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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Microbiol.</journal-id>
<journal-title>Frontiers in Microbiology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Microbiol.</abbrev-journal-title>
<issn pub-type="epub">1664-302X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fmicb.2024.1415237</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Microbiology</subject>
<subj-group>
<subject>Original Research</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>The causal association between gut microbiota and postpartum depression: a two-sample Mendelian randomization study</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" equal-contrib="yes">
<name><surname>Jin</surname> <given-names>Wenjun</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref rid="fn0041" ref-type="author-notes"><sup>&#x2020;</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/2825355/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
<role content-type="https://credit.niso.org/contributor-roles/data-curation/"/>
<role content-type="https://credit.niso.org/contributor-roles/formal-analysis/"/>
</contrib>
<contrib contrib-type="author" corresp="yes" equal-contrib="yes">
<name><surname>Li</surname> <given-names>Bo</given-names></name>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="corresp" rid="c001"><sup>&#x002A;</sup></xref>
<xref rid="fn0041" ref-type="author-notes"><sup>&#x2020;</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/2525807/overview"/>
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<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Wang</surname> <given-names>Lijun</given-names></name>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/2274296/overview"/>
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<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Zhu</surname> <given-names>Lin</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
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</contrib>
<contrib contrib-type="author">
<name><surname>Chai</surname> <given-names>Songhao</given-names></name>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Hou</surname> <given-names>Rui</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
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<aff id="aff1"><sup>1</sup><institution>Medical Department, Sias University</institution>, <addr-line>Zhengzhou, Henan</addr-line>, <country>China</country></aff>
<aff id="aff2"><sup>2</sup><institution>Medical Department, Zhengzhou University of Industry Technology</institution>, <addr-line>Zhengzhou, Henan</addr-line>, <country>China</country></aff>
<aff id="aff3"><sup>3</sup><institution>Ultrasound Department, The First Affiliated Hospital of Zhengzhou University</institution>, <addr-line>Zhengzhou</addr-line>, <country>China</country></aff>
<author-notes>
<fn fn-type="edited-by" id="fn0001">
<p>Edited by: Wei Peng, Chengdu University of Traditional Chinese Medicine, China</p>
</fn>
<fn fn-type="edited-by" id="fn0002">
<p>Reviewed by: Nadia Andrea Andreani, Max Planck Institute for Evolutionary Biology, Germany</p>
<p>Raju Baskar, University of Texas Southwestern Medical Center, United States</p>
<p>Manigandan Venkatesan, The University of Texas Health Science Center at San Antonio, United States</p>
</fn>
<corresp id="c001">&#x002A;Correspondence: Bo Li, <email>mildsir93@163.com</email></corresp>
<fn id="fn0041" fn-type="equal">
<p><sup>&#x2020;</sup>These authors have contributed equally to this work and share first authorship</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>02</day>
<month>09</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>15</volume>
<elocation-id>1415237</elocation-id>
<history>
<date date-type="received">
<day>10</day>
<month>04</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>21</day>
<month>08</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x00A9; 2024 Jin, Li, Wang, Zhu, Chai and Hou.</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Jin, Li, Wang, Zhu, Chai and Hou</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<sec id="sec1">
<title>Background</title>
<p>An escalating body of clinical trials and observational studies hints at a plausible link between gut flora and postpartum depression (PPD). The definitive causal dynamics between these two entities remain shrouded in ambiguity. Therefore, in this study, we employed the two-sample Mendelian randomization approach to ascertain the causal link between gut microbiota and PPD.</p>
</sec>
<sec id="sec2">
<title>Methods</title>
<p>Summary-level GWAS data related to the human gut microbiota were obtained from the international consortium MiBioGen and the Dutch Microbiome Project (species). For PPD, GWAS data were derived from the FinnGen biobank, consisting 57,604 cases and 596,601 controls. The inverse variance weighted method (IVW) as the cornerstone of our analytical approach. Subsequent to this, a comprehensive suite of tests for pleiotropy and heterogeneity were conducted to ensure the reliability and robustness of our findings.</p>
</sec>
<sec id="sec3">
<title>Results</title>
<p>We identified 12 bacterial taxa associated with the risk of PPD. Veillonellaceae, <italic>Ruminococcaceae UCG 011</italic>, <italic>Bifidobacterium adolescentis</italic>, <italic>Paraprevotella clara</italic>, <italic>Clostridium leptum</italic>, <italic>Eubacterium siraeum</italic>, <italic>Coprococcus catus</italic> exhibited an inversely associated with the risk of PPD. Alphaproteobacteria, <italic>Roseburia</italic>, <italic>FamilyXIIIAD3011group</italic>, <italic>Alistipes onderdonkii</italic>, <italic>Bilophila wadsworthia</italic> showed a positive correlation with the risk of PPD.</p>
</sec>
<sec id="sec4">
<title>Limitations</title>
<p>The GWAS data derived from the MiBioGen consortium, DMP, and FinnGen consortium, may introduce selection bias. Moreover, the data primarily originates from European populations, hence extrapolating these results to diverse populations should be approached with caution. The etiological factors behind PPD remain enigmatic, alluding to the existence of potential undisclosed confounders.</p>
</sec>
<sec id="sec5">
<title>Conclusion</title>
<p>Based on this MR analysis, we found a causal relationship between certain gut microbial communities and PPD. Future clinical studies can further explore the treatment of PPD through the combined use of microorganisms. This not only offers insights into the pathogenesis of PPD but also lays the foundation for utilizing gut microbiota as biotherapeutics in treating neurological disorders.</p>
</sec>
</abstract>
<kwd-group>
<kwd>gut microbiota</kwd>
<kwd>postpartum depression</kwd>
<kwd>Mendelian randomization</kwd>
<kwd>instrumental variables (IVs)</kwd>
<kwd>single nucleotide polymorphisms (SNPs)</kwd>
</kwd-group>
<counts>
<fig-count count="2"/>
<table-count count="4"/>
<equation-count count="0"/>
<ref-count count="71"/>
<page-count count="11"/>
<word-count count="7441"/>
</counts>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Systems Microbiology</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec sec-type="intro" id="sec6">
<label>1</label>
<title>Introduction</title>
<p>Postpartum depression (PPD) represents a grave mental health concern, typically manifesting within a week to several weeks following childbirth. Beyond the evident physical and psychological toll on the mother, PPD has far-reaching implications for the child, potentially hampering their emotional, behavioral, cognitive, and intellectual trajectory in ways that can span their lifetime (<xref ref-type="bibr" rid="ref28">Josefsson et al., 2002</xref>; <xref ref-type="bibr" rid="ref57">Sohr-Preston and Scaramella, 2006</xref>; <xref ref-type="bibr" rid="ref64">van der Waerden et al., 2017</xref>). Globally, it&#x2019;s estimated that 10&#x2013;15% of new mothers grapple with PPD, although the prevalence fluctuates across regions (<xref ref-type="bibr" rid="ref46">Palumbo et al., 2017</xref>). Alarmingly, the prevalence is heightened in developing nations. Countries with the lowest incidence rates of PPD include: Singapore (3%), the Netherlands (8%), the United States (8.4%), and Switzerland (11%). Countries with higher incidence rates include: Chile (38%), South Africa (37%), Turkey (28%), and China (21.4%) (<xref ref-type="bibr" rid="ref20">Hahn-Holbrook et al., 2017</xref>; <xref ref-type="bibr" rid="ref37">Liu et al., 2022</xref>).</p>
