PSYCHOTROPIC EFFECTS OF SOME PSYCHOBIOTIC STRAINS IN STUDY MODELS

Modelling for ASD: Patients with ASD typically receive treatment aimed at easing the disorder's symptoms to lessen how much of an impact they have on their daily lives. To do this, it is common for patients to receive a mix of therapeutic modalities, such as behavioural therapy and/or medication. There is no drug that can totally cure ASD or lessen its symptoms. Moreover, it has been mentioned previously that risk factors for developing ASD include both hereditary and environmental elements. Hence, it was very challenging for the researchers to find out the individual effects of each risk factor in the occurance of ASD. For that, the development of several in vivo and in vitro pre-clinical models of human illnesses that could assist in understanding the molecular processes that underlie the emergence of a particular pathology has been observed ⁵⁶.

Genome Editing System: A promising Tool for modelling human disorders is genome editing Systems. The current three foremost types of genome-editing technologies are Zinc Finger Nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), and CRISPR/C as (Clustered Regularly Interspaced Short Palindromic Repeats). Each of these three systems causes distinct DNA breaks that set off the cellular DNA repair processes. The most recent genomic editing technology, CRISPR/Cas9, is rooted in the bacterial defence mechanism CRISPR type II and differs from ZFN and TALENs in that it only requires two components to operate: Cas9 nuclease and single guide RNA (sg RNA) ⁵⁷.

Furthermore, several enzymes can replace Cas9, increasing the technique's usefulness. In order to increase the variety of CRISPR/Cas modifying enzymes available to us, it may be helpful to develop new types of Cas nucleases, but it's also intriguing to consider whether existing nucleases like Cas9 could be modified. For instance, much work has gone into creating Cas9 that is induced, also modifying its recognition site (PAM sequence), and increasing its exactness ^{58, 59}. The functional basis for CRISPR interference (CRISPRi) ⁶⁰, CRISPR activation (CRISPRa) ⁶¹, base editing ⁶², and prime editing ⁶³ is a modified Cas9 that can be coupled with various enzyme domains. The existence of inaccurate impact in the genome of the modified cells is a significant downside of CRISPR/Cas technology, which can be particularly risky for therapeutic applications ⁶⁴. Several model organisms, including zebrafish ⁶⁵, Drosophila melanogaster ⁶⁶, rodents ⁶⁷, etc., have been successfully edited genetically using the CRISPR/Cas system. Human somatic ⁵⁷ and embryonic cell lines ⁶⁸ have both been cultured using CRISPR/Cas.

In-vitro Modelling of ASD: It was not possible to use cell culture as a model for ASD because there was little chance of collecting CNS cells through biopsies. This obstacle has been overcome in 2006 at the time when Yamanaka and his colleagues discovered pathways that permit reprogramming grownup somatic cells by enabling the conversion of altered cell lines to induced pluripotent stem cells (hiPSCs) by introducing four genes i.e., the Yamanaka factors (Oct3/4, Sox2, Klf4,and c-Myc). Now it is feasible to create cell lines precisely from patients thanks to the development of modern reprogramming techniques and differentiation regimens. As a result, it is possible to create specific in vitro models to investigate the underlying causes of a certain condition in an individual. Patient-derived cellular models have been verified to be extremely strong, trustworthy, and realistic while preserving the genetic makeup of the origin.

Since, they complement the genetic makeup of the patients, it is possible to examine the biological basis of each condition. These models are helpful for determining the connection between a genotype and phenotype as well as for creating new therapeutic strategies, such as cell therapy and pharmaceutical remedies. Drug sensitivity tests, which are useful to authenticate the activity of the chosen medications prior to medical assays, can help achieve this by helping to identify new targets for therapy or biomarkers. This method gives up fresh opportunities for the investigation of the molecular origins of convoluted illnesses like ASD for all the previously mentioned reasons ^{68, 69, 70, 71}. Even with the benefits of in-vitro models, which will never fully replicate the complexities behind their development, animal models remain an essential tool for understanding ASDs.

