Gut microbiota dysbiosis affects intestinal sensitivity through epithelium-to-neuron signaling: novel insights from a colon organoid-based model to improve visceral pain therapy

Margiotta, Francesco, Lucarini, Elena, Toti, Alessandra, Curti, Lorenzo, Masi, Alessio, Mello, Tommaso, Le Gall, Gwenaelle, Mattei, Gianluca, Magi, Alberto, Vauzour, David, Mannaioni, Guido, Di Cesare Mannelli, Lorenzo and Ghelardini, Carla (2025) Gut microbiota dysbiosis affects intestinal sensitivity through epithelium-to-neuron signaling: novel insights from a colon organoid-based model to improve visceral pain therapy. Gut Microbes, 17 (1). ISSN 1949-0976

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Abstract

Chronic gastrointestinal pain is a hallmark of most intestinal pathologies, yet effective treatments remain elusive given the complexity of the underlying mechanisms. Aiming to investigate the intestinal epithelium contribution to visceral pain modulation in dysbiosis context, we first demonstrated that intracolonic instillation of microbe-free fecal supernatants from mice with post-inflammatory dysbiosis induced by dextran sodium sulfate (FSDSS) provokes visceral hypersensitivity in recipient mice. Epithelium involvement in the response to FSDSS was analyzed through a novel in vitro approach comprising murine epithelial colon organoids and primary dorsal root ganglia (DRG) neurons. FSDSS treatment induced growth and metabolic impairment in colon organoids, which revealed a dysbiosis-driven epithelial dysfunction. Notably, the combination of FSDSS and conditioned medium from FSDSS-treated colon organoids induced an increase in DRG neuron intrinsic excitability, along with greater immunoreactivity to c-Fos and calcitonin-gene related peptide, implicating an integrated role of both microbial and epithelial products in visceral sensitivity regulation. By investigating the underlying signaling, metabolomic analysis revealed reduced levels of short chain fatty acids in FSDSS, such as butyrate, acetate, valerate, and propionate. Moreover, transcriptomic analysis of FSDSS-treated colon organoids showed the dysregulated expression of several signaling factors by which intestinal epithelium may modulate sensory neuron excitability, including proteases, cytokines, neuromodulators, growth factors, and hormones. These findings provide novel insights into the role of gut epithelium in the modulation of sensory neuron excitability under dysbiosis conditions, emphasizing that targeting epithelial-neuronal signaling might represent a promising therapeutic strategy for visceral pain management.

Item Type:	Article
Additional Information:	Data availability statement: The RNA-seq data, including both raw FASTQ files and the resulting raw count matrices generated using Salmon, have been deposited in the NCBI Gene Expression Omnibus (GEO) database under accession number GSE294757. The other data that support the findings of this study are openly available in Mendeley Data at https://doi.org/10.17632/4k5yfp4nxd.1. Funding: This research was supported by the European Union - NextGenerationEU - National Recovery and Resilience Plan, Mission 4 Component 2 - Investment 1.5 - THE - Tuscany Health Ecosystem - ECS00000017 - CUP B83C22003920001; European Union - NextGenerationEU - National Recovery and Resilience Plan, Mission 4 Component 2 - Investment 1.4 – Strengthening research facilities and creation of “Campioni Nazionali di R&S” on Key Enabling Technologies - National Center for Gene Therapy and Drugs based on RNA Technology - CN00000041 - CUP B13C22001010001; and Italian Ministry of University and Research (MIUR) – “Dipartimenti di Eccellenza 2023-2027” - 58514_DIPECC_23_27- to the Department NEUROFARBA.
Uncontrolled Keywords:	visceral pain,organoids,epithelial-neuronal signaling,microbiota,dysbiosis,drg neurons,intestinal epithelium,sdg 3 - good health and well-being,3* ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health Faculty of Medicine and Health Sciences > Research Groups > Nutrition and Preventive Medicine Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging
Depositing User:	LivePure Connector
Date Deposited:	08 Sep 2025 10:30
Last Modified:	08 Sep 2025 10:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/100298
DOI:	10.1080/19490976.2025.2547029

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