<p>The human gut is a bustling microcosm, In the case of an average adult weighing 70&#x2009;kg, the gut microbiota comprises approximately 3.8&#x2009;&#x00D7;&#x2009;10<sup>13</sup> microorganisms, collectively possessing genomic content that dwarfs our own by over 100-fold (<xref ref-type="bibr" rid="ref17">Gill et al., 2006</xref>; <xref ref-type="bibr" rid="ref55">Sender et al., 2016</xref>). The human gut microbiota is composed of four major phyla: Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria (<xref ref-type="bibr" rid="ref14">Eckburg et al., 2005</xref>). In some cohort studies, compared to healthy controls (HC), patients with Major Depressive Disorder (MDD) exhibit higher abundances of Bacteroidetes, Proteobacteria, and Actinobacteria (<xref ref-type="bibr" rid="ref27">Jiang et al., 2015</xref>). In patients with PPD, a relatively lower abundance of the Firmicutes phylum is observed (<xref ref-type="bibr" rid="ref76">Zhou et al., 2020</xref>). A burgeoning body of evidence points to intricate bidirectional communication between our brains and gut, with the microbial denizens and their metabolic by-products playing pivotal roles. This intricate dialogue is called the brain-gut-microbiota axis (<xref ref-type="bibr" rid="ref41">Mayer et al., 2014</xref>; <xref ref-type="bibr" rid="ref9">Cryan et al., 2019</xref>). In patients with depression, the homeostasis of the gut microbiota is disrupted, leading to impaired gut function. This, in turn, results in intestinal barrier dysfunction and various inflammatory responses (<xref ref-type="bibr" rid="ref36">Liu et al., 2023</xref>). These inflammatory responses are correlated with the pathogenesis of depression. The brain-gut axis is bidirectional, with the vagus nerve being the primary regulatory pathway between the brain and the gut microbiota. Some studies suggest that subdiaphragmatic vagotomy may reduce inflammatory responses, thereby alleviating depressive symptoms (<xref ref-type="bibr" rid="ref73">Zhang et al., 2020</xref>; <xref ref-type="bibr" rid="ref48">Pu et al., 2021</xref>). Clinically, vagal nerve stimulation (VNS) is an FDA-approved neuromodulation therapy for the treatment of severe treatment-resistant depression (TRD). VNS increases the levels of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine, and through the anti-inflammatory pathway of the vagus nerve, it reduces systemic inflammatory responses, thereby improving depressive symptoms (<xref ref-type="bibr" rid="ref29">Kamel et al., 2022</xref>). Short-chain fatty acids (SCFAs) act as intermediary products between the gut microbiota and the brain, primarily including acetate, propionate, and butyrate. SCFA produced by gut microbiota inhibit histone deacetylases and activate G-protein-coupled receptors, influencing systemic physiological responses (<xref ref-type="bibr" rid="ref60">Tan et al., 2014</xref>). Among these, propionate can reduce levels of &#x03B3;-aminobutyric acid (GABA), and the indoleamine serotonin (<xref ref-type="bibr" rid="ref15">El-Ansary et al., 2012</xref>). During pregnancy, alterations in the GABA(A) receptor may increase neuronal excitability in the brain. However, the sharp decrease in neuroactive steroids in the brain after childbirth has a causal relationship with the expression of GABA(A) receptors in the hippocampus. This dynamic could contribute to the development of postpartum neurological and psychiatric disorders (<xref ref-type="bibr" rid="ref40">Maguire et al., 2009</xref>). Regulating the gut microbiota can improve intestinal barrier function, reduce systemic inflammatory responses, and increase the abundance of beneficial bacteria in the gut. This enhances their ability to produce beneficial metabolites such as SCFAs and GABA, which have positive effects on alleviating and treating postpartum depression (<xref ref-type="bibr" rid="ref52">Ramsteijn et al., 2020</xref>; <xref ref-type="bibr" rid="ref62">Tian et al., 2021</xref>).</p>
<p>Mendelian Randomization (MR), rooted in epidemiology, leverages single nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS) as instrumental variables (IVs) to estimate the causal relationship between exposure factors and disease outcomes. These SNPs are genetically associated with the exposure factors but are not influenced by confounding factors and reverse causation. The advantage of MR is that these instrumental variables are predetermined conceptually, greatly minimizing the impact of potential confounders and reverse causality (<xref ref-type="bibr" rid="ref16">Ellervik et al., 2019</xref>). Recent studies have applied MR to analyze the causal relationship between psychiatric disorders and the gut microbiome. Actinobacteria, <italic>Bifidobacterium</italic>, <italic>Ruminococcus1</italic>, and <italic>Streptococcaceae</italic> have been associated with MDD (<xref ref-type="bibr" rid="ref8">Chen et al., 2022</xref>), <italic>Prevotellaceae</italic> with autism spectrum disorder, Betaproteobacteria with bipolar disorder (<xref ref-type="bibr" rid="ref42">Ni et al., 2021</xref>). Despite the presence of symptomatic and genetic parallels between PPD and MDD, substantial disparities in their etiology and treatment methodologies are evident (<xref ref-type="bibr" rid="ref26">Jairaj and Rucker, 2022</xref>).</p>
<p>Therefore, this study aims to use the MR method to analyze the potential causal relationships between various levels of gut microbiota and PPD, to explore the differences in the gut microbiota between PPD and MDD, and other psychiatric disorders, thus providing new insights into treatment approaches for PPD.</p>
</sec>
<sec sec-type="materials|methods" id="sec7">
<label>2</label>
<title>Materials and methods</title>
<sec id="sec8">
<label>2.1</label>
<title>Mendelian randomization analysis</title>
<p>MR provides one method for assessing the causal nature of some exposures (<xref ref-type="bibr" rid="ref56">Smith and Ebrahim, 2003</xref>; <xref ref-type="bibr" rid="ref32">Lawlor et al., 2008</xref>). In epidemiological research, MR harnesses genetic variants as instrumental variables (IVs) to decipher the causal interplay between exposure and its consequent outcome (<xref ref-type="bibr" rid="ref5">Bowden and Holmes, 2019</xref>).</p>
<p>To perform an MR study, three main assumptions must be fulfilled (<xref ref-type="bibr" rid="ref30">Konig and Greco, 2018</xref>). (1) There must be a strong correlation between the genetic variant and the exposure; (2) the genetic instrument is independent of potential confounders of the exposure-outcome association; (3) the genetic variant should be solely associated with the outcome through the exposure, without being influenced by other confounders (<xref ref-type="bibr" rid="ref22">Haycock et al., 2016</xref>; <xref ref-type="bibr" rid="ref30">Konig and Greco, 2018</xref>; <xref ref-type="bibr" rid="ref24">Hirtz et al., 2022</xref>).</p>
</sec>
<sec id="sec9">
<label>2.2</label>
<title>Study design</title>
<p>In this research design, gut microbiota SNPs are taken as the exposure variable, and PPD is considered as the outcome variable. <xref ref-type="fig" rid="fig1">Figure 1</xref> illustrates the detailed flowchart.</p>
<fig position="float" id="fig1">
<label>Figure 1</label>
<caption>
<p>Overview of the analysis process of the causal relationship between the gut microbiota and PPD through MR analysis.</p>
</caption>
<graphic xlink:href="fmicb-15-1415237-g001.tif"/>
</fig>
</sec>
<sec id="sec10">
<label>2.3</label>
<title>Data source</title>
<p>Summary-level GWAS data related to the human gut microbiota from the international consortium MiBioGen (<xref ref-type="bibr" rid="ref31">Kurilshikov et al., 2021</xref>) and the Dutch Microbiome Project (DMP) (<xref ref-type="bibr" rid="ref38">Lopera-Maya et al., 2022</xref>). GWAS summary-level data on PPD were obtained from the FinnGen biobank, comprising a total of 67,205 individuals of European ancestry, including 7,604 cases, 59,601 controls. The detailed descriptions of exposure and outcome, including the data source are presented in <xref ref-type="table" rid="tab1">Table 1</xref>.</p>
<table-wrap position="float" id="tab1">
<label>Table 1</label>
<caption>
<p>Information of the data source for gut microbiota and PPD.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="top">Variables</th>
<th align="left" valign="top">Consortium</th>
<th align="left" valign="top">Traits</th>
<th align="center" valign="top">Sample size</th>
<th align="center" valign="top">nSNPs</th>
<th align="center" valign="top">nTaxa</th>
<th align="left" valign="top">Websites</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="middle" rowspan="6">Exposure</td>
<td align="left" valign="middle" rowspan="5">MiBioGen</td>
<td align="left" valign="middle">Phylum</td>
<td align="center" valign="middle" rowspan="5">18,340</td>
<td/>
<td align="center" valign="middle">9</td>
<td align="left" valign="middle" rowspan="5">
<ext-link xlink:href="https://mibiogen.gcc.rug.nl/menu/main/home" ext-link-type="uri">https://mibiogen.gcc.rug.nl/menu/main/home</ext-link>
</td>
</tr>
<tr>
<td align="left" valign="middle">Class</td>
<td/>
<td align="center" valign="middle">16</td>
</tr>
<tr>
<td align="left" valign="middle">Order</td>
<td/>
<td align="center" valign="middle">20</td>
</tr>
<tr>
<td align="left" valign="middle">Family</td>
<td/>
<td align="center" valign="middle">35</td>
</tr>
<tr>
<td align="left" valign="middle">Genus</td>
<td/>
<td align="center" valign="middle">131</td>
</tr>
<tr>
<td align="left" valign="middle">DMP</td>
<td align="left" valign="middle">Species</td>
