ORIGINAL RESEARCH

published: 18 February 2021

doi: 10.3389/fgene.2021.631061

Assessment of Causal Direction

Between Gut Microbiota and
Inflammatory Bowel Disease: A
Mendelian Randomization Analysis
Zi-Jia Zhang 1,2,3 , Hong-Lei Qu 4 , Na Zhao 3 , Jing Wang 3 , Xiu-Yan Wang 3 , Rong Hai 3,5* and
Bin Li 1*
1
Department of General Surgery, Suzhou Ninth People’s Hospital, Suzhou, China, 2 Inner Mongolia Medical University,
Hohhot, China, 3 Inner Mongolia Autonomous Region People’s Hospital, Hohhot, China, 4 Suzhou Hospital of Anhui Medical
University, Anhui, China, 5 Inner Mongolia Autonomous Region Health Management Service Center, Hohhot, China

Background: Recent studies have shown that the gut microbiota is closely related to
the pathogenesis of Inflammatory Bowel Disease (IBD), but the causal nature is largely
unknown. The purpose of this study was to assess the causal relationship between
intestinal bacteria and IBD and to identify specific pathogenic bacterial taxa via the
Mendelian randomization (MR) analysis.
Edited by:
Materials and Methods: MR analysis was performed on genome-wide association
Lei Zhang,
Soochow University, China study (GWAS) summary statistics of gut microbiota and IBD. Specifically, the TwinsUK
Reviewed by: microbiota GWAS (N = 1,126 twin pairs) was used as exposure. The UK inflammatory
Feng Zhang, bowel disease (UKIBD) and the Understanding Social Program (USP) study GWAS
Xi’an Jiaotong University, China
Sumei Xiao, (N = 48,328) was used as discovery outcome, and the British IBD study (N = 35,289)
Sun Yat-sen University, China was used as replication outcome. SNPs associated with bacteria abundance at the
*Correspondence: suggestive significance level (α = 1.0 × 10−5 ) were used as instrumental variables.
Bin Li
Bacteria were grouped into families and genera.
[email protected]
Rong Hai
Results: In the discovery sample, a total of 30 features were available for analysis,
[email protected]
including 15 families and 15 genera. Three features were nominally significant, including
Specialty section: one family (Verrucomicrobiaceae, 2 IVs, beta = −0.04, p = 0.05) and two genera
This article was submitted to
(Akkermansia, 2 IVs, beta = 0.04, p = 0.05; Dorea, 2 IVs, beta = −0.07, p = 0.04). All of
Statistical Genetics and Methodology,
a section of the journal them were successfully replicated in the replication sample (Verrucomicrobiaceae and
Frontiers in Genetics Akkermansia Preplication = 0.02, Dorea Preplication = 0.01) with consistent effect direction.
Received: 19 November 2020
Accepted: 04 January 2021 Conclusion: We identified specific pathogenic bacteria features that were causally
Published: 18 February 2021 associated with the risk of IBD, thus offering new insights into the prevention and
Citation: diagnosis of IBD.
Zhang Z-J, Qu H-L, Zhao N,
Wang J, Wang X-Y, Hai R and Li B Keywords: mendelian randomization, gut microbiota, inflammatory bowel disease, ulcerative colitis, causal
(2021) Assessment of Causal relationship
Direction Between Gut Microbiota
and Inflammatory Bowel Disease: Abbreviations: FDR, false discovery rate; GWAS, genome-wide association study; IBD, inflammatory bowel disease; IV,
A Mendelian Randomization Analysis. instrumental variable; IVW, inverse-variance weighted; LD, linkage disequilibrium; MGWAS, microbiome genome-wide
Front. Genet. 12:631061. association study; MR, Mendelian randomization; OTU, operational taxonomic unit; UKB, UK Biobank; USP, understanding
doi: 10.3389/fgene.2021.631061 social program.

