Causal inference between gut microbiota and diabetic neuropathy: a two-step Mendelian randomization study mediated by circulating metabolites and proteins

doi:10.3877/cma.j.issn.2095-123X.2026.03.002

Abstract

Abstract:

Objective

To evaluate the causal relationships between gut microbiota (GM) and diabetic neuropathy (DN) using Mendelian randomization (MR), and to identify circulating metabolites and proteins that may mediate these associations.

Methods

Genome-wide association study (GWAS) data for GM and DN were derived from the MiBioGen consortium and the FinnGen R12 dataset, respectively. GWAS summary statistics for 529 circulating metabolites and 2994 proteins were obtained from two published articles, and their corresponding GWAS results have been deposited in the GWAS Catalog database. The Steiger directionality test was employed to exclude reverse causation between GM and DN. Two-sample MR analysis was conducted to assess the causal effect of GM on DN. Two-step MR, MR mediation analysis, and multivariable MR were further utilized to screen for circulating metabolites and proteins that may mediate the aforementioned causal pathways.

Results

A total of six GM taxa were causally associated with DN. Specifically, Eubacterium coprostanoligenes group (P=0.031) and Eubacterium xylanophilum group (P<0.001) were inversely associated with DN, whereas Firmicutes (P=0.026), Adlercreutzia (P=0.022), Alistipes (P=0.046), and Christensenellaceae R-7 group (P=0.009) were positively associated with DN. MR mediation analysis revealed that Eubacterium xylanophilum group alleviated DN by upregulating myeloid cell leukemia-1 protein (MCL-1) (P=0.003) and downregulating HIV-1 Tat interactive protein 2 (HTATIP2) (P<0.001) and matrix metalloproteinase-16 (MMP-16) (P=0.002). Conversely, Firmicutes promoted DN progression by reducing circulating levels of sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) (P=0.008), while Alistipes facilitated DN progression by elevating circulating levels of X-11423—O-sulfo-L-tyrosine (P=0.014).

Conclusions

Eubacterium xylanophilum group exerts a protective effect against DN by upregulating MCL-1 and downregulating HTATIP2 and MMP-16. In contrast, Firmicutes promotes DN progression by decreasing SMPDL3A levels, and Alistipes enhances DN progression by increasing X-11423—O-sulfo-L-tyrosine levels. These findings provide novel candidate targets for microbiota- and metabolite-based interventions in DN.

Key words: Gut microbiota, Diabetic neuropathy, Circulating metabolite, Mendelian randomization

Jiaxin Liu, Ze Zhang, Li Zhang. Causal inference between gut microbiota and diabetic neuropathy: a two-step Mendelian randomization study mediated by circulating metabolites and proteins[J]. Chinese Journal of Brain Diseases and Rehabilitation(Electronic Edition), 2026, 16(03): 135-149.

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Figures/Tables 11

References 51

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数据集	数据来源	第一作者	人群	样本量	网络链接
肠道菌群	MiBioGen联盟	-	欧洲人	18 340	https://mibiogen.gcc.rug.nl
糖尿病神经病变	FinnGen R12	-	芬兰人	96 474	https://r12.finngen.fi/region/DM_NEUROPATHY/10:129319100-129819100
循环代谢物	PMID: 24816252	Shin等^[13]	欧洲人	7 824	https://www.ebi.ac.uk/gwas/publications/24816252
循环蛋白质	PMID: 29875488	Sun等^[14]	欧洲人	3 301	https://www.ebi.ac.uk/gwas/publications/29875488

数据集	数据来源	第一作者	人群	样本量	网络链接
肠道菌群	MiBioGen联盟	-	欧洲人	18 340	https://mibiogen.gcc.rug.nl
糖尿病神经病变	FinnGen R12	-	芬兰人	96 474	https://r12.finngen.fi/region/DM_NEUROPATHY/10:129319100-129819100
循环代谢物	PMID: 24816252	Shin等^[13]	欧洲人	7 824	https://www.ebi.ac.uk/gwas/publications/24816252
循环蛋白质	PMID: 29875488	Sun等^[14]	欧洲人	3 301	https://www.ebi.ac.uk/gwas/publications/29875488

