Maternal aryl hydrocarbon receptor activation protects newborns against necrotizing enterocolitis

Lü, Peng; Yamaguchi, Yoshiaki; Fulton, William B.; Wang, Sanxia; Zhou, Qienyuan; Jia, Hongpeng; Kovler, Mark L.; Salazar, Andres; Sampah, Maame Efua; Prindle, Thomas; Wipf, Peter; Sodhi, Chhinder P.; Hackam, David J.

doi:10.1038/s41467-021-21356-4

Cited by 51 publications

(36 citation statements)

References 56 publications

(81 reference statements)

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“…Findings from Alvarado et al ( 14 ) revealed that upregulation of IDO1, an enzyme in tryptophan metabolism for endogenous AhR ligand derivation, resulted in increased secretory cell differentiation, increased mucous production in the epithelium, and reduced epithelial damage. Recent findings from Lu et al ( 64 ) demonstrated increased NEC severity in AhR IEC–specific knockout mice as described by a higher expression of proinflammatory Il6 and Tnf-α and more severe histology scores. However, in our studies using younger neonatal mice, we observe AhR ΔIEC pups to display a similar susceptibility to NEC compared with cre-negative littermates with no significant difference in expression of proinflammatory cytokines or chemokines and no significant difference in intestinal morphology of the terminal ileum.…”

Section: Discussionmentioning

confidence: 97%

Indole-3-Carbinol–Dependent Aryl Hydrocarbon Receptor Signaling Attenuates the Inflammatory Response in Experimental Necrotizing Enterocolitis

et al. 2021

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Necrotizing enterocolitis (NEC) causes significant morbidity and mortality in premature infants; therefore, the identification of therapeutic and preventative strategies against NEC remains a high priority. The ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) is well known to contribute to the regulation of intestinal microbial communities and amelioration of intestinal inflammation. However, the role of AhR signaling in NEC is unclear. Experimental NEC was induced in 4-d-old wild-type mice or mice lacking AhR expression in the intestinal epithelial cells or AhR expression in CD11c+ cells (AhRΔCD11c) by subjecting animals to twice daily hypoxic stress and gavage feeding with formula supplemented with LPS and enteric bacteria. During NEC, compared with wild-type mice treated with vehicle, littermates treated with an AhR proligand, indole-3-carbinol, had reduced expression of Il1b and Marco, a scavenger receptor that mediates dendritic cell activation and the recognition and clearance of bacterial pathogens by macrophages. Furthermore, indole-3-carbinol treatment led to the downregulation of genes involved in cytokine and chemokine, as revealed by pathway enrichment analysis. AhR expression in the intestinal epithelial cells and their cre-negative mouse littermates were similarly susceptible to experimental NEC, whereas AhRΔCD11c mice with NEC exhibited heightened inflammatory responses compared with their cre-negative mouse littermates. In seeking to determine the mechanisms involved in this increased inflammatory response, we identified the Tim-4− monocyte–dependent subset of macrophages as increased in AhRΔCD11c mice compared with their cre-negative littermates. Taken together, these findings demonstrate the potential for AhR ligands as a novel immunotherapeutic approach to the management of this devastating disease.

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Section: Discussionmentioning

confidence: 97%

Indole-3-Carbinol–Dependent Aryl Hydrocarbon Receptor Signaling Attenuates the Inflammatory Response in Experimental Necrotizing Enterocolitis

et al. 2021

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“…[7,29,30] In particular, indole-containing tryptophan metabolites, enriched in the stools of human milk-fed infants supplemented with B. infantis EVC001, have been shown to down-regulate TLR4 signaling via the aryl hydrocarbon receptor pathway. [31][32][33] Human milk feeding in concert with this evolutionarily co-evolved bacterium may therefore influence the intestinal microbiota through colonization resistance, modulation of the intestinal inflammatory environment, and the host immune system. Consistent with this concept, B. infantis EVC001 has been shown to reduce the burden of antibiotic resistance genes in the stool of human milk-fed term and preterm infants, [7,34] reduce fecal markers of intestinal inflammation, [7] and modulate systemic inflammation, [25] possibly in a sustained manner.…”

Section: Discussionmentioning

confidence: 99%

Feeding Activated Bifidobacterium infantis EVC001 to Very Low Birth Weight Infants is Associated with Significant Reduction in Rates of Necrotizing Enterocolitis

