Altered Autonomic Functions and Gut Microbiome in Individuals with Autism Spectrum Disorder (ASD): Implications for Assisting ASD Screening and Diagnosis

Kong, Xuejun; Li, Jun; Liu, Kevin; Koh, Madelyn; Tian, Ruiyi; Hobbie, Clara; Fong, Michelle; Chen, Qiuyi; Zhao, Minxuan; Budjan, Christoph; Kong, Jian

doi:10.1007/s10803-020-04524-1

Cited by 24 publications

(17 citation statements)

References 49 publications

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“…Moreover, these same autonomic indices correlated with changes in the gut microbiome, for example, a positive correlation between BVP and firmicutes/bacteroidetes ratio in all subjects. Importantly, although this study attempted to develop predictive models using these indices and ATEC scores, their models were not statistically significant [47].…”

Section: Gut-brain Connectionmentioning

confidence: 90%

“…The cognitive effects of ASD can also be understood via the gut-brain axis association with the autonomic nervous system (ANS). A recent study by Kong et al found that measures of autonomic function, gut microbiome markers, and autism behaviors, assessed by the Autism Treatment Evaluation Checklist (ATEC), were significantly associated with each other [47]. Specifically, alpha diversity was negatively correlated with ATEC total score, as well as the Sensory/Cognitive Awareness and Speech/Language subsections (higher ATEC scores indicate more severe symptoms).…”

Section: Gut-brain Connectionmentioning

confidence: 99%

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Gut-Induced Inflammation during Development May Compromise the Blood-Brain Barrier and Predispose to Autism Spectrum Disorder

Eshraghi

Davies

Iyengar

et al. 2020

JCM

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Recently, the gut microbiome has gained considerable interest as one of the major contributors to the pathogenesis of multi-system inflammatory disorders. Several studies have suggested that the gut microbiota plays a role in modulating complex signaling pathways, predominantly via the bidirectional gut-brain-axis (GBA). Subsequent in vivo studies have demonstrated the direct role of altered gut microbes and metabolites in the progression of neurodevelopmental diseases. This review will discuss the most recent advancements in our understanding of the gut microbiome’s clinical significance in regulating blood-brain barrier (BBB) integrity, immunological function, and neurobiological development. In particular, we address the potentially causal role of GBA dysregulation in the pathophysiology of autism spectrum disorder (ASD) through compromising the BBB and immunological abnormalities. A thorough understanding of the complex signaling interactions between gut microbes, metabolites, neural development, immune mediators, and neurobiological functionality will facilitate the development of targeted therapeutic modalities to better understand, prevent, and treat ASD.

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Section: Gut-brain Connectionmentioning

confidence: 90%

Section: Gut-brain Connectionmentioning

confidence: 99%

Gut-Induced Inflammation during Development May Compromise the Blood-Brain Barrier and Predispose to Autism Spectrum Disorder

Eshraghi

Davies

Iyengar

et al. 2020

JCM

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“…The intestinal flora is a diverse microecosystem composed of more than 2000 species of bacteria and has 150 times more genomes than the human genome [5]. Intestinal microflora can affect the basic functions of the host, such as digestion and absorption, energy metabolism and immune defense by regulating endocrine, nerve, and immunity functions [6,7]. The composition of intestinal microflora is affected by the external environment, diet and host itself.…”

