Premature neonatal gut microbial community patterns supporting an epithelial TLR-mediated pathway for necrotizing enterocolitis
Abstract Background Necrotising enterocolitis (NEC) is a devastating bowel disease, primarily affecting premature infants, with a poorly understood aetiology. Prior studies have found associations in different cases with an overabundance of particular elements of the faecal microbiota (in particular...
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BMC
2021-08-01
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| Series: | BMC Microbiology |
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| Online Access: | https://doi.org/10.1186/s12866-021-02285-0 |
| _version_ | 1818606830099628032 |
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| author | Alexander G. Shaw Kathleen Sim Graham Rose David J. Wooldridge Ming-Shi Li Raju V. Misra Saheer Gharbia J. Simon Kroll |
| author_facet | Alexander G. Shaw Kathleen Sim Graham Rose David J. Wooldridge Ming-Shi Li Raju V. Misra Saheer Gharbia J. Simon Kroll |
| author_sort | Alexander G. Shaw |
| collection | DOAJ |
| description | Abstract Background Necrotising enterocolitis (NEC) is a devastating bowel disease, primarily affecting premature infants, with a poorly understood aetiology. Prior studies have found associations in different cases with an overabundance of particular elements of the faecal microbiota (in particular Enterobacteriaceae or Clostridium perfringens), but there has been no explanation for the different results found in different cohorts. Immunological studies have indicated that stimulation of the TLR4 receptor is involved in development of NEC, with TLR4 signalling being antagonised by the activated TLR9 receptor. We speculated that differential stimulation of these two components of the signalling pathway by different microbiota might explain the dichotomous findings of microbiota-centered NEC studies. Here we used shotgun metagenomic sequencing and qPCR to characterise the faecal microbiota community of infants prior to NEC onset and in a set of matched controls. Bayesian regression was used to segregate cases from control samples using both microbial and clinical data. Results We found that the infants suffering from NEC fell into two groups based on their microbiota; one with low levels of CpG DNA in bacterial genomes and the other with high abundances of organisms expressing LPS. The identification of these characteristic communities was reproduced using an external metagenomic validation dataset. We propose that these two patterns represent the stimulation of a common pathway at extremes; the LPS-enriched microbiome suggesting overstimulation of TLR4, whilst a microbial community with low levels of CpG DNA suggests reduction of the counterbalance to TLR4 overstimulation. Conclusions The identified microbial community patterns support the concept of NEC resulting from TLR-mediated pathways. Identification of these signals suggests characteristics of the gastrointestinal microbial community to be avoided to prevent NEC. Potential pre- or pro-biotic treatments may be designed to optimise TLR signalling. |
| first_indexed | 2024-12-16T14:17:05Z |
| format | Article |
| id | doaj.art-dacc99a9233b4a7ea6127c14dbcb27a5 |
| institution | Directory Open Access Journal |
| issn | 1471-2180 |
| language | English |
| last_indexed | 2024-12-16T14:17:05Z |
| publishDate | 2021-08-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Microbiology |
| spelling | doaj.art-dacc99a9233b4a7ea6127c14dbcb27a52022-12-21T22:28:35ZengBMCBMC Microbiology1471-21802021-08-0121111110.1186/s12866-021-02285-0Premature neonatal gut microbial community patterns supporting an epithelial TLR-mediated pathway for necrotizing enterocolitisAlexander G. Shaw0Kathleen Sim1Graham Rose2David J. Wooldridge3Ming-Shi Li4Raju V. Misra5Saheer Gharbia6J. Simon Kroll7Department of Infectious Disease Epidemiology, Imperial College London, Wright-Fleming InstituteDepartment of Medicine, Section of Paediatrics, Imperial College LondonGenomic Research Unit, Public Health England, Microbiology ServicesGenomic Research Unit, Public Health England, Microbiology ServicesDepartment of Medicine, Section of Paediatrics, Imperial College LondonMolecular Biology Laboratories, The Natural History MuseumGenomic Research Unit, Public Health England, Microbiology ServicesDepartment of Medicine, Section of Paediatrics, Imperial College LondonAbstract Background Necrotising enterocolitis (NEC) is a devastating bowel disease, primarily affecting premature infants, with a poorly understood aetiology. Prior studies have found associations in different cases with an overabundance of particular elements of the faecal microbiota (in particular Enterobacteriaceae or Clostridium perfringens), but there has been no explanation for the different results found in different cohorts. Immunological studies have indicated that stimulation of the TLR4 receptor is involved in development of NEC, with TLR4 signalling being antagonised by the activated TLR9 receptor. We speculated that differential stimulation of these two components of the signalling pathway by different microbiota might explain the dichotomous findings of microbiota-centered NEC studies. Here we used shotgun metagenomic sequencing and qPCR to characterise the faecal microbiota community of infants prior to NEC onset and in a set of matched controls. Bayesian regression was used to segregate cases from control samples using both microbial and clinical data. Results We found that the infants suffering from NEC fell into two groups based on their microbiota; one with low levels of CpG DNA in bacterial genomes and the other with high abundances of organisms expressing LPS. The identification of these characteristic communities was reproduced using an external metagenomic validation dataset. We propose that these two patterns represent the stimulation of a common pathway at extremes; the LPS-enriched microbiome suggesting overstimulation of TLR4, whilst a microbial community with low levels of CpG DNA suggests reduction of the counterbalance to TLR4 overstimulation. Conclusions The identified microbial community patterns support the concept of NEC resulting from TLR-mediated pathways. Identification of these signals suggests characteristics of the gastrointestinal microbial community to be avoided to prevent NEC. Potential pre- or pro-biotic treatments may be designed to optimise TLR signalling.https://doi.org/10.1186/s12866-021-02285-0MetagenomeNecrotising enterocolitisPremature infantMicrobiomeTLR4TLR9 |
| spellingShingle | Alexander G. Shaw Kathleen Sim Graham Rose David J. Wooldridge Ming-Shi Li Raju V. Misra Saheer Gharbia J. Simon Kroll Premature neonatal gut microbial community patterns supporting an epithelial TLR-mediated pathway for necrotizing enterocolitis BMC Microbiology Metagenome Necrotising enterocolitis Premature infant Microbiome TLR4 TLR9 |
| title | Premature neonatal gut microbial community patterns supporting an epithelial TLR-mediated pathway for necrotizing enterocolitis |
| title_full | Premature neonatal gut microbial community patterns supporting an epithelial TLR-mediated pathway for necrotizing enterocolitis |
| title_fullStr | Premature neonatal gut microbial community patterns supporting an epithelial TLR-mediated pathway for necrotizing enterocolitis |
| title_full_unstemmed | Premature neonatal gut microbial community patterns supporting an epithelial TLR-mediated pathway for necrotizing enterocolitis |
| title_short | Premature neonatal gut microbial community patterns supporting an epithelial TLR-mediated pathway for necrotizing enterocolitis |
| title_sort | premature neonatal gut microbial community patterns supporting an epithelial tlr mediated pathway for necrotizing enterocolitis |
| topic | Metagenome Necrotising enterocolitis Premature infant Microbiome TLR4 TLR9 |
| url | https://doi.org/10.1186/s12866-021-02285-0 |
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