Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (11): 3095-3112.doi: 10.4103/NRR.NRR-D-24-00607

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Exploring the interaction between the gut microbiota and cyclic adenosine monophosphate-protein kinase A signaling pathway: a potential therapeutic approach for neurodegenerative diseases

Fengcheng Deng1 , Dan Yang1 , Lingxi Qing1 , Yifei Chen1 , Jilian Zou1 , Meiling Jia1 , Qian Wang1 , Runda Jiang1 , Lihua Huang1, 2, *   

  1. 1 College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China;  2 State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
  • Online:2025-11-15 Published:2025-02-22
  • Contact: Lihua Huang, PhD, huanglihua@cdutcm.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 82003965; the Science and Technology Research Project of Sichuan Provincial Administration of Traditional Chinese Medicine, No. 2024MS167 (to LH); the Xinglin Scholar Program of Chengdu University of Traditional Chinese Medicine, No. QJRC2022033 (to LH); the Improvement Plan for the ‘Xinglin Scholar’ Scientific Research Talent Program at Chengdu University of Traditional Chinese Medicine, No. XKTD2023002 (to LH); and the 2023 National Project of the College Students’ Innovation and Entrepreneurship Training Program at Chengdu University of Traditional Chinese Medicine, No. 202310633028 (to FD).

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Abstract: The interaction between the gut microbiota and cyclic adenosine monophosphate (cAMP)- protein kinase A (PKA) signaling pathway in the host’s central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis. The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites, which activates the vagus nerve and modulates the immune and neuroendocrine systems. Conversely, alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota, creating a dynamic network of microbial-host interactions. This reciprocal regulation affects neurodevelopment, neurotransmitter control, and behavioral traits, thus playing a role in the modulation of neurological diseases. The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation, mitochondrial dysfunction, abnormal energy metabolism, microglial activation, oxidative stress, and neurotransmitter release, which collectively influence the onset and progression of neurological diseases. This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway, along with its implications for potential therapeutic interventions in neurological diseases. Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders. This can be achieved through various methods such as dietary modifications, probiotic supplements, Chinese herbal extracts, combinations of Chinese herbs, and innovative dosage forms. These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.

Key words: cyclic adenosine monophosphate, emotional disorders, gut microbiota, neurodegenerative diseases, neurological diseases, protein kinase A, reciprocal regulation, signaling pathway, strategy, therapies