Aug 2026· Medicine· Vol 105· 0 citations· 43 references
Medicine
TL;DR
This study provides genetic evidence supporting a bidirectional causal relationship between specific saliva and gut microbiota and bone neoplasm-related phenotypes and identifies several microbial taxa as potential candidates for future biomarker development and therapeutic investigation in bone neoplasm-related phenotypes.
Abstract
The human oral and gut microbiota are the 4 largest microbial communities in the body and play crucial roles in maintaining homeostasis and influencing disease. Observational studies have suggested links between these microbiota and bone neoplasm-related phenotypes, but establishing causality has been challenging due to confounding factors and reverse causality. We conducted a bidirectional, 2-sample Mendelian randomization (MR) study to investigate evidence consistent with a potential causal association between the saliva and gut microbiota and various bone neoplasm-related phenotypes. Genetic instruments for saliva and gut microbiota were sourced from large genome-wide association studies. Inverse variance weighted was the primary MR method, supplemented by 4 other MR techniques. Sensitivity analyses, including MR-Egger regression, were performed to assess pleiotropy and heterogeneity. In the forward MR analysis, Veillonella parvula from the saliva microbiota was associated with a decreased risk of bone and connective tissue neoplasms (β: −0.236, 95% CI: [−0.275, −0.197], P = 8.20E−33). MR analyses identified genetically predicted associations between several microbial taxa and bone neoplasm-related phenotypes. Reverse MR analyses showed that genetic liability to bone neoplasm-related phenotypes was associated with variation in the composition of the oral (e.g., Order Bacteroidales, Rothia mucilaginosa) and gut microbiota (e.g., Class Methanobacteria, Genus Eubacterium oxidoreducens group). Sensitivity analyses confirmed the robustness of these findings, as no statistical evidence of substantial heterogeneity or directional horizontal pleiotropy was detected. This study provides genetic evidence supporting a bidirectional causal relationship between specific saliva and gut microbiota and bone neoplasm-related phenotypes. Our findings identify several microbial taxa as potential candidates for future biomarker development and therapeutic investigation in bone neoplasm-related phenotypes. However, these genetically informed associations require further mechanistic, experimental, and prospective clinical validation before clinical application.
Previous studies have investigated the relationship between gut microbiota (GM) and oral lesions, but the reported associations across microbial taxa and oral conditions have been inconsistent. This 2-sample Mendelian randomization study using summary-level GWAS data aimed to clarify the causal links between GM and 5 oral conditions: loose teeth, toothache, bleeding gums, painful gums, and mouth ulcers. GM data were obtained from the MiBioGen consortium, while outcome data were derived from the Neale Lab and MRC-IEU consortium. We applied inverse variance weighted (IVW) and complementary MR methods to estimate causal effects, with reverse MR performed to test the possibility of reverse causality, and multivariable MR (MVMR) used to assess whether associations persisted after adjusting for conventional risk factors. The IVW method identified 42 potential associations between GM and oral conditions. For example, the Mollicutes class and Tenericutes phylum were negatively associated with loose teeth (Mollicutes: odds ratio [OR] = 0.9936, 95% confidence interval [CI]: 0.9894 to 0.9978, P = .0029), whereas the Slackia genus showed a positive association with toothache (OR = 1.0096, 95% CI: 1.0050 to 1.0142, P = 3.98 × 10−5). These associations were further confirmed in replication analyses, and MVMR demonstrated that they remained significant after accounting for established risk factors. The findings suggest robust causal links between specific GM taxa and oral conditions, offering novel insights into the GM–oral health axis and highlighting potential preventive or therapeutic targets for oral care.
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
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.
