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

Abstract

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-β1 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.

Cholesterol deficiency as a mechanism for autism: A valproic acid model

“…29,30 Derangements in amyloid processing may also be involved in ASD. [31][32][33][34] Interestingly, VPA has been found to inhibit g-secretase cleavage of amyloid precursor protein, reducing brain amyloid load and VPA hypocholesterolemic effects could be a mechanism contributing to its favorable impact on ASD via amyloid reduction. 35 This requires further exploration as most studies of this relationship have focused on cognitive impairment in older population and not on developmental effects on amyloid.…”

Relationship between Excreted Uremic Toxins and Degree of Disorder of Children with ASD

“…This suggests that p-cresol-producing bacteria may be present in the distal ileum. pCS is formed from p-cresol through its metabolism, which is absorption in the intestine [ 42 ]. It has been suggested that nearly 95% of p-cresol is metabolized in the body into pCS via O-sulphonation.…”

Exploring the Potential Role of ADAM 17 and ADAM 22 in the Etiology of Autism Spectrum Disorders

“…Two meta-analyses found comparable outcomes in children with ASD. Moreover, patients with ASD who have gastrointestinal issues may exhibit substantial behavioral manifestations such as anxiety, self-injury, and violence [ 32 , 33 , 34 ]. A growing body of research suggests that the gut microbiota is directly or indirectly linked to ASD symptoms, in part by impacting the immune system and metabolism [ 35 , 36 ].…”