Causal Relationship Between Gut Microbiota and Autoimmune Diseases: A Two-Sample Mendelian Randomization Study

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

doi:10.3389/fimmu.2021.746998

Cited by 186 publications

(160 citation statements)

References 40 publications

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“…Over 90% of GM comprises 4 bacterial phyla, including Firmicutes and Actinobacteria ( 26 ). When GM dysbiosis occurs, it causes metabolic, immune, and neurological-related disorders ( 14 , 27 , 28 ). Nonetheless, the role of GM dysbiosis in the pathogenesis of DR remains elusive.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to randomized controlled studies, Mendelian randomization (MR) studies prevent the possible effects of confounding factors (e.g., diet) and reverse causality, using genetic variation instead of exposure to assess causal associations with outcomes. Studies using MR analysis to explore the causal relationship between GM and autoimmune diseases ( 14 ) and neuropsychiatric conditions have matured ( 15 ). Nonetheless, the mechanisms by which DR applies MR analysis remain unexplored.…”

Section: Introductionmentioning

confidence: 99%

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Causal effects of gut microbiota on diabetic retinopathy: A Mendelian randomization study

et al. 2022

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BackgroundPrevious researches have implicated a vital association between gut microbiota (GM) and diabetic retinopathy (DR) based on the association of the “gut-retina” axis. But their causal relationship has not been elucidated.MethodsInstrumental variables of 211 GM taxa were obtained from genome wide association study (GWAS), and Mendelian randomization study was carried out to estimate their effects on DR risk from FinnGen GWAS (14,584 DR cases and 202,082 controls). Inverse variance weighted (IVW) is the main method to analyze causality, and MR results are verified by several sensitive analyses.ResultsAs for 211 GM taxa, IVW results confirmed that family-Christensenellaceae (P = 1.36×10-2) and family-Peptococcaceae (P = 3.13×10-2) were protective factors for DR. Genus-Ruminococcaceae_UCG_011 (P = 4.83×10-3), genus-Eubacterium_rectale_group (P = 3.44×10-2) and genus-Adlercreutzia (P = 4.82×10-2) were correlated with the risk of DR. At the phylum, class and order levels, we found no GM taxa that were causally related to DR (P>0.05). Heterogeneity (P>0.05) and pleiotropy (P>0.05) analysis confirmed the robustness of MR results.ConclusionWe confirmed that there was a potential causal relationship between some GM taxa and DR, which highlights the association of the “gut-retina” axis and offered new insights into the GM-mediated mechanism of DR. Further explorations of their association are required and will lead to find new biomarkers for targeted prevention strategies of DR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Causal effects of gut microbiota on diabetic retinopathy: A Mendelian randomization study

et al. 2022

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“…Because the allocation of genotypes from parent to offspring is random, the association between genetic variants and outcome is not affected by common confounding factors, and a causal sequence is reasonable [ 24 ]. MR has been widely applied to explore the causal association between gut microbiota and diseases, including metabolic diseases [ 25 ], autoimmune diseases [ 26 ], and rheumatoid arthritis [ 27 ]. In this study, using the genome-wide association study (GWAS) summary statistics from the MiBioGen and FinnGen consortiums, a two-sample MR analysis was conducted to evaluate the causal association between gut microbiota and PE.…”

