Together with our collaborators in Tromsø in Norway, we published a paper over the weekend in eBioMedicine describing the early colonization patterns of preterm infants, both in terms of the microbes that arrive early to the infants, but also in terms of the antibiotic resistance genes they carry.
In the paper (1), which is a continuation of an earlier study by part of the team (2), we analysed metagenomic data from six Norwegian neonatal intensive care units to better understand the bacterial microbiota of infants born preterm or on term and receiving different treatments. These groups included probiotic-supplemented and antibiotic-exposed extremely preterm infants (n = 29), antibiotic-exposed very preterm infants (n = 25), antibiotic-unexposed very preterm infants (n = 8), and antibiotic-unexposed full-term infants (n = 10). Stool samples were collected from the infants after 7, 28, 120, and 365 days of life and were analysed using shotgun metagenomics. We were particularly interested in the maturation of the preterm infant microbiome into a ‘normal’ healthy gut microbiome, and the colonization with bacteria carrying antibiotic resistance genes.
We found that microbiota maturation was largely determined by the length of hospitalisation for the infants and how much preterm they were. The use of probiotics rendered the gut microbiota and resistome of extremely preterm infants more alike to term infants on day 7 and partially restored the loss of species interconnectivity and stability associated with preterm delivery. Finally, colonisation with Escherichia coli was associated with the highest number of antibiotic-resistance genes in the infant microbiomes, followed by Klebsiella pneumoniae and Klebsiella aerogenes.
Being born very preterm, along with prolonged hospitalisation and frequent antibiotic use alters early life resistome and mobilome, leading to an increased gut carriage of antibiotic resistance genes and mobile genetic elements. On the other hand, the effect of probiotics was not unidirectional. Probiotics decreased resistome burden, but at the same time the bacterial strains in the probiotics appear to promote the activity of mobile genetic elements. Here, further study of the gut microbiota is necessary to be able to design strategies aiming to lower disease risk in vulnerable preterm infants.
As mentioned, this study was a collaboration with Veronika Pettersen‘s group in Tromsø, particularly Ahmed Bargheet, who have done a fabulous job on the bioinformatics and analysis of this study. I hope that we will continue this collaboration in the future (first step will be me visting Tromsø again in June!) This also continues a nice little “sidetrack” of the group’s research into the early life microbiome – previously represented by the work of Katariina Pärnänen (3) and Tove Wikström‘s vaginal microbiome study (4), which is a very interesting and relevant subject in terms of both medicine and microbial ecology. We are also setting up new collaborations in this area, so I hope that more will come out of this track in the next couple of years.
Finally, thank you Veronika for inviting me to participate in this great project!
- Bargheet A, Klingenberg C, Esaiassen E, Hjerde E, Cavanagh JP, Bengtsson-Palme J, Pettersen VK: Development of early life gut resistome and mobilome across gestational ages and microbiota-modifying treatments. eBio Medicine, 92, 104613 (2023). doi: 10.1016/j.ebiom.2023.104613
- Esaiassen E, Hjerde E, Cavanagh JP, Pedersen T, Andresen JH, Rettedal SI, Støen R, Nakstad B, Willassen NP, Klingenberg C: Effects of Probiotic Supplementation on the Gut Microbiota and Antibiotic Resistome Development in Preterm Infants. Frontiers in Pediatrics, 16, 6, 347 (2018). doi: 10.3389/fped.2018.00347
- Pärnänen K, Karkman A, Hultman J, Lyra C, Bengtsson-Palme J, Larsson DGJ, Rautava S, Isolauri E, Salminen S, Kumar H, Satokari R, Virta M: Maternal gut and breast milk microbiota affect infant gut antibiotic resistome and mobile genetic elements. Nature Communications, 9, 3891 (2018). doi: 10.1038/s41467-018-06393-w
- Wikström T, Abrahamsson S, Bengtsson-Palme J, Ek CJ, Kuusela P, Rekabdar E, Lindgren P, Wennerholm UB, Jacobsson B, Valentin L, Hagberg H: Microbial and human transcriptome in vaginal fluid at midgestation: association with spontaneous preterm delivery. Clinical and Translational Medicine, 12, 9, e1023 (2022). doi: 10.1002/ctm2.1023
Last week, we published a paper which has been cooking for a long time. It is the result of years of hard work from particularly the first author – Tove Wikström – but also Sanna who did the bulk of the bioinformatic analysis with some help from me (well, I mostly contributed as a sounding board for ideas, but hopefully that was useful). The paper describes the gene expression of both the human host and the microbial community in the vagina during pregnancy and how the expressed genes (and the composition of bacteria) are linked to early births (1) and was published in Clinical and Translational Medicine.
We found 17 human genes potentially influencing preterm births. Most prominently the kallikrein genes (KLK2 and KLK3) and four different forms of of metallothioneins (MT1s) were higher in the preterm group than among fullterm women. These genes may be involved in inflammatory pathways associated with preterm birth.
We also found 11 bacterial species associated with preterm birth, but most of them had low occurrence and abundance. In contrary to some earlier studies, we saw no differences in bacterial diversity or richness between women who delivered preterm and women who delivered at term. Nor did Lactobacillus crispatus – often proposed to be protective against preterm birth (2,3) – seem to be a protective factor against preterm birth. However, most other studies have used DNA-based approaches to determine the bacterial community composition, while we used a metatranscriptomic approach looking at only expressed genes. In this context it is interesting that other metatranscriptomic results (4) agree with ours in that it was mainly microbes of low occurrence that differed between the preterm and term group.
Overall, the lack of clear differences in the transcriptionally active vaginal microbiome between women with term and preterm pregnancies, suggests that the metatranscriptome has a limited ability to serve as a diagnostic tool for identification of those at high risk for preterm delivery.
Great job Tove and the rest of the team! It was a pleasure working with all of you! The entire paper can be read here.
- Wikström T, Abrahamsson S, Bengtsson-Palme J, Ek CJ, Kuusela P, Rekabdar E, Lindgren P, Wennerholm UB, Jacobsson B, Valentin L, Hagberg H: Microbial and human transcriptome in vaginal fluid at midgestation: association with spontaneous preterm delivery. Clinical and Translational Medicine, 12, 9, e1023 (2022). doi: 10.1002/ctm2.1023 [Paper link]
- Kindinger LM, Bennett PR, Lee YS, et al.: The interaction between vaginal microbiota, cervical length, and vaginal progesterone treatment for preterm birth risk. Microbiome, 5, 1, 1-14 (2017).
- Tabatabaei N, Eren AM, Barreiro LB, et al.: Vaginal microbiome in early pregnancy and subsequent risk of spontaneous preterm birth: a case-control study. BJOG, 126, 3, 349-358 (2019).
- Fettweis JM, Serrano MG, Brooks JP, et al.: The vaginal microbiome and preterm birth. Nature Medicine, 25, 6, 1012-1021 (2019).