The results indicate that the gut microbiota has causal effects on DKD and that immune cell traits exert a mediation effect to some extent.
Abstract
Abstract Observational studies have indicated that the gut microbiota is associated with diabetic kidney disease (DKD). However, it remains unclear whether disturbances in the gut microbiota causally contribute to DKD. This study aimed to investigate the causal relationships between the gut microbiota and DKD and explore peripheral immune cell traits as potential mediators. Summary statistics were extracted from genome-wide association studies of the Dutch Microbiome Project (N = 7,738), SUMMIT Consortium (N = 10,875), and GWAS summary statistics for immune cell traits (N = 3,757). We used a two-sample two-step mediation Mendelian randomization analysis to investigate genetic causality between immune cell traits and the phenotypes of DKD, causal effect of gut microbiota/microbiota metabolism pathways on DKD, and mediation effects of immune cell traits. In total, seven immune cell traits and five taxa were causally associated with the DKD phenotypes after multiple testing corrections. We performed mediation analysis on gut microbiota and immune cell traits that passed the Bonferroni correction, and identified five mediation relationships. For instance, mediation analysis indicated that Pseudoflavonifractor capillosus had adverse effects on chronic kidney disease in type 2 diabetes by downregulating CD25 expression in CD4+ regulatory T cells (proportion mediated = 19.8%, p = 0.035). These results indicate that the gut microbiota has causal effects on DKD and that immune cell traits exert a mediation effect to some extent.
Genetic evidence is provided that gut microbiota influence CKD risk partially through circulating metabolites, highlighting the gut microbiota–metabolite–CKD axis as a potential therapeutic target.
The pathogenesis of pancreatic cancer is complex. While immune dysregulation and gut microbiota disturbances are considered key factors, the causal pathway between them remains unclear. This study employs a 2-step Mendelian randomization (MR) approach to empirically investigate the “immune cells - gut microbiota - pancreatic cancer” mediation pathway from a genetic perspective. Relevant data on 731 immune cell phenotypes (N = 3757), 473 gut microbiota (N=8293), and pancreatic cancer (N = 3,87,888) were extracted from large-scale genome-wide association study (GWAS) and FinnGen summary statistics. MR was employed to assess causal relationships. Inverse-variance weighted (IVW) regression served as the primary MR method, supplemented by sensitivity analyses to ensure robustness. Mediation analysis was performed to assess potential pathways from immune cells to pancreatic cancer mediated by gut microbiota. Two-step MR analyses revealed that 8 gut microbial taxa mediate the causal relationship between 14 immune cell phenotypes and pancreatic cancer. For example, Klebsiella mediated 10.2% of the protective effect of CD39+ monocytes on pancreatic cancer risk. Ruminococcus E sp003521625 accounted for 7.09% of the risk effect associated with HLA DR on B cells. Conversely, UBA7177 sp002491225 attenuated the protective effect of CD11b on CD33dim HLA DR− cells, with a mediation proportion of–10.5%. Notably, Brevibacillales exhibited the highest mediation proportion (15.5%) between Activated & resting Treg % CD4 Treg and pancreatic cancer. Our findings support a genetically predicted causal pathway linking immune cell phenotypes to pancreatic cancer via specific gut microbiota. These results underscore the mediating role of certain microbial taxa and offer novel insights for future strategies involving immune modulation or microbiota-based interventions in pancreatic cancer.
PURPOSE
Recent observational studies have revealed gut microbiota influences the development and progression of several retinal diseases. However, the causal relationship between gut microbiota and central serous chorioretinopathy (CSCR) are still not understood.
METHODS
The data of gut microbiota and circulating immune cell traits were identifed from large‑scale genome‑wide association studies (GWAS) summary data, and the data of CSCR come from FinnGen database.Mendelian randomization (MR) was used to investigate the causal relationships between gut microbiota, circulating immune cells, and CSCR. Mendelian randomization methods included inverse variance weighting and Bayesian weighting. Cochran's Q, Egger intercept, and MR-PRESSO were used to evaluate heterogeneity, genetic pleiotropy, and horizontal pleiotropy. Sensitivity was evaluated using leave-one-out method.Finally, we explored whether immune cell act as a mediating factor in the pathway from gut microbiota to CSCR.
