The interaction between intestinal bacterial metabolites and phosphatase and tensin homolog in autism spectrum disorder.

Intestinal bacteria-associated para-cresyl sulfate (pCS) and 4-ethylphenyl sulfate (4EPS) are elevated in autism spectrum disorder (ASD). Both metabolites can induce ASD-like behaviors in mice, but the molecular mechanisms are not known. Phosphatase and tensin homolog (PTEN) is a susceptibility gene for ASD. The present study investigated the relation between pCS and 4EPS and PTEN in ASD in a valproic acid (VPA)-induced murine ASD model and an in vitro LPS-activated microglial model. The VPA-induced intestinal inflammation and compromised permeability in the distal ileum was not associated with changes of PTEN expression and phosphorylation. In contrast, VPA reduced PTEN expression in the hippocampus of mice. In vitro results show that pCS and 4EPS reduced PTEN expression and derailed innate immune response of BV2 microglial cells. The PTEN inhibitor VO-OHpic did not affect innate immune response of microglial cells. In conclusion, PTEN does not play a role in intestinal inflammation and compromised permeability in VPA-induced murine model for ASD. Although pCS and 4EPS reduced PTEN expression in microglial cells, PTEN is not involved in the pCS and 4EPS-induced derailed innate immune response of microglial cells. Further studies are needed to investigate the possible involvement of reduced PTEN expression in the ASD brain regarding synapse function and neuronal connectivity.

The Autism Spectrum Disorder-Associated Bacterial Metabolite p-Cresol Derails the Neuroimmune Response of Microglial Cells Partially via Reduction of ADAM17 and ADAM10.

The bacterial metabolite 4-methylphenol (para-cresol or p-cresol) and its derivative p-cresyl sulfate (pCS) are elevated in the urine and feces of children with autism spectrum disorder (ASD). It has been shown that p-cresol administration induces social behavior deficits and repetitive behavior in mice. However, the mechanisms of p-cresol, specifically its metabolite pCS that can reach the brain, in ASD remain to be investigated. The pCS has been shown to inhibit LPS-stimulated inflammatory response. A Disintegrin And Metalloprotease 10 (ADAM10) and A Disintegrin And Metalloprotease 17 (ADAM17) are thought to regulate microglial immune response by cleaving membrane-bound proteins. In the present study, a neuroinflammation model of LPS-activated BV2 microglia has been used to unveil the potential molecular mechanism of pCS in ASD pathogenesis. In microglial cells pCS treatment decreases the expression or maturation of ADAM10 and ADAM17. In addition, pCS treatment attenuates TNF-α and IL-6 releases as well as phagocytosis activity of microglia. In in vitro ADAM10/17 inhibition experiments, either ADAM10 or ADAM17 inhibition reduces constitutive and LPS-activated release of TNF-α, TNFR-1 and IL-6R by microglial cells, while it increases constitutive and LPS-activated microglial phagocytotic activity. The in vivo results further confirm the involvement of ADAM10 and ADAM17 in ASD pathogenesis. In in utero VPA-exposed male mice, elevated concentration in serum of p-cresol-associated metabolites pCS and p-cresyl glucuronide (pCG) is associated with a VPA-induced increased ADAM10 maturation, and a decreased ADAM17 maturation that is related with attenuated levels of soluble TNF-α and TGF-ß1 in the mice brain. Overall, the present study demonstrates a partial role of ADAM10 and ADAM17 in the derailed innate immune response of microglial cells associated with pCS-induced ASD pathogenesis.

Functions of 'A disintegrin and metalloproteases (ADAMs)' in the mammalian nervous system.