Animal Models for ASD: The use of animal models in ASD research has the potential to be significant. For the research of autistic disorders, there are numerous genetic models available ⁷². Animal models do not, however, display all the signs of human neurodevelopmental disorder. Animal models for ASD have been found using two basic methods. Forward genetics is the first method, in which ASD-like traits are found in the chosen animal model, after which the molecular causes of the detected changes are clarified. Reverse genetics is the second method, in which certain mutations are inserted into the animal model's genome after which the phenotype is identified ⁷³. Typically, laboratory-bred rodents like rats or mice have been mostly used in ASD research experiments ⁷⁴. Rodents are ideal for the research of ASD as their social behaviour has been extensively examined by a set of tests like the three-chambered social interaction, the Morris water task, swimming tests, or even just a simple assessment of exploratory behaviours, and their neurological system may be manipulated using a variety of well-established methods. Furthermore, since rats and mice are sociable, it is well-known how they relate to one another in terms of parental, sexual, and territorial activities. Rats were used in the first ASD investigations because of their obvious social behaviour. However, because mice are less expensive, their use in ASD research has been rising ⁷⁵.

Mus Musculus or house mice in ASD Research: Despite the abundance of ASD genetic models, there are fewer and largely inbred (e.g., Black and Tan Brachyury, or BTBR) or environmental (e.g., VPA, MIA) animal models available for the research of the gut microbiota-ASD connection ⁷². The BTBR mouse strain has been utilised in numerous investigations evaluating the impact of medications and gut microbiota products on ASD-related outcomes because it consistently replicates the ASD phenotype in various lab settings⁷⁶. The C57Bl/6J mouse strain, which is more motivated and less impulsive, is another one used in ASD research ⁷⁷.

As a maternal immune activation (MIA) mouse model, pregnant C57Bl/6J females were also administered B. fragilis. Due to the disruption of the GI barrier, which results in inflammatory actions that may eventually influence the neuro-development of the progenies, MIA, throughout pregnancy, has been proven to upsurge the risk of developing neurodevelopmental psychiatric problems like ASD ^{78, 79}.

Rattus norvegicus or Common Rats in ASD Research: Rats have been suggested as a model creatures with a great possibility to study NDDs, counting ASD, due to their more complicated behaviour and social interactions. With the use of ZFN and also ENU-induced mutagenesis, the first rat knockout models for the investigation of ASD were produced in 2010 ⁸⁰. However, despite the clear applicability of rodent models for ASD modelling along with the priceless data they provide, there are yet some glaring limitations that have prompted scientists to choose more controllable models.

Clinical Studies of ASD: Several recent clinical trials of psychobiotics mentioned in the U. S. National Library of Medicine have been listed down below Table 2. Some of these trials are either completed successfully or still in the process of examining.

TABLE 2: RECENT CLINICAL TRIALS OF PSYCHOBIOTICS IN ASD-RELATED HUMAN SUBJECTS MENTIONED IN THE U.S. NATIONAL LIBRARY OF MEDICINE ²⁷

Zebrafish Model: Reasons to accept it to Study ASD: Zebrafish have been proposed as asupreme animal model in recent years for the investigation of the genetic basis of a number of human diseases also astonishingly, they are currently used as a model in more than 800 laboratories worldwide ⁸¹. Over 70% of the zebrafish genome is similar to human genes, and zebrafish and human neurodevelopmental processes are the same ⁸². Compared to more conventional model systems, this one has certain clear advantages ⁷³. For instance, zebrafish embryos are transparent and develop quickly in the external environment, making it possible to directly see neurodevelopmental processes and brain activity in a healthy, functional nervous system. Additionally, zebrafish are very tractable and have substantial offspring, making it possible to conduct high-throughput pharmacological screens on a larger scale than is possible with rodent models. Furthermore, with improvements in zebrafish CRISPR/Cas9 gene-editing methods, it is now possible to quickly and cheaply produce mutant zebrafish with loss-of-function mutations in a gene of interest ^{83, 84}. Zebrafish, therefore, have great promise for enhancing our knowledge of the functions of risk genes inneurodevelopment and illuminating the fundamental biological processes behind NDDs.

Zebrafish are effective model organisms for studies examining the role of the microbiome. It is conceivable to nurture them in sterile environments that produce germ-free individuals because they are initially colonised by microorganisms through their environment. Experiments incorporating selective colonisation, the addition of metabolites, and the impacts of conventionalization are conceivable after germ-free subjects have been created. The optical transparency of larvae allows for in-vivo imaging of the zebrafish stomach during the early stages of development. This enables investigation of the localization and cross-species dynamics of fluorescently labelled bacterial species as well as GI function such as motility and barrier function. Additionally, the gut is simply cut open, making it possible to remove the microbiota for 16S sequencing ^{85, 86, 87}. Zebrafish have a considerable advantage over mammalian models when it comes to GI research because of their external fertilisation, rapid development also early transparency, which make investigating GI function in vivo much simpler. Before the larvae start feeding (with spontaneous motility appearing before 5 dpf), estimation of digestive transit, peristaltic rate along with general GI ontogeny can be conducted without the need for difficult or possibly variable-confounding surgical procedures ⁸⁸. Combining the two has drawn a lot of attention recently because of the growth in zebrafish-based GI research and the connection between ASD and GI disorders in non-zebrafish models.

