Gut Microbiota and Psychiatric Disorders: A Two-Sample Mendelian Randomization Study

Ni, Jun; Xu, Qian; Yan, Shanshan; Han, Bai‐Xue; Zhang, Hong; Wei, Xin‐Tong; Feng, Guoliang; Zhao, Min; Pei, Yu‐Fang; Zhang, Lei

doi:10.3389/fmicb.2021.737197

Cited by 96 publications

(89 citation statements)

References 69 publications

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“…In the current study, the difference of taxa was significant between SMPS and VPA groups, especially in Prevotellaceae and Lachnospiraceae_NK4A136_group. One study has reported that Prevotellaceae was the specific causal microbe taxa for autism spectrum disorder (Ni et al, 2021). In comparative studies between ASD and normal children, the relative abundance of Prevotellaceae in the ASD children was significantly lower than that of control children, whereas our study indicated that SMPS intervention was able to increase the abundance of Prevotellaceae (Pulikkan et al, 2018;Qiao et al, 2018;Sun et al, 2019).…”

Section: Discussioncontrasting

confidence: 50%

Effect of stigma maydis polysaccharide on the gut microbiota and transcriptome of VPA induced autism model rats

Yang

Zhang

et al. 2022

Front. Microbiol.

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Stigma maydis polysaccharide (SMPS) is a plant polysaccharide that participates in immune regulation and gastrointestinal motility. Autism spectrum disorder (ASD) refers to a group of neurodevelopmental disorders, and ASD patients often present intestinal microflora imbalance problems; however, there is no effective treatment method. This study explores the effect of SMPS intervention on the gut microbiota in autism model rats as well as the potential action pathways. Female Wistar rats were intraperitoneally injected with sodium valproic acid (VPA) or normal saline at embryonic day 12.5 to establish an autism model or normal control in their offspring. The offspring prenatally exposed to VPA were randomly assigned to the VPA and the SMPS groups. The SMPS group was administered SMPS from E0.5 to postnatal day (PND) 21. We performed 16S rRNA and transcriptomics analyses to reveal the gut microbiota (GM) and differentially expressed genes in the autism model rats in response to SMPS intervention. SMPS intervention significantly improved the diversity and structure of the GM in autism model rats compared with the VPA rats. Moreover, the relative abundance of Prevotellaceae and Lachnospiraceae_NK4A136_group was increased after SMPS intervention. Transcriptome sequencing showed that 496 differentially expressed genes (DEGs) were identified after SMPS administration compared with the VPA group. Meanwhile, gene ontology (GO) enrichment analysis of DEGs was showed that the SMPS group had significant 653 GO terms. SMPS intervention had a major influence on oxidative phosphorylation, retrograde endocannabinoid signaling, thermogenesis, ribosome, protein digestion and absorption, renin-angiotensin system, calcium signaling pathway, glycosphingolipid biosynthesis-ganglio series, and propanoate metabolism pathways. Overall, this study suggests that SMPS interventions in early life may have an impact on gut microbiota, and then affect the transcriptomics levels of the hippocampal tissue in the VPA-induced autism model rats. It provides scientific evidence for the role of the microbe-gut-brain axis in ASD research.

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Section: Discussioncontrasting

confidence: 50%

Effect of stigma maydis polysaccharide on the gut microbiota and transcriptome of VPA induced autism model rats

Yang

Zhang

et al. 2022

Front. Microbiol.

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“…These include, for example, the statistical problems derived from the fact that, in MR, the randomization process is confided to the natural distribution in the population of genetic variants, which may sometimes be, in fact, nonrandom (e.g. due to linkage disequilibrium, or ‘cryptic relatedness’), which have been discussed in detail in the MR literature (Voight and Pritchard, 2005; Nitsch et al , 2006; Boef et al , 2015). Furthermore, the heterogeneity of the populations included in the MR studies may represent a confounder in the analyses performed by the papers that we reviewed.…”

Section: Discussion and Limitationsmentioning

confidence: 99%

Applications of Mendelian randomization in psychiatry: a comprehensive systematic review

Saccaro

Gasparini

Rutigliano

2022

Psychiatric Genetics

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Psychiatric diseases exact a heavy socioeconomic toll, and it is particularly difficult to identify their risk factors and causative mechanisms due to their multifactorial nature, the limited physiopathological insight, the many confounding factors, and the potential reverse causality between the risk factors and psychiatric diseases. These characteristics make Mendelian randomization (MR) a precious tool for studying these disorders. MR is an analytical method that employs genetic variants linked to a certain risk factor, to assess if an observational association between that risk factor and a health outcome is compatible with a causal relationship. We report the first systematic review of all existing applications and findings of MR in psychiatric disorders, aiming at facilitating the identification of risk factors that may be common to different psychiatric diseases, and paving the way to transdiagnostic MR studies in psychiatry, which are currently lacking. We searched Web of Knowledge, Scopus, and Pubmed databases (until 3 May 2022) for articles on MR in psychiatry. The protocol was preregistered in PROSPERO (CRD42021285647). We included methodological details and results from 50 articles, mainly on schizophrenia, major depression, autism spectrum disorders, and bipolar disorder. While this review shows how MR can offer unique opportunities for unraveling causal links in risk factors and etiological elements of specific psychiatric diseases and transdiagnostically, some methodological flaws in the existing literature limit reliability of results and probably underlie their heterogeneity. We highlight perspectives and recommendations for future works on MR in psychiatry.

