Paneth cell defensins and the regulation of the microbiome

Salzman, Nita H.

doi:10.4161/gmic.1.6.14076

Cited by 112 publications

(93 citation statements)

References 50 publications

(49 reference statements)

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“…It is likely that the nucleotide triphosphates represent just one factor in the overall regulation of the commensal bacterial population within the gut, working in concert with other endogenous factors, e.g., antibacterial peptides (29,49). The idea that extracellular nucleotide triphosphates inhibit bacterial growth in the intestine raises the question of whether these molecules play a similar role in other sites, e.g., the mouth, vagina, and urinary and respiratory tracts.…”

Section: Discussionmentioning

confidence: 99%

Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates

Malo

Moaven

Muhammad

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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The intestinal microbiota plays a pivotal role in maintaining human health and well-being. Previously, we have shown that mice deficient in the brush-border enzyme intestinal alkaline phosphatase (IAP) suffer from dysbiosis and that oral IAP supplementation normalizes the gut flora. Here we aimed to decipher the molecular mechanism by which IAP promotes bacterial growth. We used an isolated mouse intestinal loop model to directly examine the effect of exogenous IAP on the growth of specific intestinal bacterial species. We studied the effects of various IAP targets on the growth of stool aerobic and anaerobic bacteria as well as on a few specific gut organisms. We determined the effects of ATP and other nucleotides on bacterial growth. Furthermore, we examined the effects of IAP on reversing the inhibitory effects of nucleotides on bacterial growth. We have confirmed that local IAP bioactivity creates a luminal environment that promotes the growth of a wide range of commensal organisms. IAP promotes the growth of stool aerobic and anaerobic bacteria and appears to exert its growth promoting effects by inactivating (dephosphorylating) luminal ATP and other luminal nucleotide triphosphates. We observed that compared with wild-type mice, IAP-knockout mice have more ATP in their luminal contents, and exogenous IAP can reverse the ATP-mediated inhibition of bacterial growth in the isolated intestinal loop. In conclusion, IAP appears to promote the growth of intestinal commensal bacteria by inhibiting the concentration of luminal nucleotide triphosphates.

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Section: Discussionmentioning

confidence: 99%

Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates

Malo

Moaven

Muhammad

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…These peptides are secreted into the gut lumen by leukocytes and epithelial cells and regulate host microbial interaction and the composition of the commensal microbiota [74,85]. The expression of -defensins by Paneth cells is associated with NOD2 signaling [86] and decreased -defensin production was observed in CD patients with NOD2 mutations [87,88] although it has also been raised that reduced -defensin production is only the consequence, and not the cause of the inflammation [89].…”

Section: Immune Dysregulationmentioning

confidence: 99%

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gyires¹,

Tóth²,

Zádori

2014

CPD

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Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory condition of the gastrointestinal tract. The two main forms of IBD are Crohn's disease and ulcerative colitis. According to the recent concept the disease is caused by a combination of factors, including genetics, immune dysregulation, barrier dysfunction and the change in microbial flora. Environmental factors, such as changes in diet, antibiotic use, smoking or improved domestic hygiene (e.g. eradication of intestinal helminths) probably contribute to the development and increased prevalence of IBD. Dysregulation of mucosal immunity in IBD causes an overproduction of inflammatory cytokines which resulted in uncontrolled intestinal inflammation. Based on extensive research over the last decade, besides the conventional therapy, there are several novel pathways and specific targets, on which focus new therapeutics. New therapeutics aim 1./ to correct genetic susceptibility by stimulating NOD2 expression, TLR3 signaling or inhibition of TLR4 pathway, 2./ to restore the immune dysregulation by inhibition of pro-inflammatory cytokines (TNF-, IL-6, IL-13, IL-17, IL-18, IL-21), Th1 polarisation (IL-2, IL-12, IL-23, IFN-), T-cell activation, leukocyte adhesion, as well as by immunostimulation (GM-CSF, G-CSF) and anti-inflammatory cytokines (IL-10, IL-11, IFN--1a), 3./ to restore mucosal barrier function and stimulate mucosal healing by different growth factors, such as GH, EGF, KGF, TGF-, VEGF, 4./ to restore the normal bacterial flora by antibiotics, probiotics. However, in spite of these numerous potential targets, the true value and clinical significance of most of the new biologics and molecules are not clear yet.

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“…Furthermore, non-commensal bacteria were selectively targeted and killed by α-defensins, while commensal microbiota were preserved. Equally, several studies have observed that the composition of the intestinal microbiome is directly influenced by alterations in the expression of AMPs [88,89].…”

Section: Amps and Gvhdmentioning

confidence: 99%

The Microbiome and Graft Versus Host Disease

Mathewson

Reddy

2015

Curr Stem Cell Rep

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Allogeneic hematopoietic bone marrow transplantation (BMT) is an established and curative treatment for many aggressive hematological malignancies. However, the success of allogeneic BMT is limited by graft versus host disease (GVHD) due to the attack of recipient organs. There is growing evidence that the commensal microbiota is dysregulated following allogeneic BMT. Recent studies have made significant strides in examining the role of the host and donor microbiome on GVHD severity and pathogenesis. In this review, we summarize the current knowledge of the complex roles of the microbiome on GVHD, as well as the role of the metabolome through which it confers its effects.

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Paneth cell defensins and the regulation of the microbiome

Cited by 112 publications

References 50 publications

Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates

Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

The Microbiome and Graft Versus Host Disease

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