Frontiers in Genetics | www.frontiersin.org 1 February 2021 | Volume 12 | Article 631061

Zhang et al. UC and GM’s MR Analysis

INTRODUCTION as exposure, and GWAS summary statistics from two IBD GWAS
were used as discovery and replication outcomes.
Inflammatory bowel disease (IBD) is a chronic non-specific
inflammatory disease that invades colonic mucosa without
gender advantage (Matsuoka et al., 2018). The peak age of IBD is MATERIALS AND METHODS
between 20 and 40 years old (Loftus, 2004; Bernstein et al., 2006;
Cosnes et al., 2011). The main symptoms of IBD are abdominal GWAS Summary Statistics
pain, diarrhea, mucous bloody stool, as well as extra-intestinal The MR analysis was performed on GWAS summary statistics of
symptoms. IBD is mostly common in developed countries both microbiota and IBD. All data were retrieved from previously
including North America, Europe, Australia, and New Zealand, published studies that were released to the public.
with incidence rate as high as 20–100 per million people. It is The microbiota GWAS summary statistics from the TwinsUK
estimated that as many as 1 million Americans suffer from IBD study (Goodrich et al., 2016) served as exposure. In brief,
(Cohen et al., 2010; Magro et al., 2012). In recent decades, the The TwinsUK study collected 3,261 fecal samples from 1,126
incidence of IBD has been rising all over the world, especially in twin pairs from the TwinsUK Registry in British. Microbiota
East Asian (Loftus et al., 2007; Bengtson et al., 2009; Cosnes et al., 16S rRNA was sequenced using Illumina Miseq 2 × 250 bp
2011; Molodecky et al., 2012). sequencing platform, followed by host genome genotyping using
The pathogenesis of IBD has not been fully elucidated. It Illumina HumanHap610 Quad Chip. For genotype imputation,
has a strong genetic determinant. For instance, first-degree the 1,000 Genomes project (Phase 3) reference panel was used.
relatives of patients with IBD are 4 to 20 times more likely Sixty-one bacteria taxa were found to be associated with 307 host
to develop IBD (Kevans et al., 2016). Recent genome-wide SNPs with p-values ranging from 7.33 × 10−5 to 4.94 × 10−9
association studies (GWASs) have identified more than 200 (Supplementary Table 1).
responsible genomic loci associated with IBD (Turpin et al., The discovery outcome sample UK IBD and Understanding
2018). Despite these fruitful findings, its pathogenic mechanism Social Program (UKIBD and USP) is a GWAS study based on a
has not been fully understood yet. On the other hand, general prospective population cohort of European ancestry with
gut microbiota may be related to the pathogenesis of IBD 12,924 cases and 35,391 controls. Host genome was genotyped
(Nishida et al., 2018). Imbalance of gut microbiota coupled by the HumanCyto SNP-12 BeadChip and the Immunochip
with impaired intestinal bacterial clearance could enhance the arrays, and was imputed into the UK IBD Genetics Consortium
invasiveness of pathogens, disrupt intestinal immune response, and UK10K Consortium reference panel (Burgess et al., 2013).
accelerate intestinal inflammation, and eventually lead to IBD. A total of 38 genomic loci were identified at the genome-wide
In a recent controlled trial, patients in the fecal microbiota significance level (p < 5.0 × 10−8 ), increasing the number of
transplantation group showed significant clinical improvement, known IBD risk sites to 200.
indicating that high-dose fecal microbiota transplantation is an The replication British IBD sample was the GWAS of
effective method for the treatment of active IBD (Paramsothy 16,452 IBD British cases and 18,837 controls. Participants were
et al., 2017). Another study indicates that the low abundance genotyped on the Human Core Exome v12.1, the Affymetrix
of Phascolarctobacterium is positively correlated with the 500K, or the Affymetrix 6.0 genotyping array.
occurrence of IBD (Bajer et al., 2017).
Although previous extensive studies have established Instrumental Variable Selection
observational associations between gut microbiota and IBD The same criteria were used for IV selection in both discovery and
developing risk, the causal nature is largely unclear. Mendelian replication samples. IVs were grouped at family or genus level.
randomization (MR) analysis is a statistical approach that aims Specifically, a bacterial feature was defined as a family or genus.
to infer causal relationship from observational association SNPs associated with bacterial taxa in one feature were grouped
results (Lee and Lim, 2019). With the rapidly increasing genetic together for that feature. As a QC step, palindrome SNPs,
data at both microbiota and complex disease sides, MR has which are defined as SNPs with ambiguous strand information
been widely applied in recent years. MR approach has three (e.g., A/T or G/C polymorphisms), were removed. SNP-feature
essential assumptions: (1) Instrumental variable (IV) is strongly association threshold was set to be 1.0 × 10−5 . In order to
associated with exposure; (2) IV is not associated with any eliminate the effect of linkage disequilibrium (LD), SNPs within
confounders of exposure; and (3) The association of IV with each feature were clumped with PLINK (v1.9). The LD threshold
outcome is only through exposure. It has been used to infer was set to be r2 < 0.1, and the clustering window was set to
the causal relationship from gut microbiota to type 2 diabetes, be 500 kb. LD was estimated on the 1,000 Genome Project
neurodegenerative diseases, and bone density (Burgess et al., sequencing data (Phase 3).
2013; Bowden et al., 2015; Goodrich et al., 2016; Quigley, 2017; In order to minimize the effect of horizontal pleiotropy. MR-
Verbanck et al., 2018). PRESSO global test and outlier test were applied (Verbanck
In the present study, in order to explore the causal relationship et al., 2018). The MR-PRESSO outlier test calculates the p-value
from gut microbiota to IBD, and to identify specific pathogenic for the significance of pleiotropy for each SNP, while the MR-
bacteria taxa, we conducted a two-sample MR study based PRESSO Global test calculates the p-value for the overall level
on GWAS summary data. In brief, summary data from the of pleiotropy. Each individual SNP was deleted in turn and the
microbiota GWAS (MGWAS) of the TwinsUK study were used MR-PRESSO Outlier test was applied to the set of remaining