<td align="center" valign="middle">8,208</td>
<td/>
<td align="center" valign="middle">105</td>
<td align="left" valign="middle">
<ext-link xlink:href="https://dutchmicrobiomeproject.molgeniscloud.org/menu/main/home" ext-link-type="uri">https://dutchmicrobiomeproject.molgeniscloud.org/menu/main/home</ext-link>
</td>
</tr>
<tr>
<td align="left" valign="middle">Outcome</td>
<td align="left" valign="middle">FinnGen</td>
<td align="left" valign="middle">PPD</td>
<td align="center" valign="middle">67,205</td>
<td align="center" valign="middle">16,376,275</td>
<td/>
<td align="left" valign="middle">
<ext-link xlink:href="https://www.finngen.fi/en" ext-link-type="uri">https://www.finngen.fi/en</ext-link>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
<sec id="sec11">
<label>2.4</label>
<title>Selection of instrumental variable</title>
<p>To ensure the accuracy and reliability of the causal effect between gut microbiota and PPD, we adopt the following quality control methods to select microbiota-related IVs:</p>
<list list-type="order">
<list-item>
<p>Based on previous experience and to obtain more comprehensive results, we select IVs with a significance threshold of <italic>p</italic>&#x2009;&#x003C;&#x2009;10<sup>&#x2212;5</sup>.</p>
</list-item>
<list-item>
<p>To rule out the influence of linkage disequilibrium on the results, we used PLINK software with threshold values set at clump_kb&#x2009;=&#x2009;5,000 and clump_r<sup>2</sup>&#x2009;=&#x2009;0.001.</p>
</list-item>
<list-item>
<p>To ensure that SNPs for exposure and outcome are influenced by the same alleles, we are excluding palindromic SNPs from IVs.</p>
</list-item>
<list-item>
<p>The first assumption of MR can be directly validated by calculating the <italic>F</italic>-statistic. An <italic>F</italic>-statistic greater than 10 indicates the absence of weak instrument bias (<italic>F</italic> for a single SNP equals <italic>&#x03B2;</italic><sup>2</sup>/SE<sup>2</sup>) (<xref ref-type="bibr" rid="ref24">Hirtz et al., 2022</xref>).</p>
</list-item>
</list>
</sec>
<sec id="sec12">
<label>2.5</label>
<title>Mendelian randomization methods</title>
<p>In the current study, all analyses were performed using R software version 4.3.2, utilizing the &#x201C;Mendelian-Randomization&#x201D; package. Five popular MR methods were used: Inverse-variance weighted (IVW), MR-Egger, weighted median estimator, simple modal-based estimation, and the weighted mode method. Each statistical method operates under its own set of methodological assumptions. The IVW method estimates the overall causal effect of an exposure on an outcome by performing a weighted average of the effects of multiple genetic variants. This approach assumes the absence of horizontal pleiotropy (<xref ref-type="bibr" rid="ref6">Burgess et al., 2013</xref>). The MR-Egger assumes the presence of pleiotropy in &#x003E;50% of SNPs (<xref ref-type="bibr" rid="ref2">Bowden et al., 2015</xref>). When less than 50% of the information comes from invalid IVs, the weighted median estimator offers a consistent estimate of causal effects (<xref ref-type="bibr" rid="ref3">Bowden et al., 2016</xref>). While the modal-based estimate (MBE) has a weaker ability to detect causal effects, it relaxes instrumental variable assumptions and requires a smaller sample size (<xref ref-type="bibr" rid="ref21">Hartwig et al., 2017</xref>). Under different methodological assumptions, IVW results are more reliable in the absence of heterogeneity and pleiotropy. In the presence of heterogeneity but no pleiotropy, the WM method is more reliable. When pleiotropy exists, the MR-Egger method performs better (<xref ref-type="bibr" rid="ref7">Burgess and Thompson, 2017</xref>).</p>
<p>To satisfy the third assumption of MR and ensure the accuracy and stability of the results, further sensitivity analysis was conducted:</p>
<list list-type="order">
<list-item>
<p>Cochran&#x2019;s <italic>Q</italic> test is used to quantify the heterogeneity between SNPs. A <italic>p</italic>-value less than 0.05 indicates significant heterogeneity (<xref ref-type="bibr" rid="ref4">Bowden et al., 2019</xref>).</p>
</list-item>
<list-item>
<p>MR-PRESSO and MR-Egger regression tests are employed to detect potential horizontal pleiotropic effects. If the intercept term is significant, it means the existence of horizontal multiplicity. Compared to MR-Egger, MR-PRESSO offers higher accuracy (<xref ref-type="bibr" rid="ref65">Verbanck et al., 2018</xref>).</p>
</list-item>
<list-item>
<p>The leave-one-out sensitivity analysis is adopted to assess the stability of the results.</p>
</list-item>
</list>
</sec>
</sec>
<sec sec-type="results" id="sec13">
<label>3</label>
<title>Results</title>
<sec id="sec14">
<label>3.1</label>
<title>Instrumental variables selection</title>
<p>Detailed information for 3,509 IVs is presented in <xref ref-type="supplementary-material" rid="SM1">Supplementary Table S1</xref> (<italic>p</italic>-value&#x2009;&#x003C;&#x2009;1e&#x2212;5). These IVs are categorized into 9 phyla (121 SNPs, range 10&#x2013;18), 20 orders (275 SNPs, range 5&#x2013;19), 16 classes (219 SNPs, range 8&#x2013;22), 33 families (438 SNPs, range 5&#x2013;21), 119 genera (1,511 SNPs, range 3&#x2013;26), 105 species (945 SNPs, range 1&#x2013;17). The <italic>F</italic>-statistic of each IV was greater than 10 (<xref ref-type="supplementary-material" rid="SM1">Supplementary Table S1</xref>).</p>
</sec>
<sec id="sec15">
<label>3.2</label>
<title>Two-sample MR</title>
<p>We employed IVW as the primary analysis method for MR. The results indicate an association between the risk of PPD and 13 genetically predicted bacterial taxa (<xref ref-type="fig" rid="fig2">Figure 2</xref>). The results are presented in <xref ref-type="table" rid="tab2">Table 2</xref>.</p>
<fig position="float" id="fig2">
<label>Figure 2</label>
<caption>
<p>Forrest plot results from MR between the gut microbiota and PPD risk.</p>
</caption>
<graphic xlink:href="fmicb-15-1415237-g002.tif"/>
</fig>
<table-wrap position="float" id="tab2">
<label>Table 2</label>
<caption>
<p>Full result of MR estimates for the association between gut microbiota and PPD.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="top">Level</th>
<th align="left" valign="top">Bacterial taxa</th>
<th align="left" valign="top">Method</th>
<th align="center" valign="top">nSNP</th>
<th align="center" valign="top">Bate</th>
<th align="center" valign="top">SE</th>
<th align="center" valign="top">OR (95% CI)</th>
<th align="center" valign="top"><italic>p</italic>-value</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="middle" rowspan="5">Class</td>
<td align="left" valign="middle" rowspan="5">Alphaproteobacteria</td>
<td align="left" valign="middle">MR Egger</td>
<td align="center" valign="middle" rowspan="5">7</td>
<td align="center" valign="middle">0.595</td>
<td align="center" valign="middle">0.358</td>
<td align="center" valign="middle">1.812 (0.898&#x2013;3.656)</td>
<td align="center" valign="middle">0.158</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted median</td>
<td align="center" valign="middle">0.177</td>
<td align="center" valign="middle">0.121</td>
<td align="center" valign="middle">1.194 (0.943&#x2013;1.513)</td>
<td align="center" valign="middle">0.142</td>
</tr>
<tr>
<td align="left" valign="middle">Inverse variance weighted</td>
<td align="center" valign="middle">0.196</td>
<td align="center" valign="middle">0.096</td>
<td align="center" valign="middle">1.216 (1.008&#x2013;1.468)</td>
<td align="center" valign="middle">0.041</td>
</tr>
<tr>
<td align="left" valign="middle">Simple mode</td>
<td align="center" valign="middle">0.165</td>
<td align="center" valign="middle">0.178</td>
<td align="center" valign="middle">1.179 (0.832&#x2013;1.671)</td>
<td align="center" valign="middle">0.390</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted mode</td>
<td align="center" valign="middle">0.181</td>
<td align="center" valign="middle">0.170</td>
<td align="center" valign="middle">1.198 (0.86&#x2013;1.671)</td>
<td align="center" valign="middle">0.327</td>
</tr>
<tr>
<td align="left" valign="middle" rowspan="5">family</td>
<td align="left" valign="middle" rowspan="5">Clostridiales vadin BB60 group</td>
<td align="left" valign="middle">MR Egger</td>
<td align="center" valign="middle" rowspan="5">15</td>
<td align="center" valign="middle">&#x2212;0.010</td>
<td align="center" valign="middle">0.257</td>
<td align="center" valign="middle">0.99 (0.598&#x2013;1.639)</td>
<td align="center" valign="middle">0.970</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted median</td>
<td align="center" valign="middle">&#x2212;0.200</td>
<td align="center" valign="middle">0.099</td>
<td align="center" valign="middle">0.819 (0.675&#x2013;0.994)</td>
<td align="center" valign="middle">0.043</td>
</tr>
<tr>
<td align="left" valign="middle">Inverse variance weighted</td>
<td align="center" valign="middle">&#x2212;0.188</td>
<td align="center" valign="middle">0.093</td>
<td align="center" valign="middle">0.829 (0.691&#x2013;0.994)</td>