Section: Introductionmentioning

confidence: 99%

Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study

Wang

Guo

et al. 2022

BMC Med

264

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Background Several recent observational studies have reported that gut microbiota composition is associated with preeclampsia. However, the causal effect of gut microbiota on preeclampsia-eclampsia is unknown. Methods A two-sample Mendelian randomization study was performed using the summary statistics of gut microbiota from the largest available genome-wide association study meta-analysis (n=13,266) conducted by the MiBioGen consortium. The summary statistics of preeclampsia-eclampsia were obtained from the FinnGen consortium R7 release data (5731 cases and 160,670 controls). Inverse variance weighted, maximum likelihood, MR-Egger, weighted median, weighted model, MR-PRESSO, and cML-MA were used to examine the causal association between gut microbiota and preeclampsia-eclampsia. Reverse Mendelian randomization analysis was performed on the bacteria that were found to be causally associated with preeclampsia-eclampsia in forward Mendelian randomization analysis. Cochran’s Q statistics were used to quantify the heterogeneity of instrumental variables. Results Inverse variance weighted estimates suggested that Bifidobacterium had a protective effect on preeclampsia-eclampsia (odds ratio = 0.76, 95% confidence interval: 0.64–0.89, P = 8.03 × 10−4). In addition, Collinsella (odds ratio = 0.77, 95% confidence interval: 0.60–0.98, P = 0.03), Enterorhabdus (odds ratio = 0.76, 95% confidence interval: 0.62–0.93, P = 8.76 × 10−3), Eubacterium (ventriosum group) (odds ratio = 0.76, 95% confidence interval: 0.63–0.91, P = 2.43 × 10−3), Lachnospiraceae (NK4A136 group) (odds ratio = 0.77, 95% confidence interval: 0.65–0.92, P = 3.77 × 10−3), and Tyzzerella 3 (odds ratio = 0.85, 95% confidence interval: 0.74–0.97, P = 0.01) presented a suggestive association with preeclampsia-eclampsia. According to the results of reverse MR analysis, no significant causal effect of preeclampsia-eclampsia was found on gut microbiota. No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. Conclusions This two-sample Mendelian randomization study found that Bifidobacterium was causally associated with preeclampsia-eclampsia. Further randomized controlled trials are needed to clarify the protective effect of probiotics on preeclampsia-eclampsia and their specific protective mechanisms.

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“…After quality control, 10 SNPs were obtained to predict EIF4EBP (Supplementary Table 1 ). IVW showed that EIF4EBP was positively associated with cataract, and the result of MR. RAPS was similar (Table 1 ), which strengthened the confidence of the true causal associations[ 46 ]. Meanwhile, the association remained directionally consistent in weight median, whereas MR-Egger showed no association between mTORC1-dependent protein level of EIF4EBP with cataract (Table 1 ).…”

Section: Resultsmentioning

confidence: 83%

Association of mTORC1‑dependent circulating protein levels with cataract formation: a mendelian randomization study

Cai

Liu

et al. 2022

BMC Genomics

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Background The mechanistic target of rapamycin (mTOR) signal pathway plays a critical regulating role in the occurrence and development of cataract. However, the role of mTORC1 downstream proteins, including ribosomal protein S6K (RP-S6K), eukaryotic initiation factor 4E-binding protein (EIF4EBP), eukaryotic initiation factor 4G (EIF-4G), eukaryotic initiation factor 4E (EIF-4E), and eukaryotic initiation factor 4A (EIF-4A), in regulating cataract development is still unknown. Herein, we conducted a mendelian randomization (MR) study to understand the function of mTORC1 signaling in the process of cataract development. Results The causal estimate was evaluated with inverse-variance weighted (IVW) estimate, weighted median estimator, MR-Egger and MR robust adjusted profile score (MR. RAPS). The single-nucleotide polymorphisms (SNPs), P<5 × 10− 6 and r2<0.05, were selected to genetically predict the RP-S6K, EIF4EBP, EIF-4E, EIF-4A, and EIF-4G. We included a total of 26,758 cases and 189,604 controls in this MR study. The study revealed causal association between circulating EIF4EBP (OR 1.09, 95% confidence interval 1.03,1.16, P = 0.004), RP-S6K (OR 1.04, 95% confidence interval 1.01, 1.08, P = 0.02) and cataract formation with IVW estimate. Whereas after correcting outliers, MR robust adjusted profile score (MR. RAPS) shows consistent result with IVW for EIF4EBP (OR = 1.08, 95%CI:1.05–1.11, P = 0.007). The observation strengthened the confidence in the true causal associations. However, no association was found for circulating EIF-4E (OR 1.03, 95% confidence interval 0.97, 1.09, P = 0.31), EIF-4A (OR 1.02, 95% confidence interval 0.98, 1.07, P = 0.34), and EIF-4G (OR 1.02, 95% confidence interval 0.94, 1.01, P = 0.64) levels with cataract formation. No evidence of heterogeneity and unbalanced horizontal pleiotropy was detected. Conclusion The MR study suggests that EIF4EBP is a high-risk factor for cataract development. There may be a potential causal association between the mTORC1/EIF4EBP axis and cataract. This research highlights the potential mechanism for cataract development and a genetic target to prevent as well as treat cataracts.

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Causal Relationship Between Gut Microbiota and Autoimmune Diseases: A Two-Sample Mendelian Randomization Study

Cited by 186 publications

References 40 publications

Causal effects of gut microbiota on diabetic retinopathy: A Mendelian randomization study

Causal effects of gut microbiota on diabetic retinopathy: A Mendelian randomization study

Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study

Association of mTORC1‑dependent circulating protein levels with cataract formation: a mendelian randomization study

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