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“…Nevertheless, this study has some limitations. First, as SNPs in the MiBioGen study less than 5 × 10 –8 are not sufficient for MR analysis, the significance level of gut microbiota IV selection is set at 1 × 10 –5 instead of 5 × 10 –8 , which is the same as that in a previous publication ( Ni et al, 2021 ). However, the F-statistics are guaranteed to be > 10 to exclude potential weak instrument bias and make the statistical results more robust ( Burgess and Thompson, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

“…Bacterial taxa were classified and analyzed at six levels (phylum, class, order, family, genus, and species) based on SNPs available in the gut microbiome GWAS summary data. Candidate IVs were identified at a significance level of P < 1.0 × 10 –5 according to the previously published studies ( Sanna et al, 2019 ; Ni et al, 2021 ). The parameters of the clump function in the R package were set at r 2 < 0.1 and kb = 500 kb, guaranteeing the independence of each IV, which was the same as in a previous publication, to minimize the impact of linkage disequilibrium violating the randomized allele allocation ( Ni et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

“…Candidate IVs were identified at a significance level of P < 1.0 × 10 −5 according to the previously published studies (Sanna et al, 2019;Ni et al, 2021). The parameters of the clump function in the R package were set at r 2 < 0.1 and kb = 500 kb, guaranteeing the independence of each IV, which was the same as in a previous publication, to minimize the impact of linkage disequilibrium violating the randomized allele allocation (Ni et al, 2021). Furthermore, as our significance level was 2 https://gwas.mrcieu.ac.uk/ set at P < 1.0 × 10 −5 , the F statistic was used to exclude the weak instrument bias violating the first assumption of MR (Burgess and Thompson, 2011).…”

Section: Instrumental Variables Selectionmentioning

confidence: 99%

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Genetically proxied gut microbiota, gut metabolites with risk of epilepsy and the subtypes: A bi-directional Mendelian randomization study

Ouyang

Chen

Wang

et al. 2022

Front. Mol. Neurosci.

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BackgroundAn increasing number of observational studies have revealed an association among the gut microbiota, gut metabolites, and epilepsy. However, this association is easily influenced by confounders such as diet, and the causality of this association remains obscure.MethodsAiming to explore the causal relationship and ascertain specific gut microbe taxa for epilepsy, we conducted a bi-directional Mendelian randomization (MR) study based on the genome-wide association study (GWAS) data of epilepsy from the International League Against Epilepsy, with the gut microbiota GWAS results from MiBioGen, and summary-level GWAS data of gut microbiota-dependent metabolites trimethylamine N-oxide and its predecessors.ResultsNine phyla, 15 classes, 19 orders, 30 families, and 96 genera were analyzed. A suggestive association of host-genetic-driven increase in family Veillonellaceae with a higher risk of childhood absence epilepsy (odds ratio [OR]: 1.033, confidential interval [CI]: 1.015–1.051, PIVW = 0.0003), class Melainabacteria with a lower risk of generalized epilepsy with tonic-clonic seizures (OR = 0.986, CI = 0.979–0.994, PIVW = 0.0002), class Betaproteobacteria (OR = 0.958, CI = 0.937–0.979, PIVW = 0.0001), and order Burkholderiales (OR = 0.960, CI = 0.937–0.984, PIVW = 0.0010) with a lower risk of juvenile myoclonic epilepsy were identified after multiple-testing correction. Our sensitivity analysis revealed no evidence of pleiotropy, reverse causality, weak instrument bias, or heterogeneity.ConclusionThis is the first MR analysis to explore the potential causal relationship among the gut microbiota, metabolites, and epilepsy. Four gut microbiota features (two class levels, one order level, and one family level) were identified as potential interventional targets for patients with childhood absence epilepsy, generalized epilepsy with tonic-clonic seizures, and juvenile myoclonic epilepsy. Previous associations in numerous observational studies may had been interfered by confounders. More rigorous studies were needed to ascertain the relationship among the gut microbiota, metabolites, and epilepsy.

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Gut Microbiota and Psychiatric Disorders: A Two-Sample Mendelian Randomization Study

Cited by 96 publications

References 69 publications

Effect of stigma maydis polysaccharide on the gut microbiota and transcriptome of VPA induced autism model rats

Effect of stigma maydis polysaccharide on the gut microbiota and transcriptome of VPA induced autism model rats

Applications of Mendelian randomization in psychiatry: a comprehensive systematic review

Genetically proxied gut microbiota, gut metabolites with risk of epilepsy and the subtypes: A bi-directional Mendelian randomization study

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