<td align="center" valign="middle">0.043</td>
</tr>
<tr>
<td align="left" valign="middle">Simple mode</td>
<td align="center" valign="middle">&#x2212;0.226</td>
<td align="center" valign="middle">0.141</td>
<td align="center" valign="middle">0.798 (0.606&#x2013;1.051)</td>
<td align="center" valign="middle">0.131</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted mode</td>
<td align="center" valign="middle">&#x2212;0.208</td>
<td align="center" valign="middle">0.121</td>
<td align="center" valign="middle">0.813 (0.641&#x2013;1.03)</td>
<td align="center" valign="middle">0.108</td>
</tr>
<tr>
<td align="left" valign="middle" rowspan="5">family</td>
<td align="left" valign="middle" rowspan="5">Veillonellaceae</td>
<td align="left" valign="middle">MR Egger</td>
<td align="center" valign="middle" rowspan="5">19</td>
<td align="center" valign="middle">&#x2212;0.258</td>
<td align="center" valign="middle">0.141</td>
<td align="center" valign="middle">0.773 (0.586&#x2013;1.019)</td>
<td align="center" valign="middle">0.085</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted median</td>
<td align="center" valign="middle">&#x2212;0.234</td>
<td align="center" valign="middle">0.105</td>
<td align="center" valign="middle">0.791 (0.644&#x2013;0.971)</td>
<td align="center" valign="middle">0.025</td>
</tr>
<tr>
<td align="left" valign="middle">Inverse variance weighted</td>
<td align="center" valign="middle">&#x2212;0.199</td>
<td align="center" valign="middle">0.070</td>
<td align="center" valign="middle">0.819 (0.715&#x2013;0.939)</td>
<td align="center" valign="middle">0.004</td>
</tr>
<tr>
<td align="left" valign="middle">Simple mode</td>
<td align="center" valign="middle">&#x2212;0.334</td>
<td align="center" valign="middle">0.173</td>
<td align="center" valign="middle">0.716 (0.51&#x2013;1.005)</td>
<td align="center" valign="middle">0.069</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted mode</td>
<td align="center" valign="middle">&#x2212;0.270</td>
<td align="center" valign="middle">0.123</td>
<td align="center" valign="middle">0.764 (0.6&#x2013;0.973)</td>
<td align="center" valign="middle">0.042</td>
</tr>
<tr>
<td align="left" valign="middle" rowspan="5">genus</td>
<td align="left" valign="middle" rowspan="5"><italic>FamilyXIIIAD3011 group</italic></td>
<td align="left" valign="middle">MR Egger</td>
<td align="center" valign="middle" rowspan="5">13</td>
<td align="center" valign="middle">&#x2212;0.078</td>
<td align="center" valign="middle">0.427</td>
<td align="center" valign="middle">0.925 (0.401&#x2013;2.134)</td>
<td align="center" valign="middle">0.859</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted median</td>
<td align="center" valign="middle">0.234</td>
<td align="center" valign="middle">0.120</td>
<td align="center" valign="middle">1.263 (0.999&#x2013;1.598)</td>
<td align="center" valign="middle">0.051</td>
</tr>
<tr>
<td align="left" valign="middle">Inverse variance weighted</td>
<td align="center" valign="middle">0.213</td>
<td align="center" valign="middle">0.091</td>
<td align="center" valign="middle">1.237 (1.036&#x2013;1.478)</td>
<td align="center" valign="middle">0.019</td>
</tr>
<tr>
<td align="left" valign="middle">Simple mode</td>
<td align="center" valign="middle">0.309</td>
<td align="center" valign="middle">0.208</td>
<td align="center" valign="middle">1.362 (0.906&#x2013;2.048)</td>
<td align="center" valign="middle">0.163</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted mode</td>
<td align="center" valign="middle">0.301</td>
<td align="center" valign="middle">0.184</td>
<td align="center" valign="middle">1.352 (0.943&#x2013;1.938)</td>
<td align="center" valign="middle">0.127</td>
</tr>
<tr>
<td align="left" valign="middle" rowspan="5">genus</td>
<td align="left" valign="middle" rowspan="5"><italic>Roseburia</italic></td>
<td align="left" valign="middle">MR Egger</td>
<td align="center" valign="middle" rowspan="5">14</td>
<td align="center" valign="middle">0.472</td>
<td align="center" valign="middle">0.297</td>
<td align="center" valign="middle">1.604 (0.896&#x2013;2.872)</td>
<td align="center" valign="middle">0.138</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted median</td>
<td align="center" valign="middle">0.234</td>
<td align="center" valign="middle">0.138</td>
<td align="center" valign="middle">1.264 (0.965&#x2013;1.655)</td>
<td align="center" valign="middle">0.088</td>
</tr>
<tr>
<td align="left" valign="middle">Inverse variance weighted</td>
<td align="center" valign="middle">0.211</td>
<td align="center" valign="middle">0.097</td>
<td align="center" valign="middle">1.235 (1.021&#x2013;1.493)</td>
<td align="center" valign="middle">0.030</td>
</tr>
<tr>
<td align="left" valign="middle">Simple mode</td>
<td align="center" valign="middle">0.207</td>
<td align="center" valign="middle">0.243</td>
<td align="center" valign="middle">1.23 (0.764&#x2013;1.981)</td>
<td align="center" valign="middle">0.410</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted mode</td>
<td align="center" valign="middle">0.240</td>
<td align="center" valign="middle">0.223</td>
<td align="center" valign="middle">1.271 (0.82&#x2013;1.969)</td>
<td align="center" valign="middle">0.302</td>
</tr>
<tr>
<td align="left" valign="middle" rowspan="5">genus</td>
<td align="left" valign="middle" rowspan="5"><italic>Ruminococcaceae UCG 011</italic></td>
<td align="left" valign="middle">MR Egger</td>
<td align="center" valign="middle" rowspan="5">8</td>
<td align="center" valign="middle">0.230</td>
<td align="center" valign="middle">0.279</td>
<td align="center" valign="middle">1.258 (0.728&#x2013;2.175)</td>
<td align="center" valign="middle">0.442</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted median</td>
<td align="center" valign="middle">&#x2212;0.158</td>
<td align="center" valign="middle">0.078</td>
<td align="center" valign="middle">0.854 (0.733&#x2013;0.994)</td>
<td align="center" valign="middle">0.042</td>
</tr>
<tr>
<td align="left" valign="middle">Inverse variance weighted</td>
<td align="center" valign="middle">&#x2212;0.168</td>
<td align="center" valign="middle">0.056</td>
<td align="center" valign="middle">0.845 (0.757&#x2013;0.944)</td>
<td align="center" valign="middle">0.003</td>
</tr>
<tr>
<td align="left" valign="middle">Simple mode</td>
<td align="center" valign="middle">&#x2212;0.152</td>
<td align="center" valign="middle">0.111</td>
<td align="center" valign="middle">0.859 (0.692&#x2013;1.068)</td>
<td align="center" valign="middle">0.213</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted mode</td>
<td align="center" valign="middle">&#x2212;0.145</td>
<td align="center" valign="middle">0.111</td>
<td align="center" valign="middle">0.865 (0.696&#x2013;1.074)</td>
<td align="center" valign="middle">0.231</td>
</tr>
<tr>
<td align="left" valign="middle" rowspan="5">species</td>
<td align="left" valign="middle" rowspan="5"><italic>Bifidobacterium adolescentis</italic></td>
<td align="left" valign="middle">MR Egger</td>
<td align="center" valign="middle" rowspan="5">10</td>
<td align="center" valign="middle">&#x2212;0.109</td>
<td align="center" valign="middle">0.220</td>
<td align="center" valign="middle">0.896 (0.583&#x2013;1.379)</td>
<td align="center" valign="middle">0.632</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted median</td>
<td align="center" valign="middle">&#x2212;0.144</td>
<td align="center" valign="middle">0.080</td>
<td align="center" valign="middle">0.866 (0.741&#x2013;1.012)</td>
<td align="center" valign="middle">0.070</td>
</tr>
<tr>
<td align="left" valign="middle">Inverse variance weighted</td>
<td align="center" valign="middle">&#x2212;0.159</td>
<td align="center" valign="middle">0.058</td>
<td align="center" valign="middle">0.853 (0.761&#x2013;0.956)</td>
<td align="center" valign="middle">0.006</td>
</tr>
<tr>
<td align="left" valign="middle">Simple mode</td>
<td align="center" valign="middle">&#x2212;0.086</td>
<td align="center" valign="middle">0.130</td>
<td align="center" valign="middle">0.917 (0.711&#x2013;1.184)</td>
<td align="center" valign="middle">0.524</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted mode</td>
<td align="center" valign="middle">&#x2212;0.112</td>
<td align="center" valign="middle">0.113</td>
<td align="center" valign="middle">0.894 (0.716&#x2013;1.115)</td>
<td align="center" valign="middle">0.346</td>
</tr>
<tr>
<td align="left" valign="middle" rowspan="5">Species</td>
<td align="left" valign="middle" rowspan="5"><italic>Paraprevotella clara</italic></td>
<td align="left" valign="middle">MR Egger</td>
<td align="center" valign="middle" rowspan="5">12</td>
<td align="center" valign="middle">0.154</td>
<td align="center" valign="middle">0.186</td>
<td align="center" valign="middle">1.166 (0.81&#x2013;1.679)</td>
<td align="center" valign="middle">0.428</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted median</td>
<td align="center" valign="middle">&#x2212;0.102</td>
<td align="center" valign="middle">0.062</td>
<td align="center" valign="middle">0.903 (0.8&#x2013;1.02)</td>