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Zhang et al. UC and GM’s MR Analysis

SNPs (Verbanck et al., 2018). All significant SNPs were removed. TwoSampleMR1 (Hemani et al., 2018) and MRPRESSO2
A MR-PRESSO Global test was finally performed to monitor (Sanna et al., 2019).
the overall pleiotropic effect. Non-significant SNPs were used for
subsequent MR analysis.
RESULTS
MR Analysis
Upon the selection of qualified SNPs, MR analysis was then The flow chart of the present study is displayed in Figure 1.
performed for a causal relationship from microbiota feature to In the discovery sample, there are 237 host SNPs that are
IBD risk. Specifically, each microbiota feature was tested for its associated with gut microbiota features at the significance
association. For features with multiple IVs, the inverse-variance threshold p < 1.0 × 10−5 . After clumping, 168 and 80
weighted (IVW) test (Burgess et al., 2013) was applied. For SNPs are left for 15 families and 15 genera, respectively
features with only one IV, the Wald ratio test was applied. The (Supplementary Table 2). Two families with the largest number
results of IVW were also cross-validated by three alternative of SNPs are Lachnospiraceae (51 SNPs) and Ruminococcaceae
tests, including the MR-Egger regression (Bowden et al., 2015), (51 SNPs), followed by Bacteroidaceae (36 SNPs). There are
the weighted median estimator (Bowden et al., 2016) and the five families, Barnesiellaceae, Enterobacteriaceae, Rikenellaceae,
MR-PRESSO (Verbanck et al., 2018). Streptococcaceae, and Veillonellaceae, each having only one SNP.
Nominally significant results identified in the discovery At the genus level, the genus with the largest number of SNPs is
sample were subjected to be replicated in the replication sample, Bacteroides (36 SNPs), followed by Faecalibacterium (9 SNPs) and
with the same analysis procedures. Coprococcus (6 SNPs). There are four genera each having only one
The horizontal heterogeneity effect was examined by the IVW SNP, Anaerostipes, Dorea, Streptococcus, and Veillonella. Of note,
test and the MR-Egger regression. Meanwhile, a leave-one-out genus is a child taxon of family, therefore SNPs contained in both
sensitivity analysis was performed to monitor if significant features may overlap. For example, the genus Faecalibacterium is
associations were dominated by a single SNP.
All the above analyses (including sensitivity analysis and 1
https://github.com/MRCIEU/TwoSampleMR
MR analysis) were implemented within the R packages 2
https://github.com/rondolab/MR-PRESSO

FIGURE 1 | Diagrammatic description of MR analysis in the discovery and replication. (A) The whole workflow of MR analysis. (B) The main results and the change
in the number of SNPs.

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Zhang et al. UC and GM’s MR Analysis

