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Amelioration of Maternal Immune Activation-Induced Autism Relevant Behaviors by Gut Commensal Parabacteroides goldsteinii - PubMed

  • ️Sat Jan 01 2022

Amelioration of Maternal Immune Activation-Induced Autism Relevant Behaviors by Gut Commensal Parabacteroides goldsteinii

Tzu-Lung Lin et al. Int J Mol Sci. 2022.

Abstract

Autism spectrum disorder (ASD) is characterized by cognitive inflexibility and social deficits. Probiotics have been demonstrated to play a promising role in managing the severity of ASD. However, there are no effective probiotics for clinical use. Identifying new probiotic strains for ameliorating ASD is therefore essential. Using the maternal immune activation (MIA)-based offspring ASD-like mouse model, a probiotic-based intervention strategy was examined in female mice. The gut commensal microbe Parabacteroides goldsteinii MTS01, which was previously demonstrated to exert multiple beneficial effects on chronic inflammation-related-diseases, was evaluated. Prenatal lipopolysaccharide (LPS) exposure induced leaky gut-related inflammatory phenotypes in the colon, increased LPS activity in sera, and induced autistic-like behaviors in offspring mice. By contrast, P. goldsteinii MTS01 treatment significantly reduced intestinal and systemic inflammation and ameliorated disease development. Transcriptomic analyses of MIA offspring indicated that in the intestine, P. goldsteinii MTS01 enhanced neuropeptide-related signaling and suppressed aberrant cell proliferation and inflammatory responses. In the hippocampus, P. goldsteinii MTS01 increased ribosomal/mitochondrial and antioxidant activities and decreased glutamate receptor signaling. Together, significant ameliorative effects of P. goldsteinii MTS01 on ASD relevant behaviors in MIA offspring were identified. Therefore, P. goldsteinii MTS01 could be developed as a next-generation probiotic for ameliorating ASD.

Keywords: Parabacteroides goldsteinii; autism spectrum disorders; lipopolysaccharides; maternal immune activation; next-generation probiotic.

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Conflict of interest statement

The authors declare that they have no competing interest.

Figures

Figure 1
Figure 1

Experimental design for evaluating the ameliorative effects of Parabacteroides goldsteinii (Pg) MTS01 on the aberrant behaviors of offspring with lipopolysaccharide (LPS)-induced maternal immune activation (MIA). On gestation days (GD) 15, 16, and 17, pregnant mice were subcutaneously (SC) injected with 25, 25, and 50 μg/kg LPS, respectively. In the control group, pregnant mice were injected with phosphate-buffered saline. Female mice offspring were selected and grouped. Mouse offspring were orally gavaged with live Pg MTS01 at 1 × 109 colony-forming units (cfu) per day for 5 days per week from week 4 through to the end of the experiment. For anxiety-like behavior assessments, the open-field test (OFT), light–dark box (LDB) test, and elevated plus maze (EPM) test were conducted at the ages of 5, 6, and 8 weeks, respectively. Regarding the social behavioral deficits evaluation, the home cage test (HCT) and three-chamber behavioral test (3-CBT) were performed at 6 and 9 weeks of age, respectively.

Figure 2
Figure 2

Parabacteroides goldsteinii (Pg) MTS01 ameliorates the anxiety-like behaviors of MIAO. Offspring from phosphate-buffered sale control group (CTL, n = 30), LPS-induced MIA group (MIAO, n = 30), and MIAO orally gavaged with Pg MTS01 (MIAO + Pg, n = 30) were evaluated for anxiety-like behaviors using the open-field test (OFT; A–C), light–dark box (D–F), and elevated plus maze (G–I). The central and peripheral regions in 36 squares as well as the representative path tracing during the OFT are presented (A). The proportion of time spent in the central region (B) and the total distances moved in the test period (C) are presented. A schematic representation of the LDB is presented (D). The number of times the mice moved between the light and dark boxes within 10 min were recorded (E), and the proportion of time spent in the dark box (F) is presented. A schematic representation of the EPM test is presented (G). The proportion of open arm entries (H) and the time spent in the open arm (I) are presented. Data are presented as the mean ± standard deviation. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001; ns, not significant (one-way ANOVA, Tukey’s post hoc test).