<td align="center" valign="middle">0.099</td>
</tr>
<tr>
<td align="left" valign="middle">Inverse variance weighted</td>
<td align="center" valign="middle">&#x2212;0.103</td>
<td align="center" valign="middle">0.046</td>
<td align="center" valign="middle">0.902 (0.825&#x2013;0.987)</td>
<td align="center" valign="middle">0.025</td>
</tr>
<tr>
<td align="left" valign="middle">Simple mode</td>
<td align="center" valign="middle">&#x2212;0.205</td>
<td align="center" valign="middle">0.122</td>
<td align="center" valign="middle">0.815 (0.641&#x2013;1.035)</td>
<td align="center" valign="middle">0.121</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted mode</td>
<td align="center" valign="middle">&#x2212;0.203</td>
<td align="center" valign="middle">0.116</td>
<td align="center" valign="middle">0.816 (0.65&#x2013;1.025)</td>
<td align="center" valign="middle">0.108</td>
</tr>
<tr>
<td align="left" valign="middle" rowspan="5">Species</td>
<td align="left" valign="middle" rowspan="5"><italic>Alistipes onderdonkii</italic></td>
<td align="left" valign="middle">MR Egger</td>
<td align="center" valign="middle" rowspan="5">7</td>
<td align="center" valign="middle">&#x2212;0.085</td>
<td align="center" valign="middle">0.451</td>
<td align="center" valign="middle">0.919 (0.379&#x2013;2.225)</td>
<td align="center" valign="middle">0.859</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted median</td>
<td align="center" valign="middle">0.093</td>
<td align="center" valign="middle">0.119</td>
<td align="center" valign="middle">1.097 (0.87&#x2013;1.385)</td>
<td align="center" valign="middle">0.434</td>
</tr>
<tr>
<td align="left" valign="middle">Inverse variance weighted</td>
<td align="center" valign="middle">0.183</td>
<td align="center" valign="middle">0.088</td>
<td align="center" valign="middle">1.201 (1.011&#x2013;1.427)</td>
<td align="center" valign="middle">0.038</td>
</tr>
<tr>
<td align="left" valign="middle">Simple mode</td>
<td align="center" valign="middle">0.038</td>
<td align="center" valign="middle">0.188</td>
<td align="center" valign="middle">1.039 (0.719&#x2013;1.501)</td>
<td align="center" valign="middle">0.845</td>
</tr>
<tr>
<td align="left" valign="middle">Weighted mode</td>
<td align="center" valign="top">0.036</td>
<td align="center" valign="top">0.193</td>
<td align="center" valign="top">1.037 (0.71&#x2013;1.515)</td>
<td align="center" valign="top">0.858</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="5">Species</td>
<td align="left" valign="top" rowspan="5"><italic>Clostridium leptum</italic></td>
<td align="left" valign="top">MR Egger</td>
<td align="center" valign="top" rowspan="5">6</td>
<td align="center" valign="top">0.191</td>
<td align="center" valign="top">0.438</td>
<td align="center" valign="top">1.211 (0.513&#x2013;2.857)</td>
<td align="center" valign="top">0.685</td>
</tr>
<tr>
<td align="left" valign="top">Weighted median</td>
<td align="center" valign="top">&#x2212;0.107</td>
<td align="center" valign="top">0.079</td>
<td align="center" valign="top">0.899 (0.77&#x2013;1.049)</td>
<td align="center" valign="top">0.177</td>
</tr>
<tr>
<td align="left" valign="top">Inverse variance weighted</td>
<td align="center" valign="top">&#x2212;0.163</td>
<td align="center" valign="top">0.081</td>
<td align="center" valign="top">0.849 (0.724&#x2013;0.996)</td>
<td align="center" valign="top">0.044</td>
</tr>
<tr>
<td align="left" valign="top">Simple mode</td>
<td align="center" valign="top">&#x2212;0.094</td>
<td align="center" valign="top">0.111</td>
<td align="center" valign="top">0.91 (0.732&#x2013;1.131)</td>
<td align="center" valign="top">0.435</td>
</tr>
<tr>
<td align="left" valign="top">Weighted mode</td>
<td align="center" valign="top">&#x2212;0.064</td>
<td align="center" valign="top">0.109</td>
<td align="center" valign="top">0.938 (0.757&#x2013;1.161)</td>
<td align="center" valign="top">0.580</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="5">Species</td>
<td align="left" valign="top" rowspan="5"><italic>Eubacterium siraeum</italic></td>
<td align="left" valign="top">MR Egger</td>
<td align="center" valign="top" rowspan="5">12</td>
<td align="center" valign="top">&#x2212;0.421</td>
<td align="center" valign="top">0.328</td>
<td align="center" valign="top">0.656 (0.345&#x2013;1.249)</td>
<td align="center" valign="top">0.229</td>
</tr>
<tr>
<td align="left" valign="top">Weighted median</td>
<td align="center" valign="top">&#x2212;0.101</td>
<td align="center" valign="top">0.090</td>
<td align="center" valign="top">0.904 (0.757&#x2013;1.079)</td>
<td align="center" valign="top">0.265</td>
</tr>
<tr>
<td align="left" valign="top">Inverse variance weighted</td>
<td align="center" valign="top">&#x2212;0.158</td>
<td align="center" valign="top">0.072</td>
<td align="center" valign="top">0.854 (0.741&#x2013;0.984)</td>
<td align="center" valign="top">0.029</td>
</tr>
<tr>
<td align="left" valign="top">Simple mode</td>
<td align="center" valign="top">&#x2212;0.053</td>
<td align="center" valign="top">0.168</td>
<td align="center" valign="top">0.948 (0.683&#x2013;1.317)</td>
<td align="center" valign="top">0.757</td>
</tr>
<tr>
<td align="left" valign="top">Weighted mode</td>
<td align="center" valign="top">&#x2212;0.050</td>
<td align="center" valign="top">0.147</td>
<td align="center" valign="top">0.951 (0.713&#x2013;1.27)</td>
<td align="center" valign="top">0.741</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="5">Species</td>
<td align="left" valign="top" rowspan="5"><italic>Coprococcus catus</italic></td>
<td align="left" valign="top">MR Egger</td>
<td align="center" valign="top" rowspan="5">4</td>
<td align="center" valign="top">&#x2212;0.344</td>
<td align="center" valign="top">0.388</td>
<td align="center" valign="top">0.709 (0.331&#x2013;1.516)</td>
<td align="center" valign="top">0.469</td>
</tr>
<tr>
<td align="left" valign="top">Weighted median</td>
<td align="center" valign="top">&#x2212;0.256</td>
<td align="center" valign="top">0.126</td>
<td align="center" valign="top">0.774 (0.605&#x2013;0.99)</td>
<td align="center" valign="top">0.041</td>
</tr>
<tr>
<td align="left" valign="top">Inverse variance weighted</td>
<td align="center" valign="top">&#x2212;0.229</td>
<td align="center" valign="top">0.099</td>
<td align="center" valign="top">0.796 (0.656&#x2013;0.965)</td>
<td align="center" valign="top">0.020</td>
</tr>
<tr>
<td align="left" valign="top">Simple mode</td>
<td align="center" valign="top">&#x2212;0.271</td>
<td align="center" valign="top">0.168</td>
<td align="center" valign="top">0.763 (0.548&#x2013;1.061)</td>
<td align="center" valign="top">0.206</td>
</tr>
<tr>
<td align="left" valign="top">Weighted mode</td>
<td align="center" valign="top">&#x2212;0.289</td>
<td align="center" valign="top">0.150</td>
<td align="center" valign="top">0.749 (0.558&#x2013;1.005)</td>
<td align="center" valign="top">0.149</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="5">Species</td>
<td align="left" valign="top" rowspan="5"><italic>Bilophila wadsworthia</italic></td>
<td align="left" valign="top">MR Egger</td>
<td align="center" valign="top" rowspan="5">6</td>
<td align="center" valign="top">0.116</td>
<td align="center" valign="top">0.226</td>
<td align="center" valign="top">1.123 (0.721&#x2013;1.748)</td>
<td align="center" valign="top">0.636</td>
</tr>
<tr>
<td align="left" valign="top">Weighted median</td>
<td align="center" valign="top">0.163</td>
<td align="center" valign="top">0.100</td>
<td align="center" valign="top">1.177 (0.967&#x2013;1.432)</td>
<td align="center" valign="top">0.104</td>
</tr>
<tr>
<td align="left" valign="top">Inverse variance weighted</td>
<td align="center" valign="top">0.168</td>
<td align="center" valign="top">0.081</td>
<td align="center" valign="top">1.183 (1.01&#x2013;1.385)</td>
<td align="center" valign="top">0.038</td>
</tr>
<tr>
<td align="left" valign="top">Simple mode</td>
<td align="center" valign="top">0.157</td>
<td align="center" valign="top">0.130</td>
<td align="center" valign="top">1.17 (0.908&#x2013;1.508)</td>
<td align="center" valign="top">0.280</td>
</tr>
<tr>
<td align="left" valign="top">Weighted mode</td>
<td align="center" valign="top">0.161</td>
<td align="center" valign="top">0.133</td>
<td align="center" valign="top">1.175 (0.905&#x2013;1.525)</td>
<td align="center" valign="top">0.280</td>
</tr>
</tbody>
</table>
</table-wrap>
<p>Using the IVW method as the primary analysis, the results indicated that 13 bacterial taxa were associated with the risk of PPD when the significance level was less than 0.05. Specifically, the following taxa were inversely associated with the risk of PPD: Clostridiales vadin BB60 group, Veillonellaceae (at family level); <italic>Ruminococcaceae UCG 011</italic> (at genus level); <italic>Bifidobacterium adolescentis</italic>, <italic>Paraprevotella clara</italic>, <italic>Clostridium leptum</italic>, <italic>Eubacterium siraeum</italic>, <italic>Coprococcus catus</italic> (at species level). Whereas the following taxa may be associated with a higher risk of PPD: Alphaproteobacteria (at class level); <italic>FamilyXIIIAD3011 group, Roseburia</italic> (at genus level); <italic>Alistipes onderdonkii</italic>, <italic>Bilophila wadsworthia</italic> (at species level) (<xref ref-type="fig" rid="fig2">Figure 2</xref>; <xref ref-type="table" rid="tab2">Table 2</xref>). The scatter plots (<xref ref-type="supplementary-material" rid="SM1">Supplementary Figure S1</xref>) and forest plots (<xref ref-type="supplementary-material" rid="SM1">Supplementary Figure S2</xref>) of the above results demonstrate the stability of the findings.</p>