肠道菌群	方法	nSNP	P值	β	Q值	Q检验P值	MR-Egger截距	截距P值	全局检验P值
厚壁菌门	IVW	16	0.026	0.302	24.525	0.057	-0.011	0.649	0.068
	MR-Egger	16	0.199	0.438	24.153	0.044
	WM	16	0.296	0.167
	WMode	16	0.819	0.056
克里斯滕森菌科R-7群	IVW	9	0.009	0.417	3.672	0.886	-0.001	0.980	0.898
	MR-Egger	9	0.446	0.429	3.671	0.817
	WM	9	0.115	0.326
	WMode	9	0.486	0.226
嗜胆甾醇真杆菌属	IVW	13	0.031	-0.334	16.071	0.188	-0.039	0.317	0.216
	MR-Egger	13	0.665	0.262	14.613	0.200
	WM	13	0.135	-0.296
	WMode	13	0.378	-0.332
嗜木聚糖真杆菌属	IVW	9	0.001	-0.327	2.295	0.971	-0.019	0.445	0.707
	MR-Egger	9	0.467	-0.167	1.639	0.977
	WM	9	0.007	-0.309
	WMode	9	0.055	-0.301
阿德勒克鲁茨菌属	IVW	8	0.023	0.353	12.434	0.087	-0.091	0.143	0.119
	MR-Egger	8	0.068	1.357	8.437	0.208
	WM	8	0.027	0.383
	WMode	8	0.229	0.387
另枝菌属	IVW	13	0.047	0.320	15.767	0.202	-0.035	0.469	0.221
	MR-Egger	13	0.278	0.899	14.998	0.187
	WM	13	0.038	0.418
	WMode	13	0.264	0.404

肠道菌群	方法	nSNP	P值	β	Q值	Q检验P值	MR-Egger截距	截距P值	全局检验P值
厚壁菌门	IVW	16	0.026	0.302	24.525	0.057	-0.011	0.649	0.068
	MR-Egger	16	0.199	0.438	24.153	0.044
	WM	16	0.296	0.167
	WMode	16	0.819	0.056
克里斯滕森菌科R-7群	IVW	9	0.009	0.417	3.672	0.886	-0.001	0.980	0.898
	MR-Egger	9	0.446	0.429	3.671	0.817
	WM	9	0.115	0.326
	WMode	9	0.486	0.226
嗜胆甾醇真杆菌属	IVW	13	0.031	-0.334	16.071	0.188	-0.039	0.317	0.216
	MR-Egger	13	0.665	0.262	14.613	0.200
	WM	13	0.135	-0.296
	WMode	13	0.378	-0.332
嗜木聚糖真杆菌属	IVW	9	0.001	-0.327	2.295	0.971	-0.019	0.445	0.707
	MR-Egger	9	0.467	-0.167	1.639	0.977
	WM	9	0.007	-0.309
	WMode	9	0.055	-0.301
阿德勒克鲁茨菌属	IVW	8	0.023	0.353	12.434	0.087	-0.091	0.143	0.119
	MR-Egger	8	0.068	1.357	8.437	0.208
	WM	8	0.027	0.383
	WMode	8	0.229	0.387
另枝菌属	IVW	13	0.047	0.320	15.767	0.202	-0.035	0.469	0.221
	MR-Egger	13	0.278	0.899	14.998	0.187
	WM	13	0.038	0.418
	WMode	13	0.264	0.404

