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Childhood antibiotic treatments reduce diversity and stability of intestinal microbiota

June 22, 2016

The DIABIMMUNE project followed the development of 39 Finnish infants from birth to the age of three. Half of the children received 9-15 antibiotic treatments during the research period, and the other half did not receive any such treatments. Stool samples were collected from the children monthly between the ages of 2 and 36 months, for a total of 1069 samples. The study involved researchers from Aalto University, the University of Helsinki, Helsinki University Hospital and the Broad Institute of MIT and Harvard.

'We found that the microbial community of antibiotic-treated children is less stable and less diverse. Interestingly, this is most noticeable on the strain level, where children who received multiple antibiotic treatments had many more single-strain species, whereas children who never got any antibiotics had more diverse species, with multiple strains for each species' explains Dr. Moran Yassour, a postdoctoral fellow at Professor Ramnik Xavier's group at the Broad Institute of MIT and Harvard Yassour.

The problem of unnecessary antibiotic treatments

With every passing generation, important species of intestinal bacteria seem to be disappearing due to the effects of antibiotics. The discovery of antibiotic compounds has transformed the medical practice, and antibiotic treatments save lives on a daily basis. At the same time, antibiotics are still being unnecessarily prescribed to children, for example against viral infections, and this study highlights the consequences of repeated antibiotic treatments on the developing infant gut microbiome.

'Treatments, such as antibiotics, that have an effect on early childhood microbial populations can make children prone to long-term illnesses that manifest themselves later on, such as asthma, inflammatory bowel diseases, diabetes and obesity. Antibiotic treatments should in future be more precisely focused against the infections preceding the treatment,' says Professor Mikael Knip from the Children's Hospital and the University of Helsinki, who is leading the DIABIMMUNE research project.

The type of birth also affects the development of a child's intestinal microbiomes. The intestinal microbiomes of children born by caesarean (C) section are usually not as diverse of those that undergo a vaginal birth, and are characterized by the lower abundance of various Bacteroides species in the first 6 months of life. The microbiomes also significantly develop and establish themselves during a child's first months of life, with the composition of microbiota taking its stable adulthood composition during the child's third year. The intestinal microbiota has a significant effect on the development of a child's immunity. A healthy, diverse, and stable microbiota have been shown to promote health: they promote absorption of nutrients, support the metabolism and protect from infections.

'Like in previous studies, we also observe a very strong impact of delivery mode on the infant gut microbiome. The gut microbial signature of children born by C-section is very unique, as none of the Bacteroides species are detected in the first 6-18 months of life. Surprisingly, 20% of vaginally born children displayed a similar 'low-Bacteroides' signature, an observation that has not been previously reported. We have searched extensively for clinical variables that may explain this observation, yet the numbers are too small to find statistically significant direct associations.' Dr. Yassour notes.

In the long-term, the microbial diversity of all children with the 'low-Bacteroides' signature remained lower, regardless of their delivery mode.

Antibiotic-resistant bacteria

Often-repeated antibiotic treatments given during early childhood interfere with the development of the intestinal microbiota and lead to the development and possible spread of antibiotic-resistant microbe populations. Researchers observed a rapid increase in antibiotic resistance genes--genes that convey bacterial resistance to antibiotics--after antibiotic treatments. This increase was usually short-term, followed by a rapid decrease in the abundance of the resistance genes in the following month. On the other hand, resistance genes found on mobile elements - that transfer more easily between bacteria - sometimes remained in the intestines for significantly longer periods of time.

'If the intestinal microbiota is healthy, the resistant bacteria are not usually able to multiply because they do not find a niche in the ecology. However, during antibiotic treatment other bacteria are killed and resistant bacteria can proliferate freely. There is also the risk that certain pathogens gain resistance implicating that the diseases caused by them will become very hard to treat. This is what is being referred when people talk of hospital bacteria,' explains doctoral candidate Tommi Vatanen from the Aalto University Department of Computer Science and the Broad Institute in Cambridge, USA.

'The strength of this study lies in its unique combination of longitudinal monthly samples coupled with deep metagenomic sequencing. These were key for both the identification of strains, and quantification of antibiotic resistance genes,' Dr. Yassour emphasizes.

The study has been funded primarily by the EU (7th framework programme), the Finnish Academy and the Juvenile Diabetes Research Foundation. The research results have been published in the internationally recognised publication series Science Translational Medicine, and were featured on the issue's cover.
-end-
More information:
Tommi Vatanen
Doctoral Candidate
Aalto University, Department of Computer Science and Broad Institute
Tel. +1-857-498-4141
tommi.vatanen@aalto.fi

Mikael Knip
Professor
Children's Hospital, University of Helsinki and Helsinki University Hospital
Tel. +358504487722
mikael.knip@helsinki.fi

Moran Yassour
PhD
The Broad Institute of MIT and Harvard
moran@broadinstitute.org
phone: +1 (617) 714-7358

Article http://stm.sciencemag.org/content/8/343/343ra81

Aalto University

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