Immune and metabolic shifts during neonatal development reprogram liver identity and function
Author(s): ,
Gustavo Batista Menezes
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
Corresponding author. Address: Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil; Fax: +55 31 9
,
Rafael Machado Rezende
Affiliations:
Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
,
Bruna Araújo David
Affiliations:
University of Calgary, Alberta T2N 4N1, Canada
,
Thais Garcias Moreira
Affiliations:
Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
,
Raquel Ferraz Nogueira
Affiliations:
Beckman Coulter, São Paulo, Brazil
,
Gabriel Rocha Fernandes
Affiliations:
Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Minas Gerais 30190-002, Brazil
,
Mila Fernandes Moreira Madeira
Affiliations:
Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Germán A.B. Mahecha
Affiliations:
Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Cristiano Xavier Lima
Affiliations:
Departamento de Cirurgia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Paula Vieira Teixeira Vidigal
Affiliations:
Departamento de Anatomia Patológica e Medicina Legal, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Alan Moreira Araújo
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Matheus Silvério Mattos
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Viviane Aparecida de Souza Lacerda
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Maria Alice Freitas Lopes
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Débora Moreira Alvarenga
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Ariane Barros Diniz
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Ana Carolina Carvalho Silva
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Maísa Mota Antunes
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Camila Dutra Moreira de Miranda
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Gabriel Henrique Campolina-Silva
Affiliations:
Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Hortência Maciel de Castro-Oliveira
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Raquel Carvalho-Gontijo
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Mateus Eustáquio Lopes
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Érika de Carvalho
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
,
Kassiana Mafra
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
Brenda Naemi Nakagaki
Affiliations:
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
EASL LiverTree™. Menezes G. Dec 1, 2018; 256739
Gustavo Batista Menezes
Gustavo Batista Menezes

Access to this content is an EASL members and LiverTree™ Privileged Users benefit.

Journal Abstract
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Graphical abstract

Graphical abstract

Neonatal livers have very different cellular composition to adults. Myeloid cells govern liver immune system in newborns. Several metabolic enzymes are less expressed in newborn livers. Weaning leads to elevation of several liver metabolic functions. Early weaning leads to changes in the liver metabolism.

Background & Aims

The liver is the main hematopoietic site in embryos, becoming a crucial organ in both immunity and metabolism in adults. However, how the liver adapts both the immune system and enzymatic profile to challenges in the postnatal period remains elusive. We aimed to identify the mechanisms underlying this adaptation.

Methods

We analyzed liver samples from mice on day 0 after birth until adulthood. Human biopsies from newborns and adults were also examined. Liver immune cells were phenotyped using mass cytometry (CyTOF) and expression of several genes belonging to immune and metabolic pathways were measured. Mortality rate, bacteremia and hepatic bacterial retention after E. coli challenge were analyzed using intravital and in vitro approaches. In a set of experiments, mice were prematurely weaned and the impact on gene expression of metabolic pathways was evaluated.

Results

Human and mouse newborns have a sharply different hepatic cellular composition and arrangement compared to adults. We also found that myeloid cells and immature B cells primarily compose the neonatal hepatic immune system. Although neonatal mice were more susceptible to infections, a rapid evolution to an efficient immune response was observed. Concomitantly, newborns displayed a reduction of several macronutrient metabolic functions and the normal expression level of enzymes belonging to lipid and carbohydrate metabolism was reached around the weaning period. Interestingly, early weaning profoundly disturbed the expression of several hepatic metabolic pathways, providing novel insights into how dietary schemes affect the metabolic maturation of the liver.

Conclusion

In newborns, the immune and metabolic profiles of the liver are dramatically different to those of the adult liver, which can be explained by the differences in the liver cell repertoire and phenotype. Also, dietary and antigen cues may be crucial to guide liver development during the postnatal phase.

Lay summary

Newborns face major challenges in the extra-uterine life. In fact, organs need to modify their cellular composition and gene expression profile in order to adapt to changes in both microbiota and diet throughout life. The liver is interposed between the gastrointestinal system and the systemic circulation, being the destination of all macronutrients and microbial products from the gut. Therefore, it is expected that delicately balanced mechanisms govern the transformation of a neonatal liver to a key organ in adults.

Keyword(s)
Newborn, Immune system, Diet, Early weaning, Metabolism, !!!!i!!!!In vivo!!!!/i!!!! imaging, Immunity
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