It has been difficult to use mutant zebrafish to examine gene function, though. The fact that considerable amounts of mRNA generated by the targeted gene may still be present after genetic modifications intended to produce gene loss-of-function suggests that the goal may not have been fully attained ⁸⁹. In order to address this problem and facilitate ASD research utilizing zebrafish, “SFARI” (Simons Foundation Autism Research Initiative) is currently curating zebrafish lines with mutations in zebrafish paralogs of ASD risk genes. Gene loss-of-function is confirmed by monitoring mRNA or protein levels (where antibodies are available) rather than by evaluating phenotype. Table 3 lists all the lines that SFARI has selected and is available at the “Zebrafish International Research Centre” (ZIRC).

TABLE 3: LIST OF GENES IN ZEBRA FISH ASD MODEL AND THEIR PHENOTYPIC FEATURES

DISCUSSION & CONCLUSION: As behavioural assay development and data gathering progress, the value of zebrafish in behavioural neuroscience grows. The collecting of behavioural data is made more repeatable between studies and even labs by tools such as DanioVision, an observation box created exclusively for the monitoring of zebrafish larvae. Similar commercially accessible software programmes include Stytra ¹¹⁷, a free software programme made for tracking behavioural zebrafish investigations, and ZebraLab (Viewpoint), built for high-throughput assessment of embryos ¹¹⁸. These and other technologies enable the highly measurable behavioural traits of zebrafish.

The effects of psychobiotics on autism spectrum disorder have been extensively studied in recent years. This biological therapy has potential, as has been demonstrated. More studies are needed to do that, and as is well known, it is not practical to conduct direct psychobioticexperiments on humans. Rodents were frequently employed in the past to study the effects of psychobiotics, but recent studies have shown that zebrafish models are considerably more suitable for use in clinical trials for human diseases like ASD. Despite the discovery of several ASD-related genes in the zebrafish genome, psychobiotic studies using zebra fish models have not yet shown any conclusive results. The effects of psychobiotics can be determined using a variety of behavioural assays. Rodent models are harder to find and far less accessible than zebrafish models. It is simple to maintain in laboratory settings. In order to have revolutionary effects in the field of neuroscience or in the treatment of mental health conditions like ASD, more and more study on the effects of psychobiotics in the zebrafish model is needed.

ACKNOWLEDGEMENTS: We would like to express our special thanks of gratitude to our institute, Guru Nanak Institute of Pharmaceutical Science and Technology, for their excellent infrastructure and support.

CONFLICTS OF INTEREST: The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. We certify that the submission is original work.

REFERENCES:

