Antibiotic-induced gut microbiota depletion exacerbates host hypercholesterolemia

Abstract

Hypercholesterolemia is a major driver of atherosclerosis, thus contributing to high morbidity and mortality worldwide. Gut microbiota have been identified as modulator of blood lipids including cholesterol levels. Few studies have already linked certain bacteria and microbial mechanisms to host cholesterol. However, in particular mouse models revealed conflicting results depending on genetics and experimental protocol. To gain further insights into the relationship between intestinal bacteria and host cholesterol metabolism, we first performed fecal 16S rRNA targeted metagenomic sequencing in a human cohort (n = 24) naïve for cholesterol lowering drugs. Here, we show alterations in the gut microbiota composition of hypercholesterolemic patients with depletion of Bifidobacteria, expansion of Clostridia and increased Firmicutes/Bacteroidetes ratio. To test whether pharmacological intervention in gut microbiota impacts host serum levels of cholesterol, we treated hypercholesterolemic Apolipoprotein E knockout with oral largely non-absorbable antibiotics. Antibiotics increased serum cholesterol, but only when mice were fed normal chow diet and cholesterol was measured in the random fed state. These elevations in cholesterol already occurred few days after treatment initiation and were reversible after stopping antibiotics with re-acquisition of intestinal bacteria. Gene expression analyses pointed to increased intestinal cholesterol uptake mediated by antibiotics in the fed state. Non-targeted serum metabolomics suggested that diminished plant sterol levels and reduced bile acid cycling were involved microbial mechanisms. In conclusion, our work further enlightens the link between gut microbiota and host cholesterol metabolism. Pharmacological disruption of the gut flora by antibiotics was able to exacerbate serum cholesterol and may impact cardiovascular disease.

Keywords: 7-ketodeoxycholate (PubChem CID: 88292); Antibiotics; Cholesterol metabolism; Gut microbiota; Hypercholesterolemia; ampicillin (PubChem CID: 6249); beta-muricholate (PubChem CID: 20848962); beta-sitosterol (PubChem CID: 222284); campesterol (PubChem CID: 173183); cholesterol (PubChem CID: 5997); metronidazole (PubChem CID: 4173); neomycin (PubChem CID: 8378); ursodeoxycholate (PubChem CID: 31401); vancomycin (PubChem CID: 14969).