暴露	方法	β	P值	OR值	95%CI
循环代谢物
脯氨酸	WR	1.853	0.012	6.381	1.516~26.865
吲哚-3-乳酸	WR	-3.002	0.041	0.049	0.003~0.880
3-羧基-4-甲基-5-丙基-2-呋喃丙酸酯	WR	-1.355	0.007	0.259	0.096~0.695
乙酰左旋肉碱	IVW	-1.787	0.039	0.167	0.031~0.919
丝氨酸	IVW	-2.778	0.001	0.062	0.012~0.329
X-11423—O-磺基-L-酪氨酸	IVW	3.654	0.009	38.632	2.444~610.550
X-11452	WR	1.814	0.011	6.137	1.519~24.783
X-11786—甲基半胱氨酸	WR	1.213	0.039	3.364	1.061~10.662
ADpSGEGDFXAEGGGVR	IVW	-0.859	0.013	0.424	0.215~0.834
X-12441—12-羟基二十碳四烯酸	WR	0.507	0.016	1.659	1.097~2.510
辛酰肉碱	IVW	0.618	0.040	1.856	1.028~3.352
X-12855	IVW	-2.096	0.007	0.123	0.027~0.561
十八二酸盐	IVW	-1.970	0.003	0.139	0.037~0.522
循环蛋白质
蛋白FAM171B	WR	0.439	0.027	1.552	1.051~2.291
蛋白FAM213A	WR	-0.253	0.044	0.777	0.607~0.993
四关节盒蛋白1	IVW	-0.209	0.019	0.812	0.682~0.966
半乳糖苷3(4)-L-岩藻糖基转移酶	WR	0.062	0.034	1.064	1.005~1.126
N-乙酰乳糖胺苷β-1,6-N-乙酰氨基葡萄糖基转移酶	WR	0.417	0.008	1.518	1.115~2.066
天冬氨酸氨基转移酶	IVW	-0.203	0.008	0.816	0.702~0.948
谷胱甘肽S转移酶ω-1	IVW	-0.068	0.027	0.935	0.880~0.992
细胞间黏附分子2	IVW	0.235	0.025	1.344	1.342~1.223
干扰素α/β受体1	WR	0.309	0.021	1.363	1.047~1.773
白细胞介素-13受体亚基α-1	IVW	-0.243	0.010	0.784	0.653~0.943
白细胞介素-17受体A	IVW	-0.233	0.038	0.793	0.636~0.988
白细胞介素-27	WR	0.294	0.026	1.342	1.036~1.738
富含AT相互作用结构域蛋白3A	WR	0.367	0.030	1.443	1.036~2.010
激肽释放酶-11	WR	0.085	0.010	1.089	1.020~1.162
激肽释放酶-14	IVW	0.097	0.032	1.102	1.008~1.204
激肽释放酶-7	WR	-0.379	0.020	0.685	0.497~0.943
白细胞特异性转录本1蛋白	WR	0.479	0.007	1.615	1.143~2.281
黏膜定向细胞黏附分子1	WR	-0.382	0.003	0.68	0.529~0.879
髓样细胞白血病-1蛋白	WR	-0.923	0.001	0.397	0.244~0.647
微纤维蛋白相关蛋白2	IVW	0.190	0.029	1.209	1.019~1.436
基质金属蛋白酶-16	WR	0.496	0.003	1.642	1.189~2.265
巨噬细胞甘露聚糖受体1	WR	0.101	0.024	1.107	1.013~1.209
C型甘露糖受体2	IVW	-0.173	0.046	0.841	0.710~0.997
神经连接蛋白-3-β	IVW	-0.278	0.007	0.758	0.618~0.928
脯氨酰4-羟化酶亚基α-2	WR	-0.352	0.048	0.703	0.496~0.997
肽基甘氨酸α-酰胺化单加氧酶	IVW	0.073	0.047	1.076	1.000~1.157
原胶原C端肽酶增强因子1	WR	-0.229	0.041	0.796	0.639~0.991
蛋白精氨酸N-甲基转移酶3	WR	-0.318	0.011	0.728	0.571~0.929
妊娠特异性β-1-糖蛋白2	WR	0.498	0.047	1.646	1.006~2.692
B细胞淋巴瘤6蛋白	WR	-0.198	0.036	0.821	0.683~0.987
Ras相关蛋白26	IVW	0.172	0.041	1.187	1.007~1.400
RNF149	WR	-0.289	0.021	0.749	0.585~0.958
多聚糖二磷酸二糖-蛋白糖基转移酶亚基1	WR	0.148	0.033	1.159	1.012~1.329
分泌素蛋白	WR	0.584	0.034	1.793	1.046~3.073
14-3-3蛋白σ	WR	0.326	0.043	1.385	1.010~1.899
单免疫球蛋白IL-1相关受体	WR	-0.063	0.034	0.939	0.885~0.995
SLIT样蛋白和NTRK样蛋白5	WR	-0.522	0.019	0.594	0.383~0.920
酸性鞘磷脂酶样磷酸二酯酶3A	WR	0.067	0.018	1.069	1.012~1.131
信号转导适配蛋白1	IVW	0.231	0.049	1.260	1.000~1.587
C17orf78	WR	0.226	0.043	1.254	1.007~1.561
含SUN结构域蛋白3	WR	-0.238	0.038	0.788	0.629~0.987
TAP结合蛋白	IVW	0.196	0.027	1.217	1.023~1.448
转铁蛋白受体蛋白1	IVW	-0.240	0.001	0.787	0.681~0.909
胆汁盐激活脂肪酶	WR	0.350	0.031	1.432	1.033~1.984
补体因子H相关蛋白5	IVW	-0.072	0.029	0.931	0.873~0.993
碳水化合物硫转移酶15	WR	-0.452	0.017	0.637	0.439~0.922
碳水化合物硫转移酶1	WR	-0.357	0.017	0.700	0.523~0.938
肌酸激酶M型	IVW	-0.263	0.011	0.769	0.628~0.942
C型凝集素结构域家族2成员	WR	-0.307	0.034	0.736	0.554~0.977
CXADR样膜蛋白	WR	-0.306	0.001	0.736	0.612~0.886
UMP-CMP激酶	IVW	-0.406	0.044	0.666	0.449~0.989
硫酸软骨素N-乙酰半乳糖胺转移酶2	WR	-0.307	0.019	0.735	0.569~0.951
分泌型外胚层发育蛋白A	WR	0.404	0.040	1.498	1.019~2.203
红细胞生成素	WR	-0.408	0.014	0.665	0.480~0.920
受体酪氨酸蛋白激酶ErbB-3	WR	-0.345	0.033	0.708	0.516~0.973
结节漏斗肽	WR	0.431	0.001	1.539	1.240~1.910
精子相关抗原11B	WR	-0.624	0.001	0.536	0.395~0.729

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