Causal association of gut microbes and blood metabolites with acne identified through systematic mendelian randomization

Abstract

Acne is a prevalent inflammatory disease in dermatology, and its pathogenesis may be associated with inflammation, immunity, and other mechanisms. It commonly manifests in young individuals and frequently imposes a heavy economic, physical, and psychological burden on patients. Gut microbes and blood metabolites, as significant immune and inflammatory regulators in the body, have been hypothesized to form the "neurocutaneous axis." Nonetheless, the precise causal relationships among the gut microbes, circulating blood metabolites, and acne development have yet to be elucidated. This study employed bidirectional two-sample Mendelian randomization (MR) to probe the causal impacts of 412 distinct gut microbes and 249 blood metabolites on acne. Single nucleotide polymorphisms (SNPs), which are closely associated with gut microbes and blood metabolites, were utilized as instrumental variables. This approach was taken to discern whether these elements serve as pathogenic or protective factors in relation to acne. Furthermore, a mediation analysis encompassing gut microbes, blood metabolites, and acne was conducted to explore potential correlations between gut microbes and blood metabolites, as well as their cumulative effects on acne. This was done to substantiate the notion of causality. Bidirectional two-sample MR analysis revealed 8 gut bacteria, 6 bacterial metabolic abundance pathways determined by birdshot, and 8 blood metabolites significantly associated with acne. The mediation MR analysis revealed 2 potential causal relationships, namely, Bifidobacterium-DHA-Acne and Bifidobacterium-Degree of Unsaturation-Acne. This study identified gut microbes and blood metabolites that are causally associated with acne. A potential causal relationship between gut microbes and blood metabolites was obtained via mediation analysis. These insights pave the way for the identification of new targets and the formulation of innovative approaches for the prevention and treatment of acne.

Keywords: Acne; Blood metabolites; Gut microbes; Mediation analysis; Mendelian randomization.

Fig. 1

Flow chart of the study.

Fig. 2

Circo Heatmap showing the causal effects of gut microbes and bacterial metabolic pathways on acne. The prefixes p_, c_, o_, f_, g_, s_ and PWY represent Phylum, Class, Order, Family, Genus, Species, and Pathway, respectively. IVW, inverse-variance weighted; WM, weighted median.

Fig. 3

Scatterplots showing the causal effects of gut microbes and bacterial metabolic pathways on acne.

Fig. 4

Forest plots showing the causal effects of gut microbes and bacterial metabolic pathways on acne. The results of OR and 95%CI in this table were obtained by the method of inverse–variance weighted. OR, odds ratio; CI, confidence interval.

Fig. 5

Circo Heatmap showing the causal effects of blood metabolites on acne. VLDL, very low density lipoprotein; LDL, low density lipoprotein; HDL, high density lipoprotein; IDL, intermediate density lipoprotein.

Fig. 6

Scatterplots showing the causal effects of blood metabolites on acne. The Suffixes pct represent percentage. Ala, alanine; DHA, docosahexaenoic acid; IDL_C, intermediate-density lipoprotein cholesterol; PUFA, polyunsaturated fatty acid; XS_VLDL_PL, extra small very low density lipoprotein particle levels.

Fig. 7

Forest plots showing the causal effects of blood metabolites and acne.

Fig. 8

Gut microbes mediate the mediating effect and mediating effect ratio of metabolites on acne(two-step method). The causal effect of Bifidobacterium on acne was found to be mediated by DHA and the Degree of Unsaturation. β(EM) and P(EM) represent the beta and P values obtained by MR analysis of exposure and mediator. β(MO) and P(MO) represent the beta and P values obtained by MR analysis of the mediator and outcome. β(EO) represents the beta and P values obtained by MR analysis of the exposure and outcome.