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. 2024 Apr 23;24(1):134.
doi: 10.1186/s12866-024-03276-7.

Exertional heat stroke-induced changes in gut microbiota cause cognitive impairment in mice

Jiangang Xie #  1 , Linxiao Wang #  2 , Yunyun Xu #  3 , Yuexiang Ma  3 , Lingqin Zhang  3 , Wen Yin  4 , Yang Huang  5
Affiliations

Exertional heat stroke-induced changes in gut microbiota cause cognitive impairment in mice

Jiangang Xie et al. BMC Microbiol. .

Abstract

Background: The incidence of exertional heat stroke (EHS) escalates during periods of elevated temperatures, potentially leading to persistent cognitive impairment postrecovery. Currently, effective prophylactic or therapeutic measures against EHS are nonexistent.

Methods: The selection of days 14 and 23 postinduction for detailed examination was guided by TEM of neuronal cells and HE staining of intestinal villi and the hippocampal regions. Fecal specimens from the ileum and cecum at these designated times were analyzed for changes in gut microbiota and metabolic products. Bioinformatic analyses facilitated the identification of pivotal microbial species and metabolites. The influence of supplementing these identified microorganisms on behavioral outcomes and the expression of functional proteins within the hippocampus was subsequently assessed.

Results: TEM analyses of neurons, coupled with HE staining of intestinal villi and the hippocampal region, indicated substantial recovery in intestinal morphology and neuronal injury on Day 14, indicating this time point for subsequent microbial and metabolomic analyses. Notably, a reduction in the Lactobacillaceae family, particularly Lactobacillus murinus, was observed. Functional annotation of 16S rDNA sequences suggested diminished lipid metabolism and glycan biosynthesis and metabolism in EHS models. Mice receiving this intervention (EHS + probiotics group) exhibited markedly reduced cognitive impairment and increased expression of BDNF/TrKB pathway molecules in the hippocampus during behavioral assessment on Day 28.

Conclusion: Probiotic supplementation, specifically with Lactobacillus spp., appears to mitigate EHS-induced cognitive impairment, potentially through the modulation of the BDNF/TrKB signaling pathway within the hippocampus, illustrating the therapeutic potential of targeting the gut-brain axis.

Keywords: Cognitive impairment; Exertional heat stroke; Gut microbiota; Gut-brain axis; Probiotic.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Behavioral testing of EHS mice models. A TST and B FST reveal markedly depressive-like behavior in mice. C and D show no significant change in EPMT; E and F show no difference in EPMT; G show the time the mice were in the inner region. H, I and J are NORT experiments. Data are expressed as the mean ± SEM (sham, n = 6; EHS 14 d, n = 12; EHS 28 d, n = 12). *p < 0.05, **p < 0.01, ns = no statistical significance. vs. sham. An unpaired T test was used for data analysis
Fig. 2
Fig. 2
Intestinal villi and hippocampal region injury in EHS mice. A HE staining of intestinal villi (×100); B HE staining of hippocampal region (×100); C Nissl staining of hippocampal region (×100); D TEM of neurons in the hippocampal region; E Chiu’s scale for evaluating the degree of intestinal injury; F The Flameng scale was used to evaluate the degree of neuronal mitochondrial injury. Data are expressed as the mean ± SEM (n = 12/group). ***p < 0.001, ns = no statistical significance. vs. sham. Unpaired. A t test was used for data analysis
Fig. 3
Fig. 3
Gut microbiota 16S sequencing of EHS mice. A-C α diversity of ACE, Chao1, and Simpson indices of the gut microbiota in the two groups. D-E β diversity analysis of the samples in the two groups at the PCA and PCoA level. F Waterfall plot of EHS mice. G Distribution stacked map of family, genus, species. H Distribution circle map of 16S species composition. I PICRUSt2 Functional Distribution General Map. J Heatmap for metabolite sequencing of the gut microbiota of sham group and EHS group mice
Fig. 4
Fig. 4
Gut microbiota metabolite sequencing analysis of sham and EHS mice. A PCA score plot of the sham and EHS groups; B orthogonal T scores of the sham and EHS groups; C and D differential expression of metabolites in the EHS and sham groups; E cluster heatmap of the differentially expressed metabolites between the two groups; F KEGG functional enrichment analysis of the differentially expressed metabolites; G MSEA of the differentially expressed metabolites
Fig. 5
Fig. 5
Metabolites associated with the O2PLS model Lactobacillus
Fig. 6
Fig. 6
Influence of probiotic supplementation on behavioral and mechanistic effects in mice. A Survival curves of different groups of mice; B Distance and time to center area of OFT; C Detect the exploration time and preference index of NORT; D Western blot for protein expression of BDNF, TrkB and p-TrkB; E Quantification of BDNF protein expression; F Quantification of the p-TrkB/TrkB protein ratio. Data are expressed as the mean ± SEM (n = 12 group). *p < 0.05, **p < 0.01, ***p < 0.001, ns = no statistical significance. Data are expressed as the mean ± SEM (n = 6 group)
Fig. 7
Fig. 7
Hypothesis mechanism diagram of EHS mice. Reduced Lactobacillus and abnormal short-chain fatty acid metabolism promote cognitive impairment due to heat injury in EHS. Supplementation with probiotics improved dysbiosis and promoted the expression of the BDNF/TrKB pathway in the cortex and hippocampus via the gut-brain axis, alleviating cognitive impairment
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