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Lysine-restricted diet alleviates obesity-related anxiety-like behaviors by increasing Oscillibacter ruminantium regulating tryptophol

ABSTRACT:

Background The role of dietary interventions, particularly lysine-restricted diets(LRD), in mitigating obesity-associated anxiety-like behaviors remains poorly understood, with limited insight into gut microbiota-metabolite-brain axis mechanisms.

Results LRD significantly improved anxiety behavior related by a high-fat diet (HFD) by reducing body weight and glucose metabolism levels.In addition, LRD significantly reshaped the structure of the gut microbiota, as manifested by a significant increase in the relative abundance of Oscillibacter. We then screened and found that supplementation with either active or encapsulated Oscillibacter ruminantium could improve obesity/chronic restraint stress-related anxiety-like behavior, with microcapsule intervention having a better effect. Notably, the HFD-related reduction in tryptophol and intestinal barrier damage was restored by an LRD. Mechanistic studies further demonstrated that tryptophol supplementation can alleviate HFD-related anxiety-like behavior by inhibiting Fto-mediated reader protein IGF2BP1 and reducing m6A modification of Lgr6 mRNA.

Conclusion LRD alleviates obesity-related anxiety-like behavior by increasing O. ruminantium and further regulating tryptophol to activate the FTO-IGF2BP1-LGR6-axis.These findings position LRD as a microbiota-targeted strategy for metabolic-stress-associated neurobehavioral disorders.

INSTRUMENT(S): Liquid Chromatography MS - positive - HILIC, Liquid Chromatography MS - negative - HILIC

PROVIDER: MTBLS13013 | MetaboLights | 2025-09-18

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13013_LC-MS_negative_hilic_metabolite_profiling.txt	Txt
	a_MTBLS13013_LC-MS_positive_hilic_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13013_LC-MS_negative_hilic_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13013_LC-MS_positive_hilic_metabolite_profiling_v2_maf.tsv	Tabular

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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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Lysine-restricted diet alleviates obesity-related anxiety-like behaviors by increasing Oscillibacter ruminantium regulating tryptophol

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