RESULTS
12 gut microbiota traits were associated with increased genetic risk of CSCR, 2 were associated with decreased genetic risk of CSCR.Mediated mendelian randomization analysis identified 10 pathways through which gut microbiota affects the genetic prediction of CSCR through circulating immune cell mediation, with Demequinaceae via IgD-CD24-% lymphocyte (7.0%) and CD24 on sw mem (3.5%), Demequina via IgD-CD24-% lymphocyte (9.6%), GCA-900066575 sp900066385 via CD4 on CD28 + CD4+ (9.7%), Saccharofermentanaceae via CD45 on HLA DR+T cells (4.7%), CD80 on plasmacytoid DC (5.0%), and CD80 on CD62L + plasmacytoid DC (5.9%), UBA737 via HLA DR+CD8br AC (4.3%), CAG-1000 sp000434555 via Resting Treg% CD4 Treg (3.3%) affecting the genetic risk of CSCR.
CONCLUSIONS
Our mediated mendelian randomization analysis provides genetic evidence suggesting that circulating immune cells may mediate the causal relationship between gut microbiota and CSCR. The identified associations and mediation effects offer new insights into potential therapeutic avenues for CSCR.
Li-Yu Zhao, Chang-Fan Wu, Mao-Hua Jiang et al.· Current Eye Research· 0 citations
There is a growing number of research suggesting that there is an association between gut microbiota and central nervous system (CNS) tumor. However, the causal relationships and the mediation effects of inflammatory proteins in the associations are unclear. We extracted genetic variants associated with gut microbiota, inflammatory proteins, and 4 subtypes of CNS tumors from published genome-wide association studies and performed a Mendelian randomization analysis to identify potential causal effects. The inverse variance weighted method was used as the main method. Mediation analysis and single-cell RNA-seq analysis were performed to explore the mediation effects and the expression in cells. This study identified 73 gut microbial taxa and 11 inflammatory proteins that were significantly associated with CNS tumors. The inflammatory proteins may act as intermediate mediators in the potential causal association between gut microbiota and 4 CNS tumor subtypes. Mediation analysis suggested that CX3CL1 may partially mediate the relationship between gut microbiota and Glioblastoma, while Eotaxin, CSF-1, IL-15RA and the other 5 cytokines may serve as subtype-specific potential mediators for the remaining 3 tumor types. Our research supports a hypothesized “gut-immune-brain” axis that may mediate the effects of gut microbiota on different CNS tumor subtypes, with distinct immune proteins implicated for each. These findings strongly suggest potential targets for microbiome therapy and immune therapy, though the underlying mechanistic links require experimental validation.
Xian-Wen Cao, Hui Guo, Kun Wang et al.· Medicine· 0 citations
Emerging evidence suggests that gut microbiota is associated with functional gastrointestinal disorders (FGIDs). However, findings regarding microbial alterations in FGIDs have been inconsistent across observational studies, and the direction and causality of these associations remain unclear. We conducted a bidirectional two-sample Mendelian randomization (MR) study to investigate potential causal associations between gut microbiota and two common FGIDs, irritable bowel syndrome (IBS) and functional dyspepsia (FD). Genome-wide association study (GWAS) summary statistics of gut microbiota, IBS, and FD were obtained from public databases and applied to our MR analysis. The inverse-variance-weighted method was used as the primary analysis, with weighted median and complementary sensitivity analyses used to assess the consistency and robustness of the findings. Higher genetically predicted abundances of
order Bifidobacteriales
(OR: 0.741, 95% CI: 0.570 to 0.963,
P
= 0.025) and
genus Eubacterium ventriosum group
(OR: 0.684, 95% CI: 0.524 to 0.893,
P
= 0.005) were associated with a lower risk of IBS.
Genus Lachnospiraceae NK4A136 group
(OR: 1.368, 95% CI: 1.086 to 1.722,
P
= 0.008) correlated to a high risk of FD while
family Desulfovibrionaceae
and
order Desulfovibrionales
(OR: 0.649, 95% CI: 0.471 to 0.893,
P
= 0.008) were protective for FD. In the reverse MR analysis, genetically predicted IBS risk was associated with lower abundances of
Turicibacter
and
Slackia
, whereas no robust reverse associations were observed for FD. These findings identify several microbial taxa as candidates for further mechanistic and clinical validation rather than established risk factors or therapeutic targets. Further experimental research to investigate the underlying mechanisms is warranted.
Yu-Tong Cheng, Qiu-Ai Shu, Zi-Wei Wang et al.· Experimental biology and med...· 0 citations
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