1. Liloia D, Manuello J, Costa T, Keller R, Nani A and Cauda F: Atypical local brain connectivity in pediatric autism spectrum disorder? A coordinate-based meta-analysis of regional homogeneity studies. Eur Arch Psychiatry Clin Neurosci 2023.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed. Vol. 5. Washington, DC: American psychiatric association; 2013.
3. Li YA, Chen ZJ, Li XD, Gu MH, Xia N and Gong C: Epidemiology of autism spectrum disorders: Global burden of disease 2019 and bibliometric analysis of risk factors. Front Pediatr 2022; 10.
4. O’Nions E, Petersen I, Buckman JEJ, Charlton R, Cooper C and Corbett A: Autism in England: assessing underdiagnosis in a population-based cohort study of prospectively collected primary care data. The Lancet Regional Health - Europe 2023; 29: 100626.
5. Kogan MD, Vladutiu CJ, Schieve LA, Ghandour RM, Blumberg SJ and Zablotsky B: The Prevalence of Parent-Reported Autism Spectrum Disorder Among US Children. Pediatrics 2018; 142(6).
6. Chauhan A, Sahu J, Jaiswal N, Kumar K, Agarwal A and Kaur J: Prevalence of autism spectrum disorder in Indian children: A systematic review and meta-analysis. Neurol India 2019; 67(1): 100.
7. Bölte S, Girdler S and Marschik PB: The contribution of environmental exposure to the etiology of autism spectrum disorder. Cellular and Molecular Life Sciences 2019; 76(7): 1275–97.
8. Courchesne E, Pramparo T, Gazestani VH, Lombardo M V., Pierce K and Lewis NE: The ASD Living Biology: from cell proliferation to clinical phenotype. Mol Psychiatry 2019; 24(1): 88–107.
9. Rylaarsdam L and Guemez-Gamboa A: Genetic Causes and Modifiers of Autism Spectrum Disorder. Front Cell Neurosci 2019; 13.
10. Seesahai J, Church P, Patel L, Rotter T, Asztalos E and Lam H: Prevalence of Autism Spectrum Disorder (ASD) in all Individuals Diagnosed with Down Syndrome (DS): A Systematic Review and Meta-analysis Protocol. Res Sq 2021.
11. Tammimies K: Genetic mechanisms of regression in autism spectrum disorder. Neurosci Biobehav Rev 2019; 102: 208–20.
12. Quesnel-Vallières M, Weatheritt RJ, Cordes SP and Blencowe BJ: Autism spectrum disorder: insights into convergent mechanisms from transcriptomics. Nat Rev Genet 2019; 20(1): 51–63.
13. Satterstrom FK, Kosmicki JA, Wang J, Breen MS, De Rubeis S and An JY: Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Cell 2020; 180(3): 568-584.e23.
14. Phan BN, Bohlen JF, Davis BA, Ye Z, Chen HY and Mayfield B: A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder. Nat Neurosci 2020; 23(3): 375–85.
15. Sgritta M, Dooling SW, Buffington SA, Momin EN, Francis MB and Britton RA: Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder. Neuron 2019; 101(2): 246-259.e6.
16. Cryan JF, O’Riordan KJ, Cowan CSM, Sandhu K V., Bastiaanssen TFS and Boehme M: The Microbiota-Gut-Brain Axis. Physiol Rev 2019; 99(4): 1877–2013.
17. Menees S and Chey W: The gut microbiome and irritable bowel syndrome. F1000 Res 2018; 7: 1029.
18. Garcia-Gutierrez E, Narbad A and Rodríguez JM: Autism Spectrum Disorder Associated With Gut Microbiota at Immune, Metabolomic, and Neuroactive Level. Front Neurosci 2020; 14.
19. Sauer AK, Stanton JE, Hans S and Grabrucker AM: Autism Spectrum Disorders: Etiology and Pathology. In: Autism Spectrum Disorders. Exon Publicatio 2021; 1–16.
20. Lefter R, Ciobica A, Timofte D, Stanciu C and Trifan A: A Descriptive Review on the Prevalence of Gastrointestinal Disturbances and Their Multiple Associations in Autism Spectrum Disorder. Medicina (B Aires) 2019; 56(1): 11.
21. Fattorusso A, Di Genova L, Dell’Isola G, Mencaroni E, Esposito S. Autism Spectrum Disorders and the Gut Microbiota. Nutrients 2019; 11(3): 521.
22. Meltzer A and Van de Water J: The Role of the Immune System in Autism Spectrum Disorder. Neuropsychopharmacology 2017; 42(1): 284–98.
23. Camilleri M: Leaky gut: mechanisms, measurement and clinical implications in humans. Gut 2019; 68(8): 1516–26.
24. Garcia-Gutierrez E, Narbad A and Rodríguez JM: Autism Spectrum Disorder Associated With Gut Microbiota at Immune, Metabolomic, and Neuroactive Level. Front Neurosci 2020; 14.