Section: Introductionmentioning

confidence: 99%

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

Kong

Chen

et al. 2021

J Exp Clin Cancer Res

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Background Alcohol-induced intestinal dysbiosis disrupts and inflammatory responses are essential in the development of alcoholic fatty liver disease (AFLD). Here, we investigated the effects of Fmo5 on changes in enteric microbiome composition in a model of AFLD and dissected the pathogenic role of Fmo5 in AFLD-induced liver pathology. Methods The expression profile data of GSE8006 and GSE40334 datasets were downloaded from the GEO database. The WGCNA approach allowed us to investigate the AFLD-correlated module. DEGs were used to perform KEGG pathway enrichment analyses. Four PPI networks were constructed using the STRING database and visualized using Cytoscape software. The Cytohubba plug-in was used to identify the hub genes. Western blot and immunohistochemistry assays were used to detect protein expression. ELISA assay was used to detect the levels of serum inflammatory cytokines. Lipid droplets in the cytoplasm were observed using Oil Red O staining. Apoptosis was detected using a TUNEL assay and flow cytometry analysis. ROS levels were detected using flow cytometry analysis. Nuclear translocation of NF-κB p65 was observed using immunofluorescence staining. Co-immunoprecipitation was used to detect the co-expression of PPARα and Fmo5 in L02 cells. 16S rDNA sequencing defined the bacterial communities in mice with AFLD. Results Fmo5 is a key DEG and is closely associated with the gut microbiota and PPAR signaling pathway. Gut microbiome function in AFLD was significantly related to the PPAR signaling pathway. AFLD induced shifts in various bacterial phyla in the cecum, including a reduction in Bacteroidetes and increased Firmicutes. Fmo5 and PPARα co-expression in cell and animal models with AFLD, which decreased significantly. Silencing of Fmo5 and PPARα aggravated the functions of AFLD inducing apoptosis and inflammatory response, promoting liver injury, and activating the NF-κB signaling pathway in vivo and in vitro. The NF-κB inhibitor abolished the functions of silencing of Fmo5 and PPARα promoting AFLD-induced apoptosis, inflammatory response, and liver injury. Conclusion Our data indicated that the co-expression of Fmo5 and PPARα was involved in AFLD-related gut microbiota composition and alleviated AFLD-induced liver injury, apoptosis, and inflammatory response by inhibiting the nuclear translocation of NF-κB p65 to inhibit the NF-κB signaling pathway.

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“…Although the involvement of the gut-brain axis is increasingly implicated in the precipitation and manifestation of neurodevelopmental disorders such as autism, mechanistic evidence that directly connects gut bacteria, bacterial metabolites, and neuronal dysregulation is sparse. 1,2 Disruption of the normal gut microbiota is known to cause an overgrowth of unfavorable bacterial communities that increase toxic metabolites in the gut. 3 Several of these metabolites are known to have an impact on neurotransmission and brain functions, underscoring the importance of the gut-brain axis in health and disease.…”

Section: Introductionmentioning

confidence: 99%

Clostridioides difficileinfection increases circulating p-cresol levels and dysregulates brain dopamine metabolism: linking gut-brain axis to autism spectrum disorders?

Vinithakumari

Padhi

Hernández

et al. 2021

Preprint

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Gastrointestinal illnesses are one of the most common comorbidities reported in patients with neurodevelopmental diseases, including autism spectrum disorders (ASD). Gut dysbiosis, overgrowth of C. difficile in the gut, and gut microbiota-associated alterations in central neurotransmission have been implicated in ASD, where the dopaminergic axis plays an important role in the disease pathogenesis. Human C. difficile strains produce a significant amount of the toxic metabolite p-cresol, an inhibitor of dopamine beta-hydroxylase (DBH), which catalyzes the conversion of dopamine (DA) to norepinephrine (NE). p-cresol is known to precipitate and exacerbate autistic behavior in rodents by increasing DA levels and altering DA receptor sensitivity in brain regions relevant to ASD. Therefore, we hypothesized that C. difficile infection dysregulates dopaminergic metabolism in the brain by increasing p-cresol levels in the gut and circulation and by inhibiting DBH, ultimately leading to elevated DA in the brain. For testing this hypothesis, we induced antibiotic-associated C. difficile in mice and determined the gut and serum p-cresol levels, serum DBH activity, and dopamine and its metabolite levels in different brain regions relevant to ASD. The results showed that C. difficile infection causes significant alterations in the dopaminergic axis in mice (p < 0.05). In addition, significantly increased circulating p-cresol levels and reduced DBH activity was observed in C. difficile infected animals (p < 0.05). Therefore, the results from this study suggest a potential link between C. difficile infection and alterations in the dopaminergic axis implicated in the precipitation and aggravation of ASD.

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Altered Autonomic Functions and Gut Microbiome in Individuals with Autism Spectrum Disorder (ASD): Implications for Assisting ASD Screening and Diagnosis

Cited by 24 publications

References 49 publications

Gut-Induced Inflammation during Development May Compromise the Blood-Brain Barrier and Predispose to Autism Spectrum Disorder

Gut-Induced Inflammation during Development May Compromise the Blood-Brain Barrier and Predispose to Autism Spectrum Disorder

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

Clostridioides difficileinfection increases circulating p-cresol levels and dysregulates brain dopamine metabolism: linking gut-brain axis to autism spectrum disorders?

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