<p><xref ref-type="table" rid="tab3">Table 3</xref> shows that the instrumental variable of Clostridiales vadin BB60 group has a significant heterogeneity with the outcome by Cochran&#x2019;s <italic>Q</italic> test (<italic>p</italic>&#x2009;&#x003C;&#x2009;0.05), and the others were no significant heterogeneity identified among the SNPs (<italic>p</italic>&#x2009;&#x003E;&#x2009;0.05).</p>
<table-wrap position="float" id="tab3">
<label>Table 3</label>
<caption>
<p>The heterogeneity results from the Cochran&#x2019;s <italic>Q</italic> test.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="top" rowspan="2">No</th>
<th align="left" valign="top" rowspan="2">Level</th>
<th align="left" valign="top" rowspan="2">Bacterial taxa</th>
<th align="center" valign="top" colspan="2">MR-Egger</th>
<th align="center" valign="top" colspan="2">IVW</th>
</tr>
<tr>
<th align="center" valign="top"><italic>Q</italic></th>
<th align="center" valign="top"><italic>p</italic> value</th>
<th align="center" valign="top"><italic>Q</italic></th>
<th align="center" valign="top"><italic>p</italic> value</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top">1</td>
<td align="left" valign="top">Class</td>
<td align="left" valign="top">Alphaproteobacteria</td>
<td align="center" valign="top">0.866</td>
<td align="center" valign="top">0.973</td>
<td align="center" valign="top">2.202</td>
<td align="center" valign="top">0.900</td>
</tr>
<tr>
<td align="left" valign="top">2</td>
<td align="left" valign="top">Family</td>
<td align="left" valign="top">Clostridiales vadin BB60 group</td>
<td align="center" valign="top">24.069</td>
<td align="center" valign="top">0.031</td>
<td align="center" valign="top">25.092</td>
<td align="center" valign="top">0.034</td>
</tr>
<tr>
<td align="left" valign="top">3</td>
<td align="left" valign="top">Family</td>
<td align="left" valign="top">Veillonellaceae</td>
<td align="center" valign="top">14.444</td>
<td align="center" valign="top">0.635</td>
<td align="center" valign="top">14.673</td>
<td align="center" valign="top">0.684</td>
</tr>
<tr>
<td align="left" valign="top">4</td>
<td align="left" valign="top">Genus</td>
<td align="left" valign="top"><italic>FamilyXIIIAD3011 group</italic></td>
<td align="center" valign="top">7.184</td>
<td align="center" valign="top">0.784</td>
<td align="center" valign="top">7.671</td>
<td align="center" valign="top">0.810</td>
</tr>
<tr>
<td align="left" valign="top">5</td>
<td align="left" valign="top">Genus</td>
<td align="left" valign="top"><italic>Roseburia</italic></td>
<td align="center" valign="top">11.678</td>
<td align="center" valign="top">0.472</td>
<td align="center" valign="top">12.547</td>
<td align="center" valign="top">0.483</td>
</tr>
<tr>
<td align="left" valign="top">6</td>
<td align="left" valign="top">Genus</td>
<td align="left" valign="top"><italic>Ruminococcaceae UCG 011</italic></td>
<td align="center" valign="top">4.993</td>
<td align="center" valign="top">0.545</td>
<td align="center" valign="top">7.110</td>
<td align="center" valign="top">0.418</td>
</tr>
<tr>
<td align="left" valign="top">7</td>
<td align="left" valign="top">Species</td>
<td align="left" valign="top"><italic>Bifidobacterium adolescentis</italic></td>
<td align="center" valign="top">6.022</td>
<td align="center" valign="top">0.645</td>
<td align="center" valign="top">6.077</td>
<td align="center" valign="top">0.732</td>
</tr>
<tr>
<td align="left" valign="top">8</td>
<td align="left" valign="top">Species</td>
<td align="left" valign="top"><italic>Paraprevotella clara</italic></td>
<td align="center" valign="top">9.865</td>
<td align="center" valign="top">0.452</td>
<td align="center" valign="top">11.879</td>
<td align="center" valign="top">0.373</td>
</tr>
<tr>
<td align="left" valign="top">9</td>
<td align="left" valign="top">Species</td>
<td align="left" valign="top"><italic>Alistipes onderdonkii</italic></td>
<td align="center" valign="top">3.482</td>
<td align="center" valign="top">0.626</td>
<td align="center" valign="top">3.848</td>
<td align="center" valign="top">0.697</td>
</tr>
<tr>
<td align="left" valign="top">10</td>
<td align="left" valign="top">Species</td>
<td align="left" valign="top"><italic>Clostridium leptum</italic></td>
<td align="center" valign="top">9.267</td>
<td align="center" valign="top">0.055</td>
<td align="center" valign="top">10.847</td>
<td align="center" valign="top">0.055</td>
</tr>
<tr>
<td align="left" valign="top">11</td>
<td align="left" valign="top">Species</td>
<td align="left" valign="top"><italic>Eubacterium siraeum</italic></td>
<td align="center" valign="top">13.926</td>
<td align="center" valign="top">0.176</td>
<td align="center" valign="top">14.865</td>
<td align="center" valign="top">0.189</td>
</tr>
<tr>
<td align="left" valign="top">12</td>
<td align="left" valign="top">Species</td>
<td align="left" valign="top"><italic>Coprococcus catus</italic></td>
<td align="center" valign="top">0.803</td>
<td align="center" valign="top">0.669</td>
<td align="center" valign="top">0.898</td>
<td align="center" valign="top">0.826</td>
</tr>
<tr>
<td align="left" valign="top">13</td>
<td align="left" valign="top">Species</td>
<td align="left" valign="top"><italic>Bilophila wadsworthia</italic></td>
<td align="center" valign="top">1.168</td>
<td align="center" valign="top">0.883</td>
<td align="center" valign="top">1.229</td>
<td align="center" valign="top">0.942</td>
</tr>
</tbody>
</table>
</table-wrap>
<p><xref ref-type="table" rid="tab4">Table 4</xref> shows that there was no demonstrated pleiotropy detected in the MR Egger test (<italic>p</italic>&#x2009;&#x003C;&#x2009;0.05). MR-PRESSO suggests that Clostridiales vadin BB60 group has horizontal pleiotropy with outcome (<italic>p</italic>&#x2009;=&#x2009;0.04, <xref ref-type="table" rid="tab3">Table 3</xref>). According to the findings of the leave-one-out analysis, no SNPs were found to have affected causal association (<xref ref-type="supplementary-material" rid="SM1">Supplementary Figure S3</xref>).</p>
<table-wrap position="float" id="tab4">
<label>Table 4</label>
<caption>
<p>Pleiotropy results from Egger intercept and PRESSO analysis.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="top">No</th>
<th align="left" valign="top">Level</th>
<th align="left" valign="top">Bacterial taxa</th>
<th align="center" valign="top">Egger <italic>p</italic> value</th>
<th align="center" valign="top">PRESSO <italic>p</italic> value</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top">1</td>
<td align="left" valign="top">Class</td>
<td align="left" valign="top">Alphaproteobacteria</td>
<td align="center" valign="top">0.300</td>
<td align="center" valign="top">0.91</td>
</tr>
<tr>
<td align="left" valign="top">2</td>
<td align="left" valign="top">Family</td>
<td align="left" valign="top">Clostridiales vadin BB60 group</td>
<td align="center" valign="top">0.470</td>
<td align="center" valign="top">0.04</td>
</tr>
<tr>
<td align="left" valign="top">3</td>
<td align="left" valign="top">Family</td>
<td align="left" valign="top">Veillonellaceae</td>
<td align="center" valign="top">0.638</td>
<td align="center" valign="top">0.743</td>
</tr>
<tr>
<td align="left" valign="top">4</td>
<td align="left" valign="top">Genus</td>
<td align="left" valign="top"><italic>FamilyXIIIAD3011 group</italic></td>
<td align="center" valign="top">0.500</td>
<td align="center" valign="top">0.855</td>
</tr>
<tr>
<td align="left" valign="top">5</td>
<td align="left" valign="top">Genus</td>
<td align="left" valign="top"><italic>Roseburia</italic></td>
<td align="center" valign="top">0.370</td>
<td align="center" valign="top">0.502</td>
</tr>
<tr>
<td align="left" valign="top">6</td>
<td align="left" valign="top">Genus</td>
<td align="left" valign="top"><italic>Ruminococcaceae UCG 011</italic></td>
<td align="center" valign="top">0.196</td>
<td align="center" valign="top">0.501</td>
</tr>
<tr>
<td align="left" valign="top">7</td>
<td align="left" valign="top">Species</td>
<td align="left" valign="top"><italic>Bifidobacterium adolescentis</italic></td>
<td align="center" valign="top">0.820</td>
<td align="center" valign="top">0.756</td>
</tr>
<tr>
<td align="left" valign="top">8</td>
<td align="left" valign="top">Species</td>
<td align="left" valign="top"><italic>Paraprevotella clara</italic></td>
<td align="center" valign="top">0.186</td>
<td align="center" valign="top">0.414</td>
</tr>
<tr>
<td align="left" valign="top">9</td>
