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. 2022 Sep 18;23(18):10903.
doi: 10.3390/ijms231810903.

Regulatory T Cells in Development and Prediction of Necrotizing Enterocolitis in Preterm Neonates: A Scoping Review

Mara O Zuiderwijk  1 , Mirjam van der Burg  2 , Vincent Bekker  1 , Michiel H D Schoenaker  1   2
Affiliations

Regulatory T Cells in Development and Prediction of Necrotizing Enterocolitis in Preterm Neonates: A Scoping Review

Mara O Zuiderwijk et al. Int J Mol Sci. .

Abstract

Necrotizing enterocolitis (NEC) is a leading cause of mortality in premature infants. However, the pathophysiology and influence of regulatory T cells (Tregs) have not been sufficiently elucidated. We performed a scoping review to investigate current knowledge on the influence of Tregs in NEC, and to investigate the predictive value of Treg number in NEC development. Pubmed, Embase, Prospero and Cochrane Library were searched during December 2020. Primary research articles discussing Tregs and NEC development written in English were selected. Two reviewers screened title and abstract for relevance, after which full-text screening was performed. A total of 20 articles were selected-13 of the articles discussed studies performed in animal models, while 8 used human neonate data. One study discussed both animal and human data. It was shown that after NEC diagnosis or induction, Treg levels were decreased while Th17 levels were increased. No studies were found which investigated the predictive value of Treg number in NEC development. A reduced Treg level is found in animals and neonates with NEC. The question remains whether this effect is a factor on the causal pathway of NEC development or a bystander effect. Future research focusing on the pathophysiological timeline of NEC and the involvement of Tregs is required for better understanding of this disease.

Keywords: NEC; Th17 cell; necrotizing enterocolitis; preterm; regulatory T cell.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
PRISMA flow chart showing locations records were identified from, abstracts from records screened, full reports assessed and total studies included [12].
Figure 2
Figure 2
Cellular changes observed in NEC patients and animal models and different interventions. After NEC diagnosis or induction, Treg levels and activity were reduced (downward arrow). Th17 and CCR9 + IL-17+ Treg levels, and Th17 cell activity were increased (upward arrow). Melanin and ATRA negated the decrease in Tregs and increase in Th17 cells and IL-17. Adoptive Treg-transfer reduced NEC development in a mouse model.
Figure 3
Figure 3
Cellular changes observed in NEC patients and experimental animal models and the effect of immune modulating interventions. After NEC diagnosis or induction, the Treg/Teff cell ratio and overall Treg levels were decreased (downward arrow). Supplementation of PDHMSC-CM negated the decrease in Tregs, improving the immune regulation, and reduced development of NEC in a rat model. Adoptive Treg-transfer reduced NEC development in a mouse model.
Figure 4
Figure 4
Cellular changes observed in NEC patients and experimental animal models and the effect of breastmilk related interventions. After NEC diagnosis or induction, Treg levels were decreased (downward arrow). Formula increased NEC incidence and decreased Treg levels in piglets, whereas colostrum reduced NEC incidence and normalized Treg levels. GD3 supplementation negated the decrease in Tregs in a rat model. bLF supplementation increased Treg levels of individual NEC patients.
Figure 5
Figure 5
Cellular changes observed in NEC patients and experimental animal models and the effect of LR17938 supplementation. After NEC diagnosis or induction, Treg levels decreased (downward arrow), and Teff levels and activation increased (upward arrow). In mouse and rat models, LR17938 supplementation reduced NEC incidence. In a mouse model, the LR17938 supplementation negated the Treg level reduction. In neonates with NEC, LR17938 supplementation did not show effects.
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