International immunopharmacology · 2026
Gut microbiota-derived indole-3-acetic acid ameliorates necrotizing enterocolitis-induced adolescent-stage cognitive impairment via regulating AHR-mediated neuroinflammation and synaptic structural integrity.
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Zhang Xingdao, Zhang Yuni, Liu Xiaochen, Yan Xiaolin, Ai Qing, He Yu, Shi Yuan
Аннотация
BACKGROUND: Necrotizing enterocolitis (NEC) is the most severe acute gastrointestinal disease in preterm infants and is an independent risk factor for adolescent-stage cognitive deficits, especially persistent cognitive impairment. Accumulating evidence indicates that gut-brain axis dysfunction mediates NEC-related brain injury. However, the precise metabolic mechanism linking gut microbiota to sustained cognitive deficits remains unclear. This study aimed to explore the effects of gut microbiota-derived indole-3-acetic acid (IAA) and its downstream AHR signaling on NEC-induced neuroinflammation, synaptic damage and cognitive dysfunction.
METHODS: A well-established neonatal mouse NEC model was used in this study. All mice received behavioral tests at postnatal week 4 to evaluate adolescent-stage cognitive. We applied 16S rRNA sequencing and targeted metabolomics to characterize gut microbial dysbiosis and altered tryptophan metabolism in clinical NEC patients and animal models. Hippocampal neuroinflammation was assessed by inflammatory cytokine ELISA and Iba-1 immunofluorescence staining. Single-nucleus RNA sequencing (snRNA-seq) was used to analyze microglial phenotypic changes. Synaptic structural integrity was verified by transmission electron microscopy (TEM), Golgi staining and PSD-95immunofluorescence staining. We further conducted microbiota depletion, exogenous IAA supplementation and pharmacological AHR inhibition with CH223191 to confirm the causal role of the IAA-AHR regulatory axis.
RESULTS: Neonatal NEC exposure induced persistent cognitive deficits and anxiety-like behaviors in adolescent mice. The mouse hippocampus exhibited a severe pro-inflammatory microenvironment with increased IL-1β, IL-6 and TNF-α and decreased anti-inflammatory IL-22. snRNA-seq identified significant expansion of disease-associated microglia (DA_ Micro), which highly expressed phagocytic genes (Trem2, Cd68) and promoted excessive synaptic pruning. We further confirmed that NEC also induced obvious synaptic damage, including widened synaptic clefts, reduced postsynaptic density, and decreased dendritic spine and PSD-95 levels. Both clinical and animal results showed that disrupted tryptophan metabolism and reduced circulating IAA levels were correlated with systemic inflammation and cognitive performance, respectively. 16S rRNA sequencing confirmed the depletion of IAA-producing bacteria (Lactobacillus johnsonii and Akkermansia muciniphila) in NEC mice. Antibiotic-mediated microbiota depletion further aggravated neuroinflammation, synaptic loss and cognitive dysfunction. In contrast, exogenous IAA treatment relieved neuroinflammation and restored synaptic integrity by activating AHR, whereas AHR inhibition with CH223191 completely reversed these protective effects.
CONCLUSIONS: NEC-induced gut dysbiosis reduces microbiota-derived IAA and inhibits protective hippocampal AHR signaling. This metabolic deficiency triggers sustained microglial overactivation, persistent neuroinflammation and synaptic damage, ultimately leading to adolescent-stage cognitive deficits. Restoring the IAA-AHR axis provides a novel microbiota-metabolite-targeted strategy to prevent NEC-related neurodevelopmental complications in preterm infants.
METHODS: A well-established neonatal mouse NEC model was used in this study. All mice received behavioral tests at postnatal week 4 to evaluate adolescent-stage cognitive. We applied 16S rRNA sequencing and targeted metabolomics to characterize gut microbial dysbiosis and altered tryptophan metabolism in clinical NEC patients and animal models. Hippocampal neuroinflammation was assessed by inflammatory cytokine ELISA and Iba-1 immunofluorescence staining. Single-nucleus RNA sequencing (snRNA-seq) was used to analyze microglial phenotypic changes. Synaptic structural integrity was verified by transmission electron microscopy (TEM), Golgi staining and PSD-95immunofluorescence staining. We further conducted microbiota depletion, exogenous IAA supplementation and pharmacological AHR inhibition with CH223191 to confirm the causal role of the IAA-AHR regulatory axis.
RESULTS: Neonatal NEC exposure induced persistent cognitive deficits and anxiety-like behaviors in adolescent mice. The mouse hippocampus exhibited a severe pro-inflammatory microenvironment with increased IL-1β, IL-6 and TNF-α and decreased anti-inflammatory IL-22. snRNA-seq identified significant expansion of disease-associated microglia (DA_ Micro), which highly expressed phagocytic genes (Trem2, Cd68) and promoted excessive synaptic pruning. We further confirmed that NEC also induced obvious synaptic damage, including widened synaptic clefts, reduced postsynaptic density, and decreased dendritic spine and PSD-95 levels. Both clinical and animal results showed that disrupted tryptophan metabolism and reduced circulating IAA levels were correlated with systemic inflammation and cognitive performance, respectively. 16S rRNA sequencing confirmed the depletion of IAA-producing bacteria (Lactobacillus johnsonii and Akkermansia muciniphila) in NEC mice. Antibiotic-mediated microbiota depletion further aggravated neuroinflammation, synaptic loss and cognitive dysfunction. In contrast, exogenous IAA treatment relieved neuroinflammation and restored synaptic integrity by activating AHR, whereas AHR inhibition with CH223191 completely reversed these protective effects.
CONCLUSIONS: NEC-induced gut dysbiosis reduces microbiota-derived IAA and inhibits protective hippocampal AHR signaling. This metabolic deficiency triggers sustained microglial overactivation, persistent neuroinflammation and synaptic damage, ultimately leading to adolescent-stage cognitive deficits. Restoring the IAA-AHR axis provides a novel microbiota-metabolite-targeted strategy to prevent NEC-related neurodevelopmental complications in preterm infants.