<td align="left" valign="top">Species</td>
<td align="left" valign="top"><italic>Alistipes onderdonkii</italic></td>
<td align="center" valign="top">0.572</td>
<td align="center" valign="top">0.700</td>
</tr>
<tr>
<td align="left" valign="top">10</td>
<td align="left" valign="top">Species</td>
<td align="left" valign="top"><italic>Clostridium leptum</italic></td>
<td align="center" valign="top">0.455</td>
<td align="center" valign="top">0.098</td>
</tr>
<tr>
<td align="left" valign="top">11</td>
<td align="left" valign="top">Species</td>
<td align="left" valign="top"><italic>Eubacterium siraeum</italic></td>
<td align="center" valign="top">0.431</td>
<td align="center" valign="top">0.228</td>
</tr>
<tr>
<td align="left" valign="top">12</td>
<td align="left" valign="top">Species</td>
<td align="left" valign="top"><italic>Coprococcus catus</italic></td>
<td align="center" valign="top">0.788</td>
<td align="center" valign="top">0.803</td>
</tr>
<tr>
<td align="left" valign="top">13</td>
<td align="left" valign="top">Species</td>
<td align="left" valign="top"><italic>Bilophila wadsworthia</italic></td>
<td align="center" valign="top">0.818</td>
<td align="center" valign="top">0.956</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
</sec>
<sec sec-type="discussion" id="sec16">
<label>4</label>
<title>Discussion</title>
<p>Our MR analysis further illuminated a nominal causal bond linking PPD with 13 distinct microbial taxa. To ensure the transparency and completeness of our Mendelian Randomization study report, we adopted the STROBE-MR guidelines (<xref ref-type="supplementary-material" rid="SM1">Supplementary Table S2</xref>). STROBE-MR is a set of reporting guidelines specifically designed for Mendelian Randomization studies, consisting of 20 items. We have provided the complete STROBE-MR checklist in the appendix for readers&#x2019; reference.</p>
<p>Observational research findings indicate a decrease in the abundance of the <italic>Faecalibacterium</italic> genus in patients with PPD (<xref ref-type="bibr" rid="ref76">Zhou et al., 2020</xref>), a phenomenon that aligns with the negative correlation we observed with <italic>Ruminococcaceae UCG 011</italic> through our MR analysis. <italic>Ruminococcaceae</italic> portray a noticeable reduction in individuals with pronounced depression (<xref ref-type="bibr" rid="ref51">Radjabzadeh et al., 2022</xref>). In the realm of animal studies, they exhibit a positive association with vital sugar metabolic cascades, such as gluconeogenesis, glycolysis, and the pentose phosphate trajectory (<xref ref-type="bibr" rid="ref74">Zhang et al., 2019</xref>). Given that obesity is one of the comorbidities of depression, we hypothesize that it might indirectly affect PPD. Within <italic>Ruminococcaceae</italic>, <italic>Faecalibacterium prausnitzii</italic> is one of the main bacteria in the human gut and converts acetate to butyrate through the butyryl-CoA: acetate CoA-transferase (<xref ref-type="bibr" rid="ref13">Duncan et al., 2002</xref>). This mechanism could potentially account for the diminished abundance of the <italic>Faecalibacterium</italic> genus observed in patients with PPD.</p>
<p>Previous MR studies on the gut microbiota and MDD indicated that the Actinobacteria class, <italic>Bifidobacterium</italic> genus, and <italic>Ruminococcus1</italic> genus had a protective effect against MDD (<xref ref-type="bibr" rid="ref8">Chen et al., 2022</xref>). This aligns with our findings for <italic>Ruminococcaceae UCG 011</italic> (OR 0.845, 95%CI 0.757&#x2013;0.944) and <italic>Bifidobacterium adolescentis</italic> (OR 0.853, 95%CI 0.761&#x2013;0.956). <italic>Bifidobacterium</italic>, the most common microbe within Actinobacteria in the human gut, is also a widely-used probiotic. A study demonstrated that <italic>Bifidobacterium</italic> can alleviate depression and gut-related diseases by altering the gut microbiota and its tryptophan metabolism (<xref ref-type="bibr" rid="ref61">Tian et al., 2022</xref>). Postpartum, women experience an increase in the abundance of <italic>Bifidobacterium</italic>, a change that may also enhance the production of short-chain fatty acids, thereby aiding in the establishment and refinement of the neonatal gut microbiota environment (<xref ref-type="bibr" rid="ref49">Qin et al., 2022</xref>). Given the symptomatic similarities between PPD and MDD, <italic>Bifidobacterium</italic> may also have the potential to treat or prevent PPD.</p>
<p>Research has shown that good mental health in mothers can reduce anxiety and mitigate stress responses, which is crucial for the successful delivery and upbringing of offspring (<xref ref-type="bibr" rid="ref23">Hillerer et al., 2011</xref>). The hippocampus, a limbic structure involved in emotion and cognition, plays a critical role in these processes. Within the hippocampus, brain-derived neurotrophic factor (BDNF) and its receptor, TrkB (tyrosine kinase receptor B), are directly involved in various physiological functions of the central nervous system, such as neuronal survival, synaptic plasticity, and learning and memory (<xref ref-type="bibr" rid="ref33">Leibrock et al., 1989</xref>; <xref ref-type="bibr" rid="ref66">von Bohlen und Halbach, 2010</xref>). During pregnancy, if a mother is subjected to chronic stress or chronic restraint stress (CRS), the expression of BDNF and TrkB in the hippocampus can be significantly reduced. This reduction is believed to be one of the contributing factors to the high incidence of depression during pregnancy and postpartum (<xref ref-type="bibr" rid="ref72">Ye et al., 2011</xref>). Notably, repeated restraint stress in the final week of pregnancy can induce depressive-like behaviors in mothers (<xref ref-type="bibr" rid="ref44">O'Mahony et al., 2006</xref>).</p>
<p>The administration of <italic>Bifidobacterium adolescentis</italic> in mice subjected to CRS not only reduces anxiety and depressive-like behaviors and increases BDNF expression levels, but also reverses the dysbiosis of the gut microbiota induced by CRS (<xref ref-type="bibr" rid="ref19">Guo et al., 2019</xref>). Additionally, <italic>Bifidobacterium longum</italic> has been shown to significantly reduce depressive-like behaviors in the forced swim test (FST) and decrease anxiety-like behaviors in the open field test (OFT) (<xref ref-type="bibr" rid="ref53">Savignac et al., 2014</xref>). The combined use of <italic>Bifidobacterium longum</italic> and <italic>Lactobacillus helveticus</italic> has been found to alleviate symptoms of anxiety and depression in healthy individuals (<xref ref-type="bibr" rid="ref50">Radford-Smith and Anthony, 2023</xref>).</p>
<p>Within the MR assessment, particular bacterial groups, Veillonellaceae (OR 0.819, 95%CI 0.715&#x2013;0.939), <italic>Paraprevotella clara</italic> (OR 0.902, 95%CI 0.825&#x2013;0.987), <italic>Clostridium leptum</italic> (OR 0.849, 95%CI 0.724&#x2013;0.996), <italic>Eubacterium siraeum</italic> (OR 0.854, 95%CI 0.741&#x2013;0.984), <italic>Coprococcus catus</italic> (OR 0.796, 95%CI 0.656&#x2013;0.965), emerged as potentially protective entities.</p>
<p>Veillonellaceae, as non-fermentative microbes, distinguish themselves with their propensity to modulate the enzymatic activity of methylmalonyl-CoA decarboxylase, thereby playing a pivotal role in fatty acid metabolism. Noteworthy is their marked depletion in autism-afflicted individuals, potentially influencing lactate fermentation and specific short-chain fatty acid synthesis (<xref ref-type="bibr" rid="ref18">Gronow et al., 2010</xref>; <xref ref-type="bibr" rid="ref67">Wang et al., 2023</xref>). They also show a negative correlation with psychological stress (<xref ref-type="bibr" rid="ref39">Ma et al., 2023</xref>).</p>
<p><italic>Paraprevotella clara</italic> can reduce the levels of trypsin in the colon, thereby decreasing the likelihood of developing inflammatory bowel diseases, while also offering protection against certain viral infections in the colon (<xref ref-type="bibr" rid="ref34">Li et al., 2022</xref>). Intestinal inflammation may reduce gut permeability, leading to the translocation of microbes originally present in the intestinal tract into the peripheral circulation, thereby disrupting normal brain function and affecting specific behaviors (<xref ref-type="bibr" rid="ref12">D'Mello et al., 2015</xref>). This is consistent with our research findings that <italic>Paraprevotella clara</italic> exhibits a negative correlation with PPD.</p>
<p>Due to a lack of experimental studies, the mechanisms by which <italic>Clostridium leptum</italic>, <italic>Coprococcus catus</italic>, and <italic>Eubacterium siraeum</italic> affect PPD remain unclear. In a survey study of 1,070 patients with depression, <italic>Coprococcus</italic> was found to be nearly depleted in individuals with depression. <italic>Coprococcus</italic> possesses biosynthetic pathways related to dopamine synthesis and participates in the synthesis of GABA, improving the quality of psychological life (<xref ref-type="bibr" rid="ref63">Valles-Colomer et al., 2019</xref>). <italic>Clostridium leptum</italic> is associated with glucose metabolism (<xref ref-type="bibr" rid="ref45">Palmnas-Bedard et al., 2022</xref>), leading us to speculate that <italic>Clostridium leptum</italic> may be related to GABA produced during the body&#x2019;s glucose metabolic processes. However, this hypothesis has not yet been validated.</p>
