Intestinal 3-methylindole exacerbates sepsis-induced neuroinflammation through microglial NLRP3 inflammasome activation
- 1Department of Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
- 2Department of Emergency, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
Abstract
Gut microbiota regulates neuroinflammatory responses involved in the pathogenesis of sepsis-associated encephalopathy (SAE). However, the underlying mechanism remains elusive. 16S rRNA sequencing of fecal samples revealed an expansion of the Enterobacteriaceae family in septic mice, and quantitative PCR further detected an increase in gut Escherichia coli. Subsequent bacterial transplantation experiments showed that the exacerbation of neuroinflammatory responses in sepsis by gut microbiota dysbiosis is due to the expansion of gut E. coli. Furthermore, we observed an increase in E. coli-derived 3-methylindole (3MI) in septic mice. Although 3MI alone does not directly induce neuroinflammation, it synergistically exacerbates neuroinflammatory responses with lipopolysaccharide. Mechanistically, 3MI may reduce the ubiquitination level of NLRP3 and enhance NLRP3 inflammasome activation in lipopolysaccharide-stimulated microglia. These findings suggest that E. coli-derived 3MI is a contributing factor in aggravating neuroinflammation in SAE, offering new insights into therapeutic strategies for SAE.
IMPORTANCE: The gut-brain axis is increasingly implicated in sepsis‑associated encephalopathy (SAE) pathogenesis, yet the precise microbial mechanisms driving neuroinflammation remain poorly defined. This study identifies a specific gut microbial pathway and reveals that sepsis-induced expansion of Escherichia coli and its overproduction of the metabolite 3-methylindole are key aggravating factors. Notably, while 3-methylindole alone is non-inflammatory, it acts synergistically with lipopolysaccharide to drive NLRP3 inflammasome activation in microglia, likely via reducing NLRP3 ubiquitination. These findings pinpoint a gut bacterium-derived metabolite as a critical amplifier of brain inflammation in sepsis, which contributes to a new mechanistic understanding of SAE pathogenesis.
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BibTeX
@article{fang2026intestinal,
title = {{Intestinal 3-methylindole exacerbates sepsis-induced neuroinflammation through microglial NLRP3 inflammasome activation}},
author = {Heng Fang and Simin Wu and Peixian Huang and Qiuping Zhou and Ying Chen and Yiyan Lin and Chunbo Chen and Yiyu Deng},
journal = {Microbiology Spectrum},
year = {2026},
month = oct,
doi = {10.1128/spectrum.01542-26},
url = {https://doi.org/10.1128/spectrum.01542-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Intestinal 3-methylindole exacerbates sepsis-induced neuroinflammation through microglial NLRP3 inflammasome activation
AU - Heng Fang
AU - Simin Wu
AU - Peixian Huang
AU - Qiuping Zhou
AU - Ying Chen
AU - Yiyan Lin
AU - Chunbo Chen
AU - Yiyu Deng
PY - 2026
DA - 2026/10/06
JO - Microbiology Spectrum
DO - 10.1128/spectrum.01542-26
UR - https://doi.org/10.1128/spectrum.01542-26
AB - Gut microbiota regulates neuroinflammatory responses involved in the pathogenesis of sepsis-associated encephalopathy (SAE). However, the underlying mechanism remains elusive. 16S rRNA sequencing of fecal samples revealed an expansion of the Enterobacteriaceae family in septic mice, and quantitative PCR further detected an increase in gut Escherichia coli. Subsequent bacterial transplantation experiments showed that the exacerbation of neuroinflammatory responses in sepsis by gut microbiota dysbiosis is due to the expansion of gut E. coli. Furthermore, we observed an increase in E. coli-derived 3-methylindole (3MI) in septic mice. Although 3MI alone does not directly induce neuroinflammation, it synergistically exacerbates neuroinflammatory responses with lipopolysaccharide. Mechanistically, 3MI may reduce the ubiquitination level of NLRP3 and enhance NLRP3 inflammasome activation in lipopolysaccharide-stimulated microglia. These findings suggest that E. coli-derived 3MI is a contributing factor in aggravating neuroinflammation in SAE, offering new insights into therapeutic strategies for SAE. IMPORTANCE: The gut-brain axis is increasingly implicated in sepsis‑associated encephalopathy (SAE) pathogenesis, yet the precise microbial mechanisms driving neuroinflammation remain poorly defined. This study identifies a specific gut microbial pathway and reveals that sepsis-induced expansion of Escherichia coli and its overproduction of the metabolite 3-methylindole are key aggravating factors. Notably, while 3-methylindole alone is non-inflammatory, it acts synergistically with lipopolysaccharide to drive NLRP3 inflammasome activation in microglia, likely via reducing NLRP3 ubiquitination. These findings pinpoint a gut bacterium-derived metabolite as a critical amplifier of brain inflammation in sepsis, which contributes to a new mechanistic understanding of SAE pathogenesis.
SN - 2165-0497
ER -