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Tryptophan metabolic disorder in gut-brain axis induces anxiety-like behavior via neuronal pyroptosis in mice exposed to radiofrequency radiation

ABSTRACT:

Radiofrequency radiation (RFR) with specific parameters could alter brain function, yet the underlying mechanisms remain unclear. The gut-brain axis is reported to be important in regulating brain function. Therefore, this study used gut microbiota intervention, regulation of tryptophan metabolite and other methods to explore the effect of the gut-brain axis in brain function changes caused by RFR. It was found that 4.9 GHz (a commonly used frequency of 5G) RFR exposure 35 d induced anxiety-like behaviors in mice, accompanied by gut microbiota dysbiosis, tryptophan metabolites imbalance and neuronal pyroptosis. Intervention of intestinal flora through probiotics alleviated RFR-induced anxiety-like behaviors, improved tryptophan metabolism in the brain and reduced neuronal pyroptosis in the medial prefrontal cortex (mPFC). Furthermore, elevating the levels of tryptophan metabolism 5-hydroxytryptamine (5-HT, a key molecule for regulating anxiety) in brain through the administration of the selective serotonin reuptake inhibitor (SSRI) paroxetine ameliorated RFR-induced anxiety-like behaviors and NLRP3 inflammasome-mediated neuronal pyroptosis in the mPFC. This study reveals that RFR can induce gut microbiota dysbiosis, tryptophan metabolism imbalance of gut-brain axis, subsequent neuronal damage in the mPFC and ultimately anxiety-like behaviors in mice. These findings provide novel insights into the mechanism of RFR-induced brain function disorders.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse phase

PROVIDER: MTBLS12483 | MetaboLights | 2025-09-12

REPOSITORIES: MetaboLights

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Project description:Background and Aims Interoceptive impacts on the brain triggered by changes in the intestinal microbial ecosystem influence mood-related behaviors such as anxiety and depression. Although changes in the gut microbiome can be driven by genetic mutations in the host, how alterations in the gut microbiome caused by host genetic variations affect behavioral outcomes is not fully understood. To investigate how host genetic variation affects interoceptive responses, we analyzed the gut microbiota and investigated gut–brain interactions in sirtuin 3 (Sirt3)-knockout (KO) mice. Methods We evaluated the composition of the gut microbiome and behavior in Sirt3-KO and wild-type (WT) mice. To distinguish microbiome-driven effects from genetic influences, we conducted cohousing experiments and compared results with heterozygous littermates. Region-specific changes in gene expression in the brain were identified by transcriptomic profiling of the limbic system. We also analyzed metabolites in the nucleus of the solitary tract (NTS) generated by gut microbiome–vagal signaling. The role of the vagus nerve in the gut-brain axis was further examined through vagotomy, alongside comparative choline analysis in both mood disorder patients and mice. Results Mood-related neurobehavioral changes and alterations in synaptic plasticity-related genes in the amygdala and bed nucleus of the stria terminalis (BNST) of Sirt3-KO mice appeared to be dependent on gut microbiome composition. Elevated plasma choline levels in both mood disorder patients and Sirt3-KO mice, together with reduced neurotransmitter-related metabolites (e.g., -aminobutyric acid [GABA] in the NTS), suggested that externalizing behaviors in Sirt3-KO mice are mediated by vagus nerve-dependent gut–brain axis signaling. Consistent with this, vagotomy abolished these changes, including GABA in the NTS, as well as alterations in synaptic plasticity in the amygdala and BNST. Conclusions Our findings suggest the novel finding that an altered gut microbiome caused by a host genetic change, namely a Sirt3 deficiency, is sensed in the NTS of the brain via the vagus nerve, leading to externalizing behaviors.

Project description:Background Chronic anxiety imposes a major global health burden, yet existing treatments remain inadequate, with limited efficacy or significant side effects. Mitochondrial abnormalities have emerged as key contributors to anxiety-related phenotypes, suggesting that targeting mitochondrial function may offer a novel therapeutic avenue. Urolithin A (UA), a gut microbiota-derived metabolite known to enhance mitochondrial function, has shown neuroprotective effects in preclinical models of aging and neurodegeneration. However, its potential in modulating anxiety and underlying neuronal mechanisms remains unexplored. Methods We examined the effects of UA in two rodent models of heightened anxiety: a natural variation model and a genetically selected high stress-reactivity line. Animals received chronic UA supplementation, and anxiety-like behaviors were assessed across multiple paradigms. Single-nucleus RNA sequencing was performed to identify molecular alterations in nucleus accumbens (NAc) medium spiny neurons (MSNs), incorporating MitoPathway analyses to examine mitochondrion-related transcriptomic signatures. Electrophysiological, immunohistochemical, and morphological analyses were conducted to assess mitochondrial pathways and synaptic function. Results UA selectively reduced anxiety-like behaviors in high-anxiety animals, both males and females, leaving non-anxious controls unaffected. Transcriptomic analyses revealed widespread mitochondrial and synaptic dysregulation in high-anxiety MSNs, with impaired mitophagy emerging as a core feature. UA treatment restored these transcriptomic signatures, normalizing mitophagy-related pathways across all MSN subtypes tightly linked to restored synaptic pathways. These changes translated into structural and functional rescue of MSN dendritic architecture, spine density, and excitatory synaptic transmission. Conclusions These findings identify mitophagy deficits in NAc MSNs as a hallmark of heightened anxiety and highlight UA as a promising mechanism-based intervention.

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	Gf25WX_C_1.zip	Other
	Gf25WX_C_1L.zip	Other
	Gf25WX_C_2.zip	Other
	Gf25WX_C_2L.zip	Other
	Gf25WX_C_3.zip	Other

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Tryptophan metabolic disorder in gut-brain axis induces anxiety-like behavior via neuronal pyroptosis in mice exposed to radiofrequency radiation

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