<p>Five positive results were identified: Alphaproteobacteria (OR 1.216, 95%CI 1.008&#x2013;1.468), <italic>Roseburia</italic> (OR 1.235, 95%CI 1.021&#x2013;1.493), <italic>FamilyXIIIAD3011group</italic> (OR 1.237, 95%CI 1.036&#x2013;1.478), <italic>Alistipes onderdonkii</italic> (OR 1.201, 95%CI 1.011&#x2013;1.427), <italic>Bilophila wadsworthia</italic> (OR 1.183, 95%CI 1.01&#x2013;1.385). A surge in Alphaproteobacteria&#x2019;s presence typically heralds a perturbation in the gut&#x2019;s ecological equilibrium (<xref ref-type="bibr" rid="ref35">Litvak et al., 2017</xref>). Previous research insights spotlight Rhodospirillaceae, a member of the Alphaproteobacteria phylum, underscoring its positive correlation with the genesis of Alzheimer&#x2019;s disease (<xref ref-type="bibr" rid="ref77">Zhou et al., 2021</xref>). Therefore, we infer that an increase in the abundance of Alphaproteobacteria may signal changes in the gut ecological environment, thereby affecting the normal growth of other bacterial communities and the composition of their metabolic products.</p>
<p><italic>Roseburia</italic> stands as a significant regulator in the realms of gut microbiota ecology, immune modulation, and neurological afflictions. Within this genus, five species notably dominate: <italic>Roseburia intestinalis</italic>, <italic>R. hominis</italic>, <italic>R. inulinivorans</italic>, <italic>R. faecis</italic>, and <italic>R. cecicola</italic> (<xref ref-type="bibr" rid="ref59">Tamanai-Shacoori et al., 2017</xref>). Of these, <italic>R. intestinalis</italic> holds a particular distinction, constituting between 0.9 and 5.0% of the entire microbial community and acting as the chief butyrate producer (<xref ref-type="bibr" rid="ref25">Hold et al., 2003</xref>). In an insightful study, colitis-afflicted rats treated with <italic>R. intestinalis</italic> demonstrated a diminished display of anxiety and depressive-like symptoms. The underlying mechanism could be <italic>R. intestinalis</italic>&#x2019; influence on 5-hydroxytryptamine (5-HT) expression in colonic regions. As a neurotransmitter, 5-HT plays a pivotal role in mediating the gut-brain axis, influencing brain functionality (<xref ref-type="bibr" rid="ref69">Xu et al., 2021</xref>). While the abundance of <italic>R. intestinalis</italic> is lower in patients with depression compared to the healthy population (<xref ref-type="bibr" rid="ref75">Zheng et al., 2016</xref>), other studies have shown a higher abundance of <italic>R. intestinalis</italic> in patients with MDD compared to healthy individuals (<xref ref-type="bibr" rid="ref27">Jiang et al., 2015</xref>). These findings highlight that while <italic>Roseburia</italic> does play a role in neurological diseases, its interaction mechanisms are intricate. Furthermore, Reserpine can inhibit the central nervous system&#x2019;s regular functions by altering catecholamines and 5-HT levels in brain tissues, leading to depressive behaviors (<xref ref-type="bibr" rid="ref71">Yan et al., 2023</xref>). Taking into account <italic>Roseburia</italic>&#x2019;s position as a positive determinant in our MR analysis, it&#x2019;s plausible to hypothesize that an overabundance of <italic>Roseburia</italic> might interfere with levels of serotonergic depression markers like 5-HT, thereby affecting the functionality of the nervous system.</p>
<p>An increase in the abundance of <italic>Bilophila wadsworthia</italic> can disrupt hippocampal synaptic plasticity, neurogenesis, and gene expression. Ketogenic diets and hypoxic environments can alter the abundance of <italic>Bilophila wadsworthia</italic>, thereby impairing cognitive behavior (<xref ref-type="bibr" rid="ref43">Olson et al., 2021</xref>). However, some studies have found that ketogenic diets can increase GABA levels. Currently, there is no definitive clinical data to indicate whether ketogenic diets can improve or exacerbate PPD (<xref ref-type="bibr" rid="ref68">Wlodarczyk et al., 2021</xref>).</p>
<p><italic>Alistipes onderdonkii</italic> is a relatively new bacterium identified to increase in abundance under conditions of high stress or prolonged fatigue. PPD often involves extended periods of battling fatigue or stress. The increase in <italic>Alistipes</italic> decreases serotonin availability and disrupts the gut-brain axis (<xref ref-type="bibr" rid="ref47">Parker et al., 2020</xref>).</p>
<p>Previous research has conducted numerous analyses on the association between the gut microbiome and psychiatric disorders. Although PPD shares certain symptomatic and genetic similarities with other mental health conditions, the pathogenesis of PPD is influenced by multiple factors, particularly fluctuations in hormone levels. Therefore, our MR analysis has the potential to reveal more causal relationships, paving the way for future research into bacterial biosensor detection and therapeutic interventions for related diseases.</p>
<p>This study possesses several strengths and limitations. Employing the MR method to analyze the causal relationship between PPD and the gut microbiota minimizes interference from confounding factors. Techniques such as MR-PRESSO and MR-Egger were utilized to eliminate the effects of horizontal pleiotropy and heterogeneity, ensuring the accuracy of the results. This study refined the classification of the gut microbiome down to the species level, making the results more comprehensive and detailed compared to previous research. However, the study also has its limitations; the GWAS data derived from the MiBioGen consortium, DMP, and FinnGen consortium, may introduce selection bias. Moreover, the data primarily originates from European populations, hence extrapolating these results to diverse populations should be approached with caution. The etiological factors behind PPD remain enigmatic, alluding to the existence of potential undisclosed confounders. Despite employing various methods for sensitivity analysis, the impact of horizontal pleiotropy could not be fully assessed. Lastly, <italic>in vitro</italic> experimental validation was not conducted. In future studies, we will strengthen the functional validation through related experiments to further substantiate our research findings.</p>
<p>In conclusion, with the continuous development of medical statistical techniques and the refinement of GWAS data, future studies should focus on the integrated development of multiple disciplines and omics, exploring complex diseases, genetic variations, and environmental changes at various levels of interaction.</p>
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</body>
<back>
<sec sec-type="data-availability" id="sec17">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/<xref ref-type="supplementary-material" rid="SM1">Supplementary material</xref>, further inquiries can be directed to the corresponding author.</p>
</sec>
<sec sec-type="author-contributions" id="sec18">
<title>Author contributions</title>
<p>WJ: Writing &#x2013; review &#x0026; editing, Data curation, Formal analysis. BL: Conceptualization, Writing &#x2013; original draft, Formal analysis, Writing &#x2013; review &#x0026; editing. LW: Supervision, Writing &#x2013; original draft. LZ: Writing &#x2013; review &#x0026; editing, Visualization. SC: Methodology, Writing &#x2013; review &#x0026; editing. RH: Supervision, Writing &#x2013; review &#x0026; editing.</p>
</sec>
<sec sec-type="funding-information" id="sec19">
<title>Funding</title>
<p>The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the 2019 Henan Province Private Higher Education Brand Professional Support Project.</p>
</sec>
<ack>
<p>We thank the FinnGen consortium, MiBioGen consortium and the Dutch Microbiome Project for sharing the genetic data.</p>
</ack>
<sec sec-type="COI-statement" id="sec20">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec sec-type="disclaimer" id="sec21">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<sec sec-type="supplementary-material" id="sec22">
<title>Supplementary material</title>
<p>The Supplementary material for this article can be found online at: <ext-link xlink:href="https://www.frontiersin.org/articles/10.3389/fmicb.2024.1415237/full#supplementary-material" ext-link-type="uri">https://www.frontiersin.org/articles/10.3389/fmicb.2024.1415237/full#supplementary-material</ext-link></p>
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<supplementary-material xlink:href="Data_Sheet_1.DOCX" id="SM3" mimetype="application/vnd.openxmlformats-officedocument.wordprocessingml.document" xmlns:xlink="http://www.w3.org/1999/xlink"/>
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