Gut microbiota and breast cancer risk: a Mendelian randomization study stratified by ER status

The potential causal relationship between gut microbiota (GM) and breast cancer (BC), particularly its estrogen receptor (ER)-positive (ER+) and ER-negative (ER-) subtypes, remains insufficiently characterized.

We conducted a two-sample Mendelian randomization (MR) analysis to examine genetically predicted causal associations between 473 GM features (abundance in stool) and BC, including overall BC (Ncase = 24,270, Ncontrol = 222,078), ER+ BC (Ncase = 14,540, Ncontrol = 221,705) and ER- BC (Ncase = 9,724, Ncontrol = 221,705).

The MR results demonstrated differential causal associations between GM and BC subtypes: For overall BC risk, lower Barnesiella abundance (OR = 0.93; 95%CI 0.88-0.98; P = 0.006) was protective, whereas higher Providencia abundance (OR = 1.30; 95%CI 1.11-1.51; P = 0.0008) increased risk. Among ER+ BC cases, five GM showed significant associations: Dokdonella (OR = 1.38; 95%CI 1.12-1.70; P = 0.0024), Flavonifractor sp900199495 (OR = 0.81; 95%CI 0.69-0.94; P = 0.0054), Rhodanobacter (OR = 1.45; 95%CI 1.10-1.92; P = 0.0087), Ruminococcus (OR = 0.73; 95%CI 0.58-0.92; P = 0.0080), and UBA7177 sp002491225 (OR = 1.33; 95%CI 1.08-1.63; P = 0.0067). In ER- BC, seven GM factors exhibited causal relationships: Bacteroides A plebeius (OR = 0.90; 95%CI 0.84-0.97; P = 0.0077), CAG-273 sp003507395 (OR = 0.89; 95%CI 0.82-0.95; P = 0.0009), CAG-390 sp003523225 (OR = 0.82; 95%CI 0.71-0.95; P = 0.0064), CAG-433 (OR = 0.86; 95%CI 0.78-0.95; P = 0.0030), Chromobacteriaceae (OR = 0.57; 95%CI 0.39-0.83; P = 0.0034), Providencia (OR = 1.48; 95%CI 1.18-1.86; P = 0.0007), and Syntrophorhabdaceae (OR = 1.52; 95%CI 1.14-2.04; P = 0.0050).

Our genetically informed MR analysis provides suggestive evidence for the differential causal roles of specific GM in overall, ER + and ER- BC pathogenesis, offering potential biomarkers for therapeutic intervention strategies.