25. Stilling RM, Moloney GM, Ryan FJ, Hoban AE, Bastiaanssen TF and Shanahan F: Social interaction-induced activation of RNA splicing in the amygdala of microbiome-deficient mice. Elife 2018; 7.
26. Gonatopoulos-Pournatzis T, Blencowe BJ. Microexons: at the nexus of nervous system development, behaviour and autism spectrum disorder. CurrOpin Genet Dev 2020; 65: 22–33.
27. Cheng LH, Liu YW, Wu CC, Wang S and Tsai YC: Psychobiotics in mental health, neurodegenerative and neurodevelopmental disorders. J Food Drug Anal 2019; 27(3): 632–48.
28. Fried S, Wemelle E, Cani PD and Knauf C: Interactions between the microbiota and enteric nervous system during gut-brain disorders. Neuropharmacology 2021; 197: 108721.
29. Huo R, Zeng B, Zeng L, Cheng K, Li B and Luo Y: Microbiota Modulate Anxiety-Like Behavior and Endocrine Abnormalities in Hypothalamic-Pituitary-Adrenal Axis. Front Cell Infect Microbiol 2017; 7.
30. Liu X, Li X, Xia B, Jin X, Zeng Z and Yan S: Gut Microbiota Mediates High-Fiber Diet Alleviation of Maternal Obesity-Induced Cognitive and Social Deficits in Offspring. bioRxiv 2020.
31. AG SK: Microbes and the Mind. Cowan CSM, Leonard BE, editors. Vol. 32. S. Karger AG; 2021.
32. Miranda M, Morici JF, Zanoni MB and Bekinschtein P: Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain. Front Cell Neurosci 2019; 13.
33. Méndez-Couz M, Krenzek B and Manahan-Vaughan D: Genetic Depletion of BDNF Impairs Extinction Learning of a Spatial Appetitive Task in the Presence or Absence of the Acquisition Context. Front Behav Neurosci 2021; 15.
34. Li Y, Hao Y, Fan F and Zhang B: The Role of Microbiome in Insomnia, Circadian Disturbance and Depression. Front Psychiatry 2018; 9.
35. Roth W, Zadeh K, Vekariya R, Ge Y and Mohamadzadeh M: Tryptophan Metabolism and Gut-Brain Homeostasis. Int J Mol Sci 2021; 22(6): 2973.
36. Ochoa-de la Paz LD, Gulias-Cañizo R, D´AbrilRuíz-Leyja E, Sánchez-Castillo H and Parodí J: The role of GABA neurotransmitter in the human central nervous system, physiology, and pathophysiology. Revista Mexicana de Neurociencia 2021; 22(2).
37. Patterson E, Ryan PM, Wiley N, Carafa I, Sherwin E and Moloney G: Gamma-aminobutyric acid-producing lactobacilli positively affect metabolism and depressive-like behaviour in a mouse model of metabolic syndrome. Sci Rep 2019; 9(1): 16323.
38. Lyte JM and Lyte M: Review: Microbial endocrinology: intersection of microbiology and neurobiology matters to swine health from infection to behavior. Animal 2019; 13(11): 2689–98.
39. Agus A, Clément K and Sokol H: Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut 2021; 70(6): 1174–82.
40. Zhang L, Song J, Bai T, Qian W and Hou XH: Stress induces more serious barrier dysfunction in follicle-associated epithelium than villus epithelium involving mast cells and protease-activated receptor-2. Sci Rep 2017; 7(1): 4950.
41. Chelakkot C, Ghim J and Ryu SH: Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp Mol Med 2018; 50(8): 1–9.
42. Cani PD and Knauf C: How gut microbes talk to organs: The role of endocrine and nervous routes. Mol Metab 2016; 5(9): 743–52.
43. Coates MD, Tekin I, Vrana KE and Mawe GM: Review article: the many potential roles of intestinal serotonin (5-hydroxytryptamine, 5-HT) signalling in inflammatory bowel disease. Aliment Pharmacol Ther 2017; 46(6): 569–80.
44. Costedio MM, Hyman N and Mawe GM: Serotonin and Its Role in Colonic Function and in Gastrointestinal Disorders. Dis Colon Rectum 2007; 50(3): 376–88.
45. Liu YW, Liu WH, Wu CC, Juan YC, Wu YC and Tsai HP: Psychotropic effects of Lactobacillus plantarum PS128 in early life-stressed and naïve adult mice. Brain Res 2016; 1631: 1–12.
46. Liu WH, Yang CH, Lin CT, Li SW, Cheng WS and Jiang YP: Genome architecture of Lactobacillus plantarum PS128, a probiotic strain with potential immunomodulatory activity. Gut Pathog 2015; 7(1): 22.
47. Liang S, Wang T, Hu X, Luo J, Li W and Wu X: Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress. Neuroscience 2015; 310: 561–77.
48. Savignac HM, Kiely B, Dinan TG and Cryan JF: Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice. Neurogastroenterology& Motility 2014; 26(11): 1615–27.
49. Bravo JA, Forsythe P, Chew M V., Escaravage E, Savignac HM and Dinan TG: Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences 2011; 108(38): 16050–5.
