Promotion of Autoimmune Diabetes by Cereal Diet in the Presence or Absence of Microbes Associated With Gut Immune Activation, Regulatory Imbalance, and Altered Cathelicidin Antimicrobial Peptide

Patrick, Christopher; Wang, Gensheng; Lefebvre, David E.; Crookshank, Jennifer A.; Sonier, Brigitte; Eberhard, Chandra E.; Mahdavi, Majid; Kennedy, C. R.; Brooks, Stephen P. J.; Kalmokoff, Martin; Maglio, Mariantonia; Troncone, Riccardo; Poussier, Philippe; Scott, Fraser W.

doi:10.2337/db12-1243

Cited by 51 publications

(72 citation statements)

References 53 publications

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“…We recently demonstrated that when diabetes is prevented in the diet-protected, hydrolyzed, casein-fed BBdp rat, Camp gene expression was significantly upregulated in the gut, with expression colocalizing in CD163 + M2 macrophages (3). Surprisingly, CRAMP is also detectable in the rat b-cell (Fig.…”

Section: Camp Is Expressed In the Islet B-cell And D-cell But Not In mentioning

confidence: 87%

“…Rats were anesthetized with 4% isoflurane (Abbott Laboratories, Montreal, Quebec, Canada) in oxygen and killed by exsanguination. Sterile/germ-free pancreas tissue was obtained during our previous study (3). Animals were maintained in accordance with the Canadian Council on Animal Care guidelines for the care and use of laboratory animals.…”

Section: Methodsmentioning

confidence: 99%

“…Pancreas tissue was fixed in Bouin fixative and was embedded in paraffin for histological analysis and immunohistochemistry as previously described (3). In separate experiments, anti-cathelicidin (Abcam, Toronto, ON, Canada) and anti-insulin (DAKO Canada, Inc., Burlington, ON, Canada) primary antibodies were used.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…The gut lumen contains large numbers of dietary antigens and microbes that impact the gut immune system and T1D incidence in diabetes-prone BBdp rats, NOD mice, and humans (1)(2)(3)(4)(5). The innate immune system plays a critical role in maintaining immune tolerance to commensal bacteria and dietary antigens.…”

mentioning

confidence: 99%

“…The innate immune system plays a critical role in maintaining immune tolerance to commensal bacteria and dietary antigens. Recently, our group demonstrated that innate immune host defense peptides in the gut are involved in protection from T1D in the BBdp rat (3). Specifically, Camp, the gene encoding the cathelicidin-related antimicrobial peptide (CRAMP), was upregulated in the gut of the BBdp rat when T1D was prevented by feeding a low antigen diet.…”

mentioning

confidence: 99%

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Cathelicidin Antimicrobial Peptide: A Novel Regulator of Islet Function, Islet Regeneration, and Selected Gut Bacteria

et al. 2015

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Cathelicidin antimicrobial peptide (CAMP) is a naturally occurring secreted peptide that is expressed in several organs with pleiotropic roles in immunomodulation, wound healing, and cell growth. We previously demonstrated that gut Camp expression is upregulated when type 1 diabetes–prone rats are protected from diabetes development. Unexpectedly, we have also identified novel CAMP expression in the pancreatic β-cells of rats, mice, and humans. CAMP was present even in sterile rat embryo islets, germ-free adult rat islets, and neogenic tubular complexes. Camp gene expression was downregulated in young BBdp rat islets before the onset of insulitis compared with control BBc rats. CAMP treatment of dispersed islets resulted in a significant increase in intracellular calcium mobilization, an effect that was both delayed and blunted in the absence of extracellular calcium. Additionally, CAMP treatment promoted insulin and glucagon secretion from isolated rat islets. Thus, CAMP is a promoter of islet paracrine signaling that enhances islet function and glucoregulation. Finally, daily treatment with the CAMP/LL-37 peptide in vivo in BBdp rats resulted in enhanced β-cell neogenesis and upregulation of potentially beneficial gut microbes. In particular, CAMP/LL-37 treatment shifted the abundance of specific bacterial populations, mitigating the gut dysbiosis observed in the BBdp rat. Taken together, these findings indicate a novel functional role for CAMP/LL-37 in islet biology and modification of gut microbiota.