Tobias¹,

Olyaei

Laraway³

et al. 2021

Preprint

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Objectives: To assess the effects of Bifidobacterium infantis EVC001 administration on the rate of necrotizing enterocolitis (NEC) in preterm infants in a single Level IV NICU. Study Design: This was a retrospective observational analysis of 2 cohorts of VLBW infants (+/- B. infantis EVC001 probiotic) at OHSU from 2014 to 2020. Outcomes included NEC rates and NEC-associated mortality, including subgroup analysis of ELBW infants. Fishers exact test and log binomial models were used to determine differences between cohorts and risk reduction of NEC. Adjusted number needed to treat was calculated from the cohort coefficient of the model. Results: In this analysis of 483 infants, the difference in rates of NEC between cohorts was statistically significant (11.0% vs. 2.7%, P = 0.0008). The EVC001-fed cohort had a 73% risk reduction of NEC compared to the No EVC001 cohort (adjusted risk ratio 0.270, 95% CI 0.094, 0.614, P = 0.0054) resulting in an adjusted number needed to treat of 12.4 (95% CI 10.0, 23.5) for B. infantis EVC001. There was no NEC-related mortality in the EVC001-fed cohort, yielding statistically significant differences from the No EVC001 cohort overall (0% vs. 2.7%, P = 0.0274) and the ELBW subgroup (0% vs. 5.6%, P = 0.0468). Conclusion(s): B. infantis EVC001 feeding was associated with a significant reduction in the rate of NEC and NEC-related mortality in an observational study of 483 VLBW infants. B. infantis EVC001 supplementation may be considered safe and effective for reducing morbidity and mortality in the NICU.

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“…As recently shown in mice, higher maternal SCFA (e.g., acetate) was shown to reduce the allergy risk of their offspring mediated through regulatory T-cell expansion and function [17]. Similarly, in a rodent model, maternal intake of aryl hydrocarbon receptor (AHR) ligands reduces postnatal TLR4 signaling in pups and thereby protects from NEC [18]. Microbial metabolites such as indole-lactate derived from tryptophan can activate AHR, indicating that maternal microbial metabolites may also influence neonatal gut immune compartments through AHR signaling.…”

Section: Establishment Of the Gut-microbiome Mutualismmentioning

confidence: 80%

Nurturing the Early Life Gut Microbiome and Immune Maturation for Long Term Health

et al. 2021

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Early life is characterized by developmental milestones such as holding up the head, turning over, sitting up and walking that are typically achieved sequentially in specific time windows. Similarly, the early gut microbiome maturation can be characterized by specific temporal microorganism acquisition, colonization and selection with differential functional features over time. This orchestrated microbial sequence occurs from birth during the first years of age before the microbiome reaches an adult-like composition and function between 3 and 5 years of age. Increasingly, these different steps of microbiome development are recognized as crucial windows of opportunity for long term health, primarily linked to appropriate immune and metabolic development. For instance, microbiome disruptors such as preterm and Cesarean-section birth, malnutrition and antibiotic use are associated with increased risk to negatively affect long-term immune and metabolic health. Different age discriminant microbiome taxa and functionalities are used to describe age-appropriate microbiome development, and advanced modelling techniques enable an understanding and visualization of an optimal microbiome maturation trajectory. Specific microbiome features can be related to later health conditions, however, whether such features have a causal relationship is the topic of intense research. Early life nutrition is an important microbiome modulator, and ‘Mother Nature’ provides the model with breast milk as the sole source of nutrition for the early postnatal period, while dietary choices during the prenatal and weaning period are to a large extent guided by tradition and culture. Increasing evidence suggests prenatal maternal diet and infant and child nutrition impact the infant microbiome trajectory and immune competence development. The lack of a universal feeding reference for such phases represents a knowledge gap, but also a great opportunity to provide adequate nutritional guidance to maintain an age-appropriate microbiome for long term health. Here, we provide a narrative review and perspective on our current understanding of age-appropriate microbiome maturation, its relation to long term health and how nutrition shapes and influences this relationship.

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Maternal aryl hydrocarbon receptor activation protects newborns against necrotizing enterocolitis

Cited by 51 publications

References 56 publications

Indole-3-Carbinol–Dependent Aryl Hydrocarbon Receptor Signaling Attenuates the Inflammatory Response in Experimental Necrotizing Enterocolitis

Indole-3-Carbinol–Dependent Aryl Hydrocarbon Receptor Signaling Attenuates the Inflammatory Response in Experimental Necrotizing Enterocolitis

Feeding Activated Bifidobacterium infantis EVC001 to Very Low Birth Weight Infants is Associated with Significant Reduction in Rates of Necrotizing Enterocolitis

Nurturing the Early Life Gut Microbiome and Immune Maturation for Long Term Health

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