Abstract
Intestinal microbiota disruption is associated with acute gastrointestinal (GI) Graft-versus-Host Disease (GvHD) and poor outcome after allogeneic stem cell transplantation (ASCT). Here, in a retrospective analysis of 200 patients undergoing ASCT at the Regensburg University Medical Center, we assessed the relative expression of Paneth cell antimicrobial peptides (AMPs), Human Defensins (HD) 5 and 6 and regenerating islet-derived 3α (Reg3α), in 292 human intestinal biopsies as well as Reg3α serum levels in relation to acute GI GvHD. In the absence of GI GvHD, the relative expression of Paneth cell AMPs was significantly higher in the small intestine (duodenum to ileum) than in the stomach and large intestine (cecum to rectum) for Reg3α (p≤0.001), HD5 (p≤0.002) and HD6 (p≤0.02). Acute stage 2–4 GI GvHD was associated with reduced expression of AMPs in the small intestine (p≤0.01) in comparison to stage 0–1 disease, accompanied by a decrease in Paneth cell count in case of severe acute GI GvHD (p<0.001). The opposite held true for the large intestine as we found stage 2–4 GI GvHD correlated with significantly higher expression of HD5, HD6, and Reg3α compared to mild or no acute GI GvHD (p≤0.002). Severe GI GvHD in both the lower and the upper GI tract also correlated with higher serum concentrations of Reg3α (p = 0.002). As indirect markers of intestinal microbiome diversity low levels of urinary 3-indoxyl sulfate levels were associated with severe stages of acute GI GvHD compared to mild stage or no acute GI GvHD (p = 0.05). In conclusion, acute GI GvHD correlates with intestinal expression of HD5, HD6 and Reg3α as well as Reg3α serum levels and is associated with intestinal dysbiosis.
Highlights
For all three Paneth cell antimicrobial peptides (AMPs) (Reg3α, HD5 und HD6), we found significant differences in relative expression between stomach, small intestine and large intestine according to the physiological distribution of Paneth cells in the GI tract
The composition of intestinal microbiota seems to play a key role in the pathophysiology of acute GI Graft-versus-Host Disease (GvHD) and has been reported to influence the outcome of allogeneic stem cell transplantation (ASCT) recipients. [1, 2] Paneth cells contribute essentially to the maintenance of a highly diverse intestinal microbiome and intestinal homeostasis by the production of AMPs
Graft-versus-host disease correlates with expression of antimicrobial peptides of the crypt and, prevent microbial invasion into the crypt environment. [8, 9] According to the physiological distribution of Paneth cells in the GI tract, we observed a significantly higher relative expression of Paneth cell AMPs HD5, HD6 and regenerating islet-derived 3α (Reg3α) in mucosal biopsies of the small intestine including duodenum, jejunum and ileum compared to the large intestine comprising colon and rectum
Summary
The gut microbiota play a central role in the outcome of allogeneic stem cell transplantation (ASCT). [1, 2] During the course of ASCT a loss of intestinal microbiota diversity and a shift toward an enteropathogenic flora were observed first in mice models and later in humans. [3, 4] Major shifts in microbial composition were especially pronounced in individuals, who received antibiotic treatment or suffered from acute gastrointestinal (GI) Graft-versus-Host Disease (GvHD). [4] commensal bacteria, e.g. Clostridiales, seem to be crucial for the maintenance of immunological homeostasis and intestinal epithelial integrity and for providing anti-inflammatory effects as demonstrated in both mouse models [5, 6] and humans. [1, 7]Paneth cells play an important role in the maintenance of a balanced gut microbiota composition and contribute to intestinal homeostasis and innate immunity. [8] Located mainly at the crypt base of the small intestine, Paneth cells, by sensing bacteria and bacterial antigens, release various antimicrobial peptides (AMPs) including enteric α–defensins, lysozyme and secretory phospholipase A2 into the small intestinal lumen. [9] They function as important regulators of microbial density, prevent microbial invasion into the crypt microenvironment and protect intestinal stem cells. [10] In humans two enteric α–defensins, human defensin (HD) 5 and 6, have been identified. [9, 10] Another important AMP secreted by Paneth cells is regenerating islet-derived 3α (Reg3α). [11] Together they exert a wide antimicrobial activity against Gram-positive and Gram-negative bacteria. The gut microbiota play a central role in the outcome of allogeneic stem cell transplantation (ASCT). Paneth cells play an important role in the maintenance of a balanced gut microbiota composition and contribute to intestinal homeostasis and innate immunity. In this retrospective study of patients undergoing ASCT, we analyzed relative gene expression of Paneth cell AMPs HD5, HD6 and Reg3α in 292 intestinal biopsies and determined serum levels of Reg3α in relation to acute GvHD of the GI tract. Intestinal biopsies were obtained in patients with clinical suspicion of acute GI GvHD by endoscopy. [14] 28% of the biopsies were taken after day 180 with a mean of 381 days post-transplantation from patients either suffering from prolonged delayed GI GvHD or developing GI GvHD after donor lymphocyte infusion or cessation of immunosuppression because of imminent relapse The protocol allowed inclusion of screening biopsies from asymptomatic patients early after ASCT. 72% of all biopsies were taken within the first 180 days post-transplant with a mean time of 55 days after ASCT since classic acute GI GvHD and late acute GI GvHD occur usually within the first 180 days after ASCT. [14] 28% of the biopsies were taken after day 180 with a mean of 381 days post-transplantation from patients either suffering from prolonged delayed GI GvHD or developing GI GvHD after donor lymphocyte infusion or cessation of immunosuppression because of imminent relapse
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