Figure 3
Figure 3

Parabacteroides goldsteinii (Pg) MTS01 ameliorates the social deficit behaviors of MIAO. Offspring from the phosphate-buffered saline control group (CTL), lipopolysaccharide-induced MIA group (MIAO), and MIAO orally gavaged with Pg MTS01 (MIAO + Pg) were evaluated for social deficit behaviors using the home cage test (n = 46; A,B) and three-chamber behavioral test (3-CBT, n = 34; C–F). A schematic representation of the phenotypic expression of active (nose-to-nose or nose-to-body) and passive (body-to-body) behaviors is presented (A). The number of times that passive behaviors were displayed was recorded (B). Schematic representation of the 3-CBT is presented (C,E). The proportion of time spent in the empty chamber (Object zone) in contrast to that in the Social zone was recorded (D). The proportion of time spent exploring unfamiliar (S2 zone) in contrast to familiar mice (S1 zone) is presented (F). Data are presented as the mean ± standard deviation. * p < 0.05; **** p < 0.0001 (one-way ANOVA, Tukey’s post hoc test).

Figure 4
Figure 4

Parabacteroides goldsteinii (Pg) MTS01 ameliorates the gut inflammation of lipopolysaccharide (LPS)-induced MIAO. The serum endotoxin level (A) and colon inflammatory cytokine level (B–D) of offspring from the phosphate-buffered saline control group (CTL), LPS-induced MIA group (MIAO), and MIAO orally gavaged with Pg MTS01 (MIAO + Pg) were determined. Data are presented as the mean ± standard deviation. * p < 0.05; ** p < 0.01; ns, not significant (one-way ANOVA, Tukey’s post hoc test).

Figure 5
Figure 5

Transcriptome alterations in colon of MIAO orally gavaged with Parabacteroides goldsteinii MTS01. Dot plots of the significantly upregulated (normalized enrichment score [NES] > 1 and false-discovery rate [FDR] q value < 0.25) and downregulated ([NES] < −1 and FDR q value < 0.25) gene sets from gene set enrichment analysis of the MIAO + Pg group compared to the MIAO group (top 20 gene sets in GO_BP, GO_MF and GO_CC) are presented in (A,B), respectively. Gene sets with similar functions were labeled in color, and the functions were also added. Five genes contributing to the leading-edge subset within the gene sets (immune responses such as B cell receptor, lipopolysaccharide receptor, and chemokine responses; synapse responses such as synaptic membrane exocytosis) as validated by quantitative RT-PCR are presented in (C–G). Data are presented as the mean ± standard deviation. * p < 0.05; ** p < 0.01(unpaired Student’s t-test). MIAO + Pg, MIAO treated with P. goldsteinii MTS01.

Figure 6
Figure 6

Transcriptome alterations in hippocampus of MIAO orally gavaged with Parabacteroides goldsteinii MTS01. Dot plots of the significantly upregulated (normalized enrichment score [NES] > 1 and false-discovery rate [FDR] q value < 0.25) and downregulated ([NES] < −1 and FDR q value < 0.25) gene sets from gene set enrichment analysis of the MIAO + Pg group compared to the MIAO group (top 20 gene sets in GO_BP, GO_MF and GO_CC) are presented in (A,B), respectively. Gene sets with similar functions were labeled in color, and the functions were also added. Eight genes contributing to the leading-edge subset within the gene sets (ribosome, oxidoreductase, NADH dehydrogenase, antioxidant, regulation of transmission of nerve impulse, and glutamate receptor signaling pathway) as validated by quantitative RT-PCR are presented in (C–J). Data are presented as the mean ± standard deviation. * p < 0.05; ** p < 0.01 (unpaired Student’s t-test). MIAO + Pg, MIAO treated with P. goldsteinii MTS01.

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