Perinatal origins of chronic lung disease: mechanisms–prevention–therapy—sphingolipid metabolism and the genetic and perinatal origins of childhood asthma

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Abstract

Childhood asthma derives from complex host-environment interactions occurring in the perinatal and infant period, a critical time for lung development. Sphingolipids are bioactive molecules consistently implicated in the pathogenesis of childhood asthma. Genome wide association studies (GWAS) initially identified a link between alleles within the 17q21 asthma-susceptibility locus, childhood asthma, and overexpression of the ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3), an inhibitor of de novo sphingolipid synthesis. Subsequent studies of pediatric asthma offer strong evidence that these asthma-risk alleles correlate with early-life aberrancies of sphingolipid homeostasis and asthma. Relationships between sphingolipid metabolism and asthma-related risk factors, including maternal obesity and respiratory viral infections, are currently under investigation. This review will summarize how these perinatal and early life exposures can synergize with 17q21 asthma risk alleles to exacerbate disruptions of sphingolipid homeostasis and drive asthma pathogenesis.

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An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system.

Sarkis Mazmanian, Cui Hua Liu, Arthur O Tzianabos … (2005)

The mammalian gastrointestinal tract harbors a complex ecosystem consisting of countless bacteria in homeostasis with the host immune system. Shaped by evolution, this partnership has potential for symbiotic benefit. However, the identities of bacterial molecules mediating symbiosis remain undefined. Here we show that, during colonization of animals with the ubiquitous gut microorganism Bacteroides fragilis, a bacterial polysaccharide (PSA) directs the cellular and physical maturation of the developing immune system. Comparison with germ-free animals reveals that the immunomodulatory activities of PSA during B. fragilis colonization include correcting systemic T cell deficiencies and T(H)1/T(H)2 imbalances and directing lymphoid organogenesis. A PSA mutant of B. fragilis does not restore these immunologic functions. PSA presented by intestinal dendritic cells activates CD4+ T cells and elicits appropriate cytokine production. These findings provide a molecular basis for host-bacterial symbiosis and reveal the archetypal molecule of commensal bacteria that mediates development of the host immune system.

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Principles of bioactive lipid signalling: lessons from sphingolipids.

Yusuf Hannun, Lina M. Obeid (2008)

It has become increasingly difficult to find an area of cell biology in which lipids do not have important, if not key, roles as signalling and regulatory molecules. The rapidly expanding field of bioactive lipids is exemplified by many sphingolipids, such as ceramide, sphingosine, sphingosine-1-phosphate (S1P), ceramide-1-phosphate and lyso-sphingomyelin, which have roles in the regulation of cell growth, death, senescence, adhesion, migration, inflammation, angiogenesis and intracellular trafficking. Deciphering the mechanisms of these varied cell functions necessitates an understanding of the complex pathways of sphingolipid metabolism and the mechanisms that regulate lipid generation and lipid action.

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Stunted microbiota and opportunistic pathogen colonisation in caesarean section birth

Yan Shao, Samuel Forster, Evdokia Tsaliki … (2019)

Immediately after birth, newborn babies experience rapid colonisation by microorganisms from their mothers and the surrounding environment 1 . Diseases in childhood and later in life are potentially mediated through perturbation of the infant gut microbiota colonisations 2 . However, the impact of modern clinical practices, such as caesarean section delivery and antibiotic usage, on the earliest stages of gut microbiota acquisition and development during the neonatal period (≤1 month) remains controversial 3,4 . Here we report disrupted maternal transmission of Bacteroides strains and high-level colonisation by healthcare-associated opportunistic pathogens, including Enterococcus, Enterobacter and Klebsiella species, in babies delivered by caesarean section (C-section), and to a lesser extent, in those delivered vaginally with maternal antibiotic prophylaxis or not breastfed during the neonatal period. Applying longitudinal sampling and whole-genome shotgun metagenomic analysis on 1,679 gut microbiotas of 771 full term, UK-hospital born babies and mothers, we demonstrate that the mode of delivery is a significant factor impacting gut microbiota composition during the neonatal period that persists into infancy (1 month - 1 year). Matched large-scale culturing and whole-genome sequencing (WGS) of over 800 bacterial strains cultured from these babies identified virulence factors and clinically relevant antimicrobial resistance (AMR) in opportunistic pathogens that may predispose to opportunistic infections. Our findings highlight the critical early roles of the local environment (i.e. mother and hospital) in establishing the gut microbiota in very early life, and identifies colonisation with AMR carrying, healthcare-associated opportunistic pathogens as a previously unappreciated risk factor.

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Author and article information

Contributors

Stefan Worgall: stw2006@med.cornell.edu

Journal

Journal ID (nlm-ta): Mol Cell Pediatr

Journal ID (iso-abbrev): Mol Cell Pediatr

Title: Molecular and Cellular Pediatrics

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Electronic): 2194-7791

Publication date (Electronic): 20 December 2021

Publication date PMC-release: 20 December 2021

Publication date Collection: December 2021

Volume: 8

Electronic Location Identifier: 22

Affiliations

[1 ]GRID grid.5386.8, ISNI 000000041936877X, Department of Pediatrics, , Weill Cornell Medicine, ; 525 East 68th Street, Box 225, New York, NY 10065 USA

[2 ]GRID grid.5386.8, ISNI 000000041936877X, Drukier Institute for Children’s Health, , Weill Cornell Medicine, ; 413 East 69th Street, 12th Floor, New York, NY 10021 USA

[3 ]GRID grid.5386.8, ISNI 000000041936877X, Department of Genetic Medicine, , Weill Cornell Medicine, ; 1305 York Avenue, 13th Floor, New York, NY 10065 USA

Article

Publisher ID: 130

DOI: 10.1186/s40348-021-00130-y

PMC ID: 8688659

PubMed ID: 34931265

SO-VID: 6a34dac9-efc2-46d1-8836-5dcff8d01dbb

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 2 September 2021

Date accepted : 16 November 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: R21 AI140724

Award Recipient : Stefan Worgall

Funded by: FundRef http://dx.doi.org/10.13039/100006108, National Center for Advancing Translational Sciences;

Award ID: KL2 TR0002385

Award Recipient : Emily Wasserman

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Keywords: sphingolipids,asthma,17q21,serine-palmitoyl transferase,perinatal,microbiome,rhinovirus

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Keywords: sphingolipids, asthma, 17q21, serine-palmitoyl transferase, perinatal, microbiome, rhinovirus

Perinatal origins of chronic lung disease: mechanisms–prevention–therapy—sphingolipid metabolism and the genetic and perinatal origins of childhood asthma

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Cancer Metabolism

Most cited references 90

An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system.

Principles of bioactive lipid signalling: lessons from sphingolipids.

Stunted microbiota and opportunistic pathogen colonisation in caesarean section birth

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