Omics Track Gut Microbiota Changes With Antibiotic Treatment

Ricki Lewis, PhD

January 10, 2013

Researchers have used an "omics" approach to track changes in gut microbiota during treatment with beta lactam antibiotics, according to a new study published online December 12, 2012, in Gut.

Ana Elena Pérez-Cobas, PhD, from the Unidad Mixta de Investigación en Genómica y Salud del Centro Superior de Investigación en Salud Pública e Instituto Cavanilles de Biodiversidad y Biología Evolutiva, Universitat de València, Valencia, and the CIBER en Epidemiología y Salud Pública, Madrid, Spain, and colleagues conducted a proof-of-concept study to establish the value of multiple omics approaches to study the effects of antibiotics on the bacterial populations of the human gastrointestinal tract. Their strategy extends the traditional tracking of 16S ribosomal subunit DNA analysis to identify gut bacteria.

The researchers evaluated fecal samples from a 68-year-old man hospitalized for an infected cardiac pacemaker. He received intravenous ampicillin/sulbactam and cefazolin on admission and intravenous cefazolin alone for 14 days.

The researchers collected samples at admission and on days 3, 6, 11, and 14 as well as 40 days after start of treatment and assessed them for microbial diversity. To identify microbes present, the investigators sequenced total and active 16S ribosomal RNA (transcriptionally active bacteria) and DNA (total bacteria), sequenced and analyzed the metagenome and metatranscriptome, and extracted, separated, and identified proteins and metabolites.

The gut microbiota changed more than the researchers expected in response to the drug. Early on, most species were members of phylum Firmicutes, but this shifted during the 2 weeks to favor Bacteroidetes, with genus Parabacteroides predominating. The microbiota returned to their normal state by day 40.

Monitoring the transcriptome provided a glimpse of the adjustment and recovery of the microbiota to the antibiotic. Genes encoding proteins that participate in detoxification were highly expressed on the third day, but by day 14, genes encoding proteins involved in molecular renewal and transport were more highly expressed. Genes whose products replicate DNA were expressed at constant levels during the 2 weeks.

By day 6, the diversity of Gram-negative organisms had diminished and major metabolic alterations were evident. Levels of proteins essential for cellular energetics, iron uptake, and protein synthesis peaked, perhaps to counter stress, the researchers suggest.

Microbial diversity hit its lowest on day 11, widening niches for antibiotic-resistant bacteria such as Parabacteroides and Bacteroides. However, the lowest diversity of the active microbial fraction did not happen until day 14.

Fluctuations of the population sizes of many microbial species occurred throughout the 2 weeks. Bacterial protein abundance changed, such that on day 40, typically high-abundance proteins were at a minimum and low-abundance proteins were at a maximum.

Metabolic changes also reflected adaptation to the presence of the drug. Early in the course of antibiotic treatment, as microbial diversity fell, bacteria seemed to attenuate their energy metabolism. They transported and metabolized hormones, vitamins, bile acids, and cholesterol less efficiently and produced lower amounts of bile acids, vitamin D, prostaglandins, sterol lipids, and cholesterol derivatives.

A limitation of the study was the sample size of 1. Further studies will include more participants and evaluate different antibiotics, the researchers write.

The consortium was supported by the Spanish Ministry of Economy and Competitiveness and German BMBF within the ERA NET PathoGenoMics2 program. This work was further funded by grants from the Spanish Ministry of Economy and Competitiveness and Generalitat Valenciana (Spain). The authors received financial support from the European Regional Development Fund, the European Union, the Spanish Ministry of Economy and Competitiveness, the IFB Adiposity Disease, and the Instituto de Salud Carlos III.

Gut. Published online December 12, 2012. Full text