Enteric defensins are essential regulators of intestinal microbial ecology

Salzman, Nita H.; Hung, Kuiechun; Haribhai, Dipica; Chu, Hiutung; Karlsson-Sjöberg, Jenny M. T.; Amir, El-ad David; Teggatz, Paul; Barman, Melissa; Hayward, Michael A.; Eastwood, Daniel; Stoel, Maaike; Zhou, Yanjiao; Sodergren, Erica; Weinstock, George M.; Bevins, Charles L.; Williams, Calvin B.; Bos, Nicolaas A.

doi:10.1038/ni.1825

Cited by 1,027 publications

(964 citation statements)

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“…First, epithelial differentiation from common progenitor stem cells, including the differentiation into PCs, is controlled by transcription factors, such as Math 1, under the control of the Wnt and Notch signaling pathways starting during crypt morphogenesis within the first trimester of pregnancy (12,22). It is not yet known how this pathway further develops during gestation, e.g., when it reaches its maximum and if it influences HD5 expression of the PCs.…”

Section: Discussionmentioning

confidence: 99%

Paneth cells in the developing gut: when do they arise and when are they immune competent?

et al. 2016

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Background:Little is known about the perinatal development of Paneth cells (PCs) during gestation and the relation with necrotizing enterocolitis (NEC). We aimed to investigate when PCs arise and when they become immune competent during gestation. Methods: We included 57 samples of ileum tissue of fetuses/ infants with a gestional age (GA) between 9 and 40 wk taken as part of a standard autopsy procedure. Hematoxylin-eosin staining and anti-human defensin 5 immunohistochemistry were performed. We performed a semi-quantitative assessment of (immune-competent) PC numbers per 10 crypts per tissue section per GA. results: The number of PCs and the number of immunecompetent PCs increased with increasing GA (Spearman's ρ = 0.41, P = 0.002 and ρ = 0.61, P < 0.001, respectively). Whereas significantly higher PC numbers were observed after 37 wk gestation (median 7, range 0-12) compared to preterm infants (median 0, range 0-15; P = 0.002), we counted higher numbers of immune-competent PCs already in infants with GA above 29 wk (median 6, range 0-18) compared to infants with GA under 29 wk (median 2, range 0-9; P < 0.001). conclusion: The significant increase of immune-competent PCs starting from a GA of 29 wk mimics the rise in incidence of NEC during a similar postmenstrual age in preterm infants.P aneth cells (PCs) are specialized epithelial immune cells located in the base of the crypts of Lieberkühn located in the small intestine (1,2). PCs can be seen in the gut by the first trimester and are thought to mature during gestation (1,2). PCs protect the intestinal stem cells from pathogens by stimulating stem cell differentiation, shaping the intestinal microbiota, and assist in reparation of the gut (2). To this end, they secrete (among other things) human α-defensins (HD5/HD6) (3). These defensins protect the intestinal mucosa against bacterial invasion, and are thought to be associated with initiating and adapting immunity (3). How PCs develop after the first trimester and when PCs become immune competent remains uncertain.PCs are thought to play a role in the development of NEC, a common and devastating disease most commonly observed in preterm infants (4-6). NEC involves the preterm intestine and has a complex pathophysiology in which bacterial invasion and an excessive inflammatory response is an important contributing factor (5,6). Unfortunately, the exact pathophysiology is incompletely understood.It has been hypothesized that maturation of immune-competent PCs is crucial for NEC development (4,(6)(7)(8). In the preterm gut, PCs secrete defensins that might contribute to an excessive inflammatory response as observed in NEC (4). This hypothesis is derived from the observation that extremely-low-birth-weight human infants generally have the longest interval before the onset of NEC-with a peak incidence at the postmenstrual age of 29-33 wk (4,6-8). Despite the possible role for PC-maturation in the pathophysiology of NEC, little is known about PC-maturation and functioning in the immature intestine. Therefore, we ...

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Section: Discussionmentioning

confidence: 99%

Paneth cells in the developing gut: when do they arise and when are they immune competent?

et al. 2016

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“…Furthermore, the composition of the flora is altered (69) and it is tempting to speculate that this outcome may be an important role of intestinal antimicrobial peptide expression, as it has been established that such expression responds to the microbiota (23) .…”

Section: Host Defence Influences the Microbiomementioning

confidence: 99%

Nutrition, intestinal defence and the microbiome

Kelly

2010

Proc. Nutr. Soc.

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The interaction between nutrition and infection was the subject of important work by several groups in the 1960s. The explosion of knowledge in immunology, including innate immunity, has led to increased understanding of the impact of nutrition on host defence, but much more work needs to be done in this area. In the last decade an increasing volume of work has opened up the previously obscure world of human endogenous flora. This work suggests that the microbiome, the total genetic pool of the microbiota, contributes to the already complex interaction between nutrition and infectious disease. The established concept that nutritional status, host defence and infection all impact on each other now has to be expanded into a multiple interaction, with the microbiota interacting with all three other elements. There is good evidence that the microbiome programmes host defence and drives a metabolome that impacts on energy balance, and indeed on some micronutrients. In turn, host defence shapes the microbiome, and nutritional status, particularly micronutrient status, helps determine several elements of host defence. While interventions in this area are in their infancy, the understanding of interactions that already have an enormous impact on global health is now at a threshold. The present review explores the evidence for these interactions with a view to putting potential interventions into the context of a conceptual framework.

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“…Th ese decreases in α -defensin production are probably the result of reduced expression of Wnt and Tcf-4, a transcription factor that controls the expression of several downstream target genes critical in the positioning, diff erentiation, and maturation of Paneth cells in intestinal crypts ( 34 ). Th e functional consequences of reduced α -defensin expression were subsequently confi rmed in a mouse transgenic model; in these mice, changes in HD5 expression had a profound eff ect on the intestinal microbiota, with a change from predominantly small bacilli and cocci in wild-type mice to a mixed population of bacilli and fusiform bacterial species in heterozygous mice, and fi nally to a population of predominantly fusiform bacteria in homozygous transgenic mice ( 35 ). A second study, which used peptide extracts taken from patients with active or inactive ileocolonic or colonic Crohn ' s disease, UC, and controls, compared antimicrobial activities against clinical isolates of Bacteroides vulgatus , Enterococcus faecalis , E. coli , and S. aureus .…”

Section: Host Genetic Defects In Containing Commensal Microbiotamentioning

confidence: 99%