# Simulated microgravity induces cerebral dysfunction by disturbing protective microbiota-metabolite-microglia signaling across the gut‒brain axis

## TL;DR

Simulated microgravity harms brain function by disrupting gut bacteria and their protective metabolites, which can be improved with linoleic acid.

## Contribution

Identifies a microbiota-metabolite-microglia signaling pathway linking simulated microgravity to brain dysfunction and proposes LA supplementation as a countermeasure.

## Key findings

- Simulated microgravity causes gut dysbiosis, increasing Proteobacteria and reducing linoleic acid (LA) production.
- LA supplementation mitigates neuroinflammation and cognitive deficits in simulated microgravity conditions.
- Fecal microbiota transplantation from SMG-treated rats reproduces cognitive impairments in recipients under normal gravity.

## Abstract

Long-duration spaceflight characterized by microgravity adversely affects operator proficiency postlanding, yet the mechanisms by which microgravity induces cerebral dysfunction refractory to short-term recovery among astronauts remain poorly defined. Here, we demonstrate that simulated microgravity (SMG) leads to chronic behavior disorders and cognitive deficits via a microbiota-metabolite-brain axis. Fecal microbiota transplantation (FMT) from long-term SMG-treated donor rats to recipients (n = 5 per group) under normal gravity (NG) induces anxiety-like behaviors and spatial working memory disturbances by impairing synaptic plasticity in the hippocampus, reproducing the phenotype of SMG-exposed rats. SMG destroys intestinal barriers and alters the gut microbiota to a proinflammatory state with an increased abundance of Proteobacteria but decreased production of linoleic acid (LA) and LA-derived metabolites, which is highly associated with neuroinflammation in the hippocampus. Mechanistically, LA can be taken up by the hippocampus under NG conditions, and then block inflammatory microglial activation by interacting with signal transducer and activator of transcription 1 (STAT1) and inhibiting its phosphorylation at Tyr 701 and Ser 727. However, the Proteobacteria, especially Pseudomonas aeruginosa, tend to be the dominant phylum in gut microbiota under SMG conditions and consume large amounts of LA, breaking LA-dependent immune homeostasis in the central nervous system (CNS). Dietary supplementation with LA significantly mitigated SMG-induced neuroinflammation and cognitive impairment. Taken together, our findings in SD rats models reveal a critical role for gut microbiota dysbiosis in simulated microgravity-associated encephalopathy, offering a novel strategy for LA replenishment to improve brain function during spaceflight.

Simulated microgravity-induced cognitive dysfunction is associated with gut microbiota dysbiosis.A sustained increase in the abundance of the phylum Proteobacteria contribute to the undue consumption of linoleic acid (LA), a metabolite that can be taken up by the microglia in the hippocampus and restrain neuroinflammation through inhibition of STAT1 signaling.Dietary supplementation with LA under simulated microgravity conditions could improve brain function by rebuilding the immune homeostasis in the hippocampus and mitigating the synaptic impairment.

Simulated microgravity-induced cognitive dysfunction is associated with gut microbiota dysbiosis.

A sustained increase in the abundance of the phylum Proteobacteria contribute to the undue consumption of linoleic acid (LA), a metabolite that can be taken up by the microglia in the hippocampus and restrain neuroinflammation through inhibition of STAT1 signaling.

Dietary supplementation with LA under simulated microgravity conditions could improve brain function by rebuilding the immune homeostasis in the hippocampus and mitigating the synaptic impairment.