50. Bercik P, Verdu EF, Foster JA, Macri J, Potter M and Huang X: Chronic Gastrointestinal Inflammation Induces Anxiety-Like Behavior and Alters Central Nervous System Biochemistry in Mice. Gastroenterology 2010; 139(6): 2102-2112.e1.
51. Desbonnet L, Garrett L, Clarke G, Kiely B, Cryan JF and Dinan TG: Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 2010; 170(4): 1179–88.
52. Allen AP, Hutch W, Borre YE, Kennedy PJ, Temko A and Boylan G: Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers. Transl Psychiatry 2016; 6(11): e939–e939.
53. Mohammadi AA, Jazayeri S, Khosravi-Darani K, Solati Z, Mohammadpour N and Asemi Z: The effects of probiotics on mental health and hypothalamic–pituitary–adrenal axis: A randomized, double-blind, placebo-controlled trial in petrochemical workers. NutrNeurosci 2016; 19(9): 387–95.
54. Messaoudi M, Lalonde R, Violle N, Javelot H, Desor D and Nejdi A: Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. British Journal of Nutrition 2011; 105(5): 755–64.
55. Messaoudi M, Violle N, Bisson JF, Desor D, Javelot H and Rougeot C: Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes 20117; 2(4): 256–61.
56. Adli M: The CRISPR tool kit for genome editing and beyond. Nat Commun 2018; 9(1): 1911.
57. Jinek M, East A, Cheng A, Lin S, Ma E and Doudna J: RNA-programmed genome editing in human cells. Elife 2013; 2.
58. Bak SY, Jung Y, Park J, Sung K, Jang HK and Bae S: Quantitative assessment of engineered Cas9 variants for target specificity enhancement by single-molecule reaction pathway analysis. Nucleic Acids Res 2021; 49(19): 11312–22.
59. Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS and Arkin AP: Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell. 2021 Feb;184(3):844.
60. Park JJ, Dempewolf E, Zhang W, Wang ZY. RNA-guided transcriptional activation via CRISPR/dCas9 mimics overexpression phenotypes in Arabidopsis. PLoS One 2017; 12(6): 0179410.
61. Perez-Pinera P, Kocak DD, Vockley CM, Adler AF, Kabadi AM and Polstein LR: RNA-guided gene activation by CRISPR-Cas9–based transcription factors. Nat Methods 2013; 10(10): 973–6.
62. Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH and Bryson DI: Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature 2017; 551(7681): 464–71.
63. Li H, Yang Y, Hong W, Huang M, Wu M and Zhao X: Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects. Signal Transduct Target Ther 2020; 5(1): 1.
64. Liu K, Petree C, Requena T, Varshney P and Varshney GK: Expanding the CRISPR Toolbox in Zebrafish for Studying Development and Disease. Front Cell Dev Biol 2019; 7.
65. Meltzer H, Marom E, Alyagor I, Mayseless O, Berkun V and Segal-Gilboa N: Tissue-specific (ts) CRISPR as an efficient strategy for in-vivo screening in Drosophila. Nat Commun 2019; 10(1): 2113.
66. Wang H, Wu S, Capecchi MR and Jaenisch R: A brief review of genome editing technology for generating animal models. Front Agric Sci Eng 2020; 7(2): 123.
67. Schweikart SJ, JD and MBE: What Is Prudent Governance of Human Genome Editing? AMA J Ethics 2019; 21(12): 1042-1048.
68. Benchoua A, Lasbareilles M and Tournois J: Contribution of Human Pluripotent Stem Cell-Based Models to Drug Discovery for Neurological Disorders. Cells 2021; 10(12): 3290.
69. Shi Y, Inoue H, Wu JC and Yamanaka S: Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov 2017; 16(2): 115–30.
70. Takahashi K and Yamanaka S: Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell 2006; 126(4): 663–76.
71. Vadodaria KC, Jones JR, Linker S and Gage FH: Modeling Brain Disorders Using Induced Pluripotent Stem Cells. Cold Spring HarbPerspect Biol 2020; 12(6): 035659.
72. Patel J, Lukkes JL and Shekhar A: Overview of genetic models of autism spectrum disorders. In 2018; 1–36.
73. Sakai C, Ijaz S and Hoffman EJ: Zebrafish Models of Neurodevelopmental Disorders: Past, Present, and Future. Front Mol Neurosci 2018; 11.
74. Li Z, Zhu YX, Gu LJ and Cheng Y: Understanding autism spectrum disorders with animal models: applications, insights, and perspectives. Zool Res 2021; 42(6): 800–23.
75. Sgritta M, Dooling SW, Buffington SA, Momin EN, Francis MB and Britton RA: Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder. Neuron 2019; 101(2): 246-259.e6.
