What question did this study set out to answer?

To explore how mitochondrial dysfunction affects energy metabolism in the central nervous system and its connection to colitis severity.

January 23, 2026

P0067Investigation of mitochondrial dysfunction and energy metabolic abnormalities in the central nervous system in the brain-gut axis between intestinal inflammation and depression

Key Points

To explore how mitochondrial dysfunction affects energy metabolism in the central nervous system and its connection to colitis severity.
Used a mouse model with mitochondrial DNA mutations and induced colitis via DSS and TNBS.
Evaluated colitis severity through body weight, intestinal length, and histopathology.
Measured ATP levels in brain tissue and analyzed cytokine expression in lamina propria lymphocytes.
Administered the cholinesterase inhibitor neostigmine to assess impacts on colitis in depressive model mice.
R-DSS group showed worsened colitis and decreased brain ATP concentrations compared to DSS group.
Mitochondrial swelling was observed in neural tissues of mMtDNA mice during colitis induction.
Increased expression of inflammatory cytokines, such as interferon-γ and TNF, was noted in mMtDNA groups.
Neostigmine administration improved colitis in mMtDNA-DSS mice.

Abstract

Abstract Background The association between disease activity and psychiatric symptoms in patients with inflammatory bowel disease has long been suggested, but the actual mechanism underlying this relationship remains unclear. We used a mouse model to investigate the impact of mitochondrial dysfunction on the correlation between energy metabolism in the central nervous system and the severity of colitis. Methods Mice subjected to restraint stress (2 h/day for 10 days) and mitochondrial DNA mutant mice (mMtDNA) were used as depressive model. Colitis was induced in each group by oral administration of 2% dextran sulfate sodium (DSS) (R-DSS group, mMtDNA-DSS group). Additionally, trinitrobenzenesulfonic acid (TNBS) -induced colitis was generated in mMtDNA mice via skin sensitization followed by rectal administration of TNBS (mMtDNA-TNBS group). Enteritis was evaluated by body weight change, intestinal length, and histopathology, and cytokines in the lamina propria lymphocytes (LPL) were analyzed. Cytokines were measured by quantitative polymerase chain reaction for messenger RNA and by Cytometric Bead Array for protein content. Brain tissue adenosine triphosphate (ATP) levels were measured, and mitochondrial morphology was evaluated by electron microscopy. The effect of the cholinergic anti-inflammatory pathway (CAP) on changes in the severity of colitis in a depressive model mice was examined by intraperitoneal administration of the cholinesterase inhibitor neostigmine. Results Compared to the DSS group, the R-DSS group exhibited worsened colitis, mitochondrial swelling in the cerebral cortical neurons, and decreased brain ATP concentrations. This suggests that reduced ATP production capacity in the neuron associated with mitochondrial dysfunction may be related to the severity of colitis. In the mMtDNA mice, induction of DSS- or TNBS-induced colitis resulted in swelling of neural mitochondria and decreased brain ATP concentrations compared to the wild-type mice, with worsening observed in both types of colitis. Measurement of inflammatory cytokines revealed increased interferon-γ expression in the mMtDNA-DSS group and increased TNF expression in the mMtDNA-TNBS group. The mMtDNA-TNBS group also showed elevated levels of the transcription factor T-bet and elevated Th1-type inflammatory cytokines in the LPL. The administration of neostigmine improved colitis in the mMtDNA-DSS mice. Conclusion Mitochondrial abnormalities in the central nervous system were suggested to contribute to increased cytokine expression associated with Th1 cells via impaired CAP function, thereby exacerbating of colitis. Conflict of interest: Ms. Tsujii, Yuri: No conflict of interest Yoshihara, Takeo: No conflict of interest Sawa, Hiroki: No conflict of interest Ogawa, Miyon: No conflict of interest Takahashi, Miyu: No conflict of interest Minoura, Yutaro: No conflict of interest Kasamoto-Otake, Yuriko: No conflict of interest Uema, Ryotaro: No conflict of interest Tsujii, Yoshiki: No conflict of interest Hayashi, Yoshito: No conflict of interest

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