'A disintegrin and metalloproteases' (ADAMs) are a family of transmembrane proteins with diverse functions in multicellular organisms. About half of the ADAMs are active metalloproteases and cleave numerous cell surface proteins, including growth factors, receptors, cytokines and cell adhesion proteins. The other ADAMs have no catalytic activity and function as adhesion proteins or receptors. Some ADAMs are ubiquitously expressed, others are expressed tissue specifically. This review highlights functions of ADAMs in the mammalian nervous system, including their links to diseases. The non-proteolytic ADAM11, ADAM22 and ADAM23 have key functions in neural development, myelination and synaptic transmission and are linked to epilepsy. Among the proteolytic ADAMs, ADAM10 is the best characterized one due to its substrates Notch and amyloid precursor protein, where cleavage is required for nervous system development or linked to Alzheimer's disease (AD), respectively. Recent work demonstrates that ADAM10 has additional substrates and functions in the nervous system and its substrate selectivity may be regulated by tetraspanins. New roles for other proteolytic ADAMs in the nervous system are also emerging. For example, ADAM8 and ADAM17 are involved in neuroinflammation. ADAM17 additionally regulates neurite outgrowth and myelination and its activity is controlled by iRhoms. ADAM19 and ADAM21 function in regenerative processes upon neuronal injury. Several ADAMs, including ADAM9, ADAM10, ADAM15 and ADAM30, are potential drug targets for AD. Taken together, this review summarizes recent progress concerning substrates and functions of ADAMs in the nervous system and their use as drug targets for neurological and psychiatric diseases.

The Gut-Brain Axis in Autism Spectrum Disorder: A Focus on the Metalloproteases ADAM10 and ADAM17.

Autism Spectrum Disorder (ASD) is a spectrum of disorders that are characterized by problems in social interaction and repetitive behavior. The disease is thought to develop from changes in brain development at an early age, although the exact mechanisms are not known yet. In addition, a significant number of people with ASD develop problems in the intestinal tract. A Disintegrin And Metalloproteases (ADAMs) include a group of enzymes that are able to cleave membrane-bound proteins. ADAM10 and ADAM17 are two members of this family that are able to cleave protein substrates involved in ASD pathogenesis, such as specific proteins important for synapse formation, axon signaling and neuroinflammation. All these pathological mechanisms are involved in ASD. Besides the brain, ADAM10 and ADAM17 are also highly expressed in the intestines. ADAM10 and ADAM17 have implications in pathways that regulate gut permeability, homeostasis and inflammation. These metalloproteases might be involved in microbiota-gut-brain axis interactions in ASD through the regulation of immune and inflammatory responses in the intestinal tract. In this review, the potential roles of ADAM10 and ADAM17 in the pathology of ASD and as targets for new therapies will be discussed, with a focus on the gut-brain axis.

The Role of Bacterial-Derived Aromatic Amino Acids Metabolites Relevant in Autism Spectrum Disorders: A Comprehensive Review.

In recent years, the idea of the gut microbiota being involved in the pathogenesis of autism spectrum disorders (ASD) has attracted attention through numerous studies. Many of these studies report microbial dysregulation in the gut and feces of autistic patients and in ASD animal models. The host microbiota plays a large role in metabolism of ingested foods, and through the production of a range of metabolites it may be involved in neurodevelopmental disorders such as ASD. Two specific microbiota-derived host metabolites, p-cresol sulfate and 4-ethylphenyl sulfate, have been associated with ASD in both patients and animal models. These metabolites originate from bacterially produced p-cresol and 4-ethylphenol, respectively. p-Cresol and 4-ethylphenol are produced through aromatic amino acid fermentation by a range of commensal bacteria, most notably bacteria from the Clostridioides genus, which are among the dysregulated bacteria frequently detected in ASD patients. Once produced, these metabolites are suggested to enter the bloodstream, pass the blood-brain-barrier and affect microglial cells in the central nervous system, possibly affecting processes like neuroinflammation and microglial phagocytosis. This review describes the current knowledge of microbial dysbiosis in ASD and elaborates on the relevance and synthesis pathways of two specific ASD-associated metabolites that may form a link between the microbiota and the brain in autism. While the two discussed metabolites are promising candidates for biomarkers and (nutritional) intervention targets, more research into the role of these metabolites in ASD is required to causally connect these metabolites to ASD pathophysiology.