76. Kratsman N, Getselter D and Elliott E: Sodium butyrate attenuates social behavior deficits and modifies the transcription of inhibitory/excitatory genes in the frontal cortex of an autism model. Neuropharmacology 2016; 102: 136–45.
77. O’Connor R, van De Wouw M, Moloney GM, Ventura-Silva AP, O’Riordan K and Golubeva AV: Strain differences in behaviour and immunity in aged mice: Relevance to Autism. Behavioural Brain Research 2021; 399: 113020.
78. Conway F and Brown AS: Maternal Immune Activation and Related Factors in the Risk of Offspring Psychiatric Disorders. Front Psychiatry 2019; 10.
79. Kreitz S, Zambon A, Ronovsky M, Budinsky L, Helbich TH and Sideromenos S: Maternal immune activation during pregnancy impacts on brain structure and function in the adult offspring. Brain Behav Immun 2020; 83: 56–67.
80. Das I, Estevez MA, Sarkar AA and Banerjee-Basu S: A multifaceted approach for analyzing complex phenotypic data in rodent models of autism. Mol Autism 2019; 10(1): 11.
81. Li J and Ge W: Zebrafish as a model for studying ovarian development: Recent advances from targeted gene knockout studies. Mol Cell Endocrinol 2020; 507: 110778.
82. Howe K, Clark MD, Torroja CF, Torrance J, Berthelot C and Muffato M: The zebrafish reference genome sequence and its relationship to the human genome. Nature 2013; 496(7446): 498–503.
83. Moreno-Mateos MA, Vejnar CE, Beaudoin JD, Fernandez JP, Mis EK and Khokha MK: CRISPRscan: designing highly efficient sgRNAs for CRISPR-Cas9 targeting in-vivo. Nat Methods 2015; 12(10): 982–8.
84. Rahman MDK and Rahman MS: CRISPRpred: A flexible and efficient tool for sgRNAs on-target activity prediction in CRISPR/Cas9 systems. PLoS One 2017; 12(8): e0181943.
85. James DM, Davidson EA, Yanes J, Moshiree B and Dallman JE: The Gut-Brain-Microbiome Axis and Its Link to Autism: Emerging Insights and the Potential of Zebrafish Models. Front Cell Dev Biol 2021; 9.
86. Ganz J, Melancon E, Wilson C, Amores A, Batzel P and Strader M: Epigenetic factors coordinate intestinal development. bioRxiv 2018.
87. Ganz J, Baker RP, Hamilton MK, Melancon E, Diba P and Eisen JS: Image velocimetry and spectral analysis enable quantitative characterization of larval zebrafish gut motility 2017.
88. Holmberg A, Schwerte T, Pelster B and Holmgren S: Ontogeny of the gut motility control system in zebrafish Danio rerio embryos and larvae. Journal of Experimental Biology 2004; 207(23): 4085–94.
89. Anderson JL, Mulligan TS, Shen MC, Wang H, Scahill CM and Tan FJ: mRNA processing in mutant zebrafish lines generated by chemical and CRISPR-mediated mutagenesis produces unexpected transcripts that escape nonsense-mediated decay. PLoS Genet 2017; 13(11): e1007105.
90. Dougnon G and Matsui H: Modelling Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) Using Mice and Zebrafish. Int J Mol Sci 2022; 23(14): 7550.
91. Mattiske T, Moey C, Vissers LE, Thorne N, Georgeson P, Bakshi M: An Emerging Female Phenotype with Loss‐of‐Function Mutations in the Aristaless‐ Related Homeodomain Transcription Factor ARX. Hum Mutat 2017; 38(5): 548–55.
92. Ishibashi M, Manning E, Shoubridge C, Krecsmarik M, Hawkins TA and Giacomotto J: Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene. Hum Genet 2015; 134(11–12): 1163–82.
93. Oksenberg N, Stevison L, Wall JD and Ahituv N: Function and Regulation of AUTS2, a Gene Implicated in Autism and Human Evolution. PLoS Genet 2013; 9(1): e1003221.
94. Ramachandran K V., Hennessey JA, Barnett AS, Yin X, Stadt HA and Foster E: Calcium influx through L-type CaV1.2 Ca2+ channels regulates mandibular development. Journal of Clinical Investigation 2013; 123(4): 1638–46.
95. Patowary A, Won SY, Oh SJ, Nesbitt RR, Archer M and Nickerson D: Family-based exome sequencing and case-control analysis implicate CEP41 as an ASD gene. Transl Psychiatry 2019; 9(1): 4.
96. Platt RJ, Zhou Y, Slaymaker IM, Shetty AS, Weisbach NR and Kim JA: Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits. Cell Rep 2017; 19(2): 335–50.
97. Sugathan A, Biagioli M, Golzio C, Erdin S, Blumenthal I and Manavalan P: CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors. Proceedings of the National Academy of Sciences 2014; 111(42).
