Table 1.

Summary of included studies referring to the influence of gut microbiome on statins lipid‐lowering effect (Outcome 1)

Study details (Author, year, country)	Sample Characteristics (n)	Treatment ‐Drug ‐dose/day ‐via of admin. ‐duration	Study design	Sequencing method	Results		Author's conclusion
					Taxonomy	Diversity
Human studies
Sun et al, 2018, China 35	Men, with newly diagnosed hypercholesterolemia (202)	Atorvastatin, 20mg, Oral, 12 wk	»Blood LDLc was measured at wk 0, 4 and 12. »Fecal samples collected at week 0. »At the end of treatment, subjects divided in two groups based on their LDLc levels: group SS < 100 mg/dL; group SR ≥ 100 mg/dL.	Amplification by PCR of the V3‐V4 regions of 16S rRNA gene.	Phylum »group SS: higher proportions of Firmicutes Genus »group SS: higher proportions of Lactobacillus, Eubacterium, Faecalibacterium and Bifidobacterium.»group SR: higher proportions of Clostridium	Group SS: greater bacterial diversity than SR group.	Higher GM diversity is associated with statin sensitive response.
Liu et al, 2018, China 36	Men (45) and women (19), with primary hypercholesterolemia b	Rosuvastatin, 10mg, Oral, 4 to 8 wk	»Blood LDLc, HDLc, TG and Tc were measured at wk 0, 4 and 8. »Fecal samples collected at wk 0. »Subjects were divided in two groups based on their BLL: group 1 if BLL dropped to normal levels from wk 4; group 2 if BLL still above normal levels after 8 wk.	Amplification by PCR of the V3‐V4 regions of 16S rRNA gene.	Phylum »group 1: higher proportions of Firmicutes »group 2: increased proportions of Actinobacteria Family »group 1: higher proportions of Ruminococcaceae, Lactobacillaceae and Bifidobacteriaceae »group 2: increased proportions of Bacteroidaceae, Pseudomonaceae, Streptococcaceae, Enterobacteriaceae, and other endotoxin‐producing bacteria	Alpha diversity»group I: higher diversity than group II. Beta diversity both groups presented a much different GM composition.	Higher diversity in GM composition was linked to RSV hypolipidemic effect.
Animal studies
He et al, 2018, China 38	Male C57BL/6J mice (60)	Simvastatin, 20 mg Kg‐1 BW, Oral, 4 wk	»Random selection of control group (n = 7) and intervention group (n = 53). »Control group: fed with NCD; intervention group fed with HFD; both for 8 wk. »Then intervention group was further divided into 4 different treatment groups: HFD (n = 8); AB (n = 10), SV (n = 13), and AB_SV (n = 12). *HFD group was given high fat diet, for 4 wk *AB and AB_SV groups received imipenem/cilastatin 100 mg/Kg id, for 4 wk *AB_SV and SV groups received simvastatin, for 4 wk »Blood LDLc, HDLc, TG and Tc, and cecal samples were collected at wk 4.	Amplification by PCR of the V3‐V4 regions of 16S rRNA gene.	Phylum »groups AB and AB_SV: higher proportions of Proteobacteria than other 3 groups (control, HFD and SV). »groups AB and AB_SV: decreased proportions of Bacteroidetes and Firmicutes.	Alpha diversity »data not shown Beta diversity »groups AB and AB_SV: distinct GM composition than the other 3 groups.	Hypolipidemic effect of SV might be associated with some metabolic pathways which, in turn, could be impaired by GM modulation.
Wang et al, 2018, China 39	Male SPF SD rats 45	Rosuvastatin, 10 mg Kg−1 BW, Oral, 4 wk	»Random selection of AB_Statin group (n = 10), Statin group (n = 10), and Water group (n = 10). »Initially AB_Statin group received ceftriaxone (2gr/Kg BW bid) for 8 days to establish a dysbiotic rat model »Then AB_Statin and Statin groups were given rosuvastatin, for 4 wk »Water group was given saline solution 2id, for 4 wk »Blood LDLc, HDLc, TG and Tc were measured at wk 0, 2 and 4. »Fecal samples collected at wk 0, 2 and 4 wks.	Amplification by PCR of the V3‐V4 regions of 16S rRNA gene.	AB_Statin group presented diminished levels of Lactobacillus and Bifidobacterium (genus) than Statin group	Alpha diversity»AB_Statin group: reduction in bacterial diversity at the beginning compared with Statin and Water groups. At wk 4, no differences in GM diversity between the three groups were shown. Beta diversity AB_Statin group: much different GM composition, while Statin and Water groups had similarities.	Lipid‐lowering ability of RSV can be affected by a disruptive intestinal flora.

Abbreviations: AB, Antibiotic; AB_SV, Antibiotic + Simvastatin; BLL, blood lipid levels; BW, Body Weight; GM, Gut Microbiome; HDLc, High Density Lipoprotein cholesterol; HFD, High Fat Diet; LDLc, Low‐Density Lipoprotein cholesterol; NCD, Normal Chow Diet; PCR, Polymerase Chain Reaction; RSV, Rosuvastatin; SR, statin resistant; SS, statin sensible; SV, Simvastatin; TC, Total cholesterol; TG, Triglycerides.

^aHypercholesterolemia was considered when serum LDLc ≥ 130 mg/dl.

^bHypercholesterolemia was considered when serum LDLc ≥ 3.64 mmol/L (≈140 mg/dl), HDLc ≤ 3.64 mmol/L (≈140 mg/dl), TG ≥ 1.70 mmol/L (≈150 mg/dl), and TC ≥ 5.72 mmol/L (≈220 mg/dl)