a child taxon of the family Ruminococcaceae. The SNPs in them is not only an important part of immune and metabolic
are partly identical. health, but also regulate central nervous system and relevant
For features containing multiple IVs, no outliers were disorders, including movement disorders, neurodegenerative
detected using the MR-PRESSO outlier test and no evidence diseases, behavioral disorders, neuroimmune-mediated diseases,
of horizontal pleiotropy (both MR-PRESSO Global test and Cerebrovascular accident (Strandwitz, 2018). More than 90%
p > 0.05/15 = p > 3.3 × 10−3 and MR-Egger regression of the gut microbiota that maintain intestinal health and balance
p > 0.05) was observed. in adults consist of four phylums of Firmicutes, Bacteroides,
Actinobacteria, and Proteobacteria (Matsuoka and Kanai, 2015).
MR Analysis The large intestine comprises the densest and metabolism-active
In the discovery sample, after removing potentially pleiotropic microorganism in healthy individuals, which is predominated by
SNPs, one family and two genera are significant at the nominal anaerobic microbiota, two phyla Firmicutes and Bacteroidetes,
level (p < = 0.05): family Verrucomicrobiaceae (2 IVs, beta = 0.04, apart from Actinobacteria, Proteobacteria, and Verrucomicrobia
p = 0.05), genus Akkermansia (2 IVs, beta = 0.04, p = 0.05) and (Eckburg et al., 2005).
genus Dorea (1 IV, beta = −0.07, p = 0.04). The Dorea identified in this study belongs to the
In sum, three features (one family ++ two genera) are causally Lachnospiraceae family, which mainly exists in the gut
associated with IBD in the discovery sample. These three features microbiota of mammals and humans. One previous study
were replicated in the British IBD replication sample. The same has established a link between Lachnospiraceae and IBD (Lee
IVs are available in the replication sample. Using the same IVW et al., 2020). Another recent studies has also confirmed that
test, the replication p-value is significant (p = 0.02) and the the level of Lachnospiraceae and butyric acid gets decreased in
effect direction is consistent for family Verrucomicrobiaceae and IBD patients (Sasaki et al., 2019). The genus Akkermansia is
genus Akkermansia (Table 1). For the other genus Dorea, only present abundantly in the human gastrointestinal tract where it is
one SNP rs10743315 is qualified as the IV. Using the Wald believed to be a key symbiont member of the microbiota (Collado
ratio test, the MR p-value is 0.01, again with consistent effect et al., 2007; Derrien et al., 2008; van Passel et al., 2011; Clarke
direction. Moreover, there is no evidence of heterogeneity at the et al., 2014; Guo et al., 2016). Extensive studies demonstrate that
three identified features in both discovery and replication sample. the lower level of Akkermansia is found in patients with IBD
Detailed information of the 3 IVs is listed in Table 2. and other metabolic disorders, suggesting that Akkermansia may
have potential anti-inflammatory properties (Zhang et al., 2016).
Previous studies have shown that the imbalance of gut
DISCUSSION microbiota is one of the pathogenic factors of IBD, but the
specific regulatory mechanism is yet poorly understood. One
In this study, we used MR analysis to evaluate the causal possible mechanism, among others, is that the anti-inflammatory
relationship between gut microbiota and IBD. Using the activity of IBD model is related to the regulation of inflammatory
summary statistics of one microbiota GWAS and 2 IBD GWASs, cytokines such as iNOS, MPO, IL-4, IL-10, EGF, MUC2, IL-
we identified and replicated three bacterial taxa, one family 6 and so on (Ma et al., 2018). However, this needs to be
Verrucomicrobiaceae and two genera Akkermansia and Dorea, confirmed by further functional studies, which is beyond the
that may have causal relationship with IBD. Our study confirmed scope of this study.
that gut microbiota can aggravate IBD, suggesting that gut Mendelian randomization analysis is an effective method to
microbiota plays a regulatory role in IBD. explore causality from exposure to outcome while controlling
The gut microbiota is an intricate and dynamic collective confounding factors. The MR analysis in this study has the
of ecological microbial communities that are colonized in following advantages. First, it is a new attempt to speculate the
the human gut, even called a “forgotten organ” (O’Hara causal relationship from gut microbiota to IBD, which provides
and Shanahan, 2006; Backhed et al., 2015). Gut microbiota a theoretical basis for the follow-up study of the regulation

TABLE 1 | MR analysis of gut microbiota on IBD in both discovery and replication samples.

Stage MR Tests Family Genus

Verrucomicrobiaceae Akkermansia Dorea

No. SNP bxy p-value No. SNP bxy p-value No. SNP bxy p-value

Discovery
IVW 2 0.04 0.05 2 0.04 0.05 – – –
Wald ratio test – – – – – – 1 −0.07 0.04
Replication
IVW 2 0.02 0.02 2 0.02 0.02 – – –
Wald ratio test – – – – – – 1 −0.08 0.01
No. SNP is the number of SNPs being used as IVs. bxy is the estimated effect coefficient. Significant p-values were marked in bold. IVW, inverse-variance weighted.