98. Gompers AL, Su-Feher L, Ellegood J, Copping NA, Riyadh MA and Stradleigh TW: Germline Chd8 haploinsufficiency alters brain development in mouse. Nat Neurosci 2017; 20(8): 1062–73.
99. Manoli DS and State MW: Autism Spectrum Disorder Genetics and the Search for Pathological Mechanisms. American Journal of Psychiatry 2021; 178(1): 30–8.
100. Turner TN, Sharma K, Oh EC, Liu YP, Collins RL and Sosa MX: Loss of δ-catenin function in severe autism. Nature 2015; 520(7545): 51–6.
101. Kim OH, Cho HJ, Han E, Hong TI, Ariyasiri K and Choi JH: Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism. Mol Autism 2017; 8(1): 50.
102. Ohno Y, Kunisawa N and Shimizu S: Emerging Roles of Astrocyte Kir4.1 Channels in the Pathogenesis and Treatment of Brain Diseases. Int J Mol Sci 2021; 22(19): 10236.
103. Tsai IC, McKnight K, McKinstry SU, Maynard AT, Tan PL and Golzio C: Small molecule inhibition of RAS/MAPK signaling ameliorates developmental pathologies of Kabuki Syndrome. Sci Rep 2018; 8(1): 10779.
104. Lintas C and Persico AM: Unraveling molecular pathways shared by Kabuki and Kabuki-like syndromes. Clin Genet 2018; 94(3–4): 283–95.
105. Leong WY, Lim ZH, Korzh V, Pietri T and Goh ELK: Methyl-CpG Binding Protein 2 (Mecp2) Regulates Sensory Function Through Sema5b and Robo2. Front Cell Neurosci 2015; 9.
106. Huang Y, Chang Z, Li X, Liang S, Yi Y and Wu L: Integrated multifactor analysis explores core dysfunctional modules in autism spectrum disorder. Int J Biol Sci 2018; 14(8): 811–8.
107. Riché R, Liao M, Pena IA, Leung KY, Lepage N and Greene NDE: Glycine decarboxylase deficiency–induced motor dysfunction in zebrafish is rescued by counterbalancing glycine synaptic level. JCI Insight 2018; 3(21).
108. Blanchet P, Bebin M, Bruet S, Cooper GM, Thompson ML and Duban-Bedu B: MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus. PLoS Genet 2017; 13(8): e1006957.
109. Miller AC, Voelker LH, Shah AN and Moens CB: Neurobeachin Is Required Postsynaptically for Electrical and Chemical Synapse Formation. Current Biology 2015; 25(1): 16–28.
110. Ruzzo EK, Pérez-Cano L, Jung JY, Wang L kai, Kashef-Haghighi D and Hartl C: Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks. Cell 2019; 178(4): 850-866.e26.
111. Ribeiro D, Nunes AR, Gliksberg M, Anbalagan S, Levkowitz G and Oliveira RF: Oxytocin receptor signalling modulates novelty recognition but not social preference in zebrafish. Journal of Neuroendocrinol 2020; 32(4).
112. Dalla Vecchia E, Di Donato V, Young AMJ, Del Bene F and Norton WHJ: Reelin Signaling Controls the Preference for Social Novelty in Zebrafish. Front BehavNeurosci 2019; 13.
113. Jordan VK, Fregeau B, Ge X, Giordano J, Wapner RJ and Balci TB: Genotype-phenotype correlations in individuals with pathogenic RERE variants. Hum Mutat 2018; 39(5): 666–75.
114. Liu C xue, Li C yang, Hu C chun, Wang Y, Lin J and Jiang Y hui: CRISPR/Cas9-induced shank3b mutant zebrafish display autism-like behaviors. Mol Autism 2018; 9(1): 23.
115. Kozol RA, James DM, Varela I, Sumathipala SH, Züchner S and Dallman JE: Restoring Shank3 in the rostral brainstem of shank3ab−/− zebrafish autism models rescues sensory deficits. Commun Biol 2021; 4(1): 1411.
116. Kozol RA, Cukier HN, Zou B, Mayo V, De Rubeis S and Cai G: Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruptions of brain morphogenesis. Hum Mol Genet 2015; 24(14): 4006–23.
117. Štih V, Petrucco L, Kist AM and Portugues R: Stytra: An open-source, integrated system for stimulation, tracking and closed-loop behavioral experiments. PLoS Comput Biol 2019; 15(4): 1006699.
118. Rea V and Van Raay TJ: Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts. Front Mol Neurosci 2020; 13.
     

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     How to cite this article:

     Samanta A and Chakraborty T: An extensive review on effects of psychobiotic based treatments in autistic spectrum of disorder and applicability of Zebrafish as a robust model for studying ASD. Int J Pharm Sci & Res 2023; 14(12): 5565-77. doi: 10.13040/IJPSR.0975-8232.14(12).5565-77.

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