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Zhang et al. UC and GM’s MR Analysis

Chr is Chromosome of SNP. Physical position is based on the human genome GRCH37 assembly. A1 is the effect allele and A0 is the other allele. Beta is the estimate coefficient of the effect allele. SE is the standard
mechanism of single strain on IBD. Second, it is based on publicly

p-value

0.05
0.16
0.01
Outcome (Replication)
available large-scale GWAS summary statistics, so it provides an
effective choice for mining reliable genetic information without
additional experimental cost.

0.02
0.02
0.02
SE
Obviously, our study has certain limitations. First, due to
limited sample size, the genetic loci identified in gut microbiota

Beta

−0.02
0.04

0.05
GWAS are still limited, which limits the statistical power of MR
analysis. Second, MR analysis based on one single IV is less
robust, which may bias the interpretation of our findings.
p-value

0.045
Outcome (Discovery)

0.42
0.04
In conclusion, we evaluated the causal relationship from
gut microbiota to IBD and identified specific bacterial taxa
that may affect the pathogenesis of IBD by a two-sample MR
0.02
0.02
0.02
SE

error of the estimate coefficient. Closest gene is the closest gene to which the SNP is mapped. Family Verrucomicrobiaceae and genus Akkermansia have the same SNPs.
analysis using publicly available GWAS summary statistics. Our
results provide a basis for revealing the causal relationship from
Beta

gut microbiota to IBD, and thus offer new insights into its
−0.01
0.04

0.04

development and treatment.

2.16 × 10−7
1.83 × 10−8
3.69 × 10−9
p-value

DATA AVAILABILITY STATEMENT

Exposure

Publicly available datasets were analyzed in this study. This

data can be found here: ftp://ftp.sanger.ac.uk/pub/project/
0.12
0.11
0.11
SE

humgen/summary_statistics/human/2016-11-07/. The accession

code EGAS00001000924. Key data were supplied in the
−0.55
Beta

−0.63

Supplementary Tables 1, 2.
0.57

ETHICS STATEMENT
Closest Gene

RN7SKP106
SLC14A1
KC6

Ethical review and approval was not required for the study on
human participants in accordance with the Local Legislation and
Institutional Requirements. The patients/participants provided
their written informed consent to participate in this study.
A0

C
T

Written informed consent was obtained from the individual(s)

for the publication of any potentially identifiable images or data
A1

C
A

included in this article.

18q12.3
18q12.3
6q24.1
Locus
TABLE 2 | Instrumental variables used in both discovery and replication studies.

AUTHOR CONTRIBUTIONS
141858751
43316270
39082090

Z-JZ: conceptualization, formal analysis, data curation, and

Position

writing – original draft. H-LQ: validation and writing – original

draft. NZ: formal analysis and writing – original draft. JW:
resources and writing – original draft. X-YW: data curation
Chr

and writing – original draft. BL: data curation, supervision,

18
18
6

methodology, writing, and revising. RH: conceptualization,

methodology, software, data curation, writing, review, editing,
rs10081087

rs12607607
rs692899

and supervision. All authors contributed to the article and

Snp

approved the submitted version.

FUNDING
Family Verrucomicrobiaceae/

This study was partially supported by the funding from

Genus Akkermansia

National Natural Science Foundation of China (81460223 to

RH) and a project funded by the Natural Science Foundation
Genus Dorea

of Inner Mongolia Autonomous Region (2016MS0879 to JW).

Stage

BL was partially supported by grants from Jiangsu Provincial

Medical Youth Talent (No. QNRC2016249), Suzhou Science and

Frontiers in Genetics | www.frontiersin.org 5 February 2021 | Volume 12 | Article 631061

Zhang et al. UC and GM’s MR Analysis

Technology Bureau (Nos. SYSD2017041 and SYS201788), Gusu microbiota GWAS summary statistics, the UKIBD and USP
Health Top-Notch Youth Talent of Suzhou Health Commission study and the British IBD study for releasing the IBD GWAS
(No. GSWS2019086), and Wujiang District Health Commission summary statistics.
(Nos. WWK201609 and WWK201806).

SUPPLEMENTARY MATERIAL
ACKNOWLEDGMENTS
The Supplementary Material for this article can be found
We appreciate all the volunteers who participated in this study. online at: https://www.frontiersin.org/articles/10.3389/fgene.
We are grateful to the TwinsUK study for releasing the gut 2021.631061/full#supplementary-material

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