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Section: Camp Is Expressed In the Islet B-cell And D-cell But Not In mentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cathelicidin Antimicrobial Peptide: A Novel Regulator of Islet Function, Islet Regeneration, and Selected Gut Bacteria

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Etiology of diabetes mellitus

Ramasamy¹,

Schmidt²

2014

Diabetes Mellitus and Oral Health

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TL1A regulates TCRγδ⁺ intraepithelial lymphocytes and gut microbial composition

et al. 2014

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TL1A is a proinflammatory cytokine, which is prevalent in the gut. High TL1A concentrations are present in patients with inflammatory bowel disease (IBD) and in IBD mouse models. However, the role of TL1A during steady-state conditions is relatively unknown. Here, we used TL1A knockout (KO) mice to analyse the impact of TL1A on the intestinal immune system and gut microbiota. The TL1A KO mice showed reduced amounts of small intestinal intraepithelial TCRγδ + and CD8 + T cells, and reduced expression of the activating receptor NKG2D. Moreover, the TL1A KO mice had significantly reduced body weight and visceral adipose tissue deposits, as well as lower levels of leptin and CXCL1, compared with wild-type mice. Analysis of the gut microbial composition of TL1A KO mice revealed a reduction of caecal Clostridial cluster IV, a change in the Firmicutes/Bacteroidetes ratio in caecum and less Lactobacillus spp. in the mucosal ileum. Our results show that TL1A deficiency impacts on the gut microbial composition and the mucosal immune system, especially the intraepithelial TCRγδ + T-cell subset, and that TL1A is involved in the establishment of adipose tissue. This research contributes to a broader understanding of TL1A inhibition, which is increasingly considered for treatment of IBD.Keywords: γδ T cells r Gut microbiota r Intraepithelial lymphocytes (IELs) r NKG2D r TL1A Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Peter Tougaard e-mail: peto@sund.ku.dk IntroductionAn increased production of proinflammatory cytokines is associated with the development of adiposity. The consequential impact of increased cytokine levels is especially pronounced in abdominal adipose tissue, and in the gut, and causes a chronic C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 866Peter Tougaard et al. Eur. J. Immunol. 2015. 45: 865-875 state of low-grade inflammation in the host [1,2]. This inflammatory state is associated with changes in the gut epithelial functions, composition of the gut microbiota and gut immune homeostasis [2][3][4]. TNF-α and other TNF family cytokines have especially been associated with this low-grade inflammatory state [2,4,5]. However, further studies about these cytokines and their role in low-grade inflammation are required. The proinflammatory cytokine TL1A is emerging as a new important player of the TNF superfamily. TL1A is prevalent in the intestine and tightly connected to inflammatory diseases of the gut, i.e. inflammatory bowel disease (IBD) [6][7][8]. However, the influence of TL1A on gut microbiota composition and low-grade inflammation remains elusive. TL1A is expressed by several different cell types, including endothelial cells and myeloid cells, such as dendritic cells and macrophages [6,9]. Multiple bacterial species from the gut have been shown to directly induce TL1A expression in monocytes and monocyte-derived dendritic cells [10]. The TL1A receptor, death receptor 3 (DR3), is primarily expre...

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Promotion of Autoimmune Diabetes by Cereal Diet in the Presence or Absence of Microbes Associated With Gut Immune Activation, Regulatory Imbalance, and Altered Cathelicidin Antimicrobial Peptide

Cited by 51 publications

References 53 publications

Cathelicidin Antimicrobial Peptide: A Novel Regulator of Islet Function, Islet Regeneration, and Selected Gut Bacteria

Cathelicidin Antimicrobial Peptide: A Novel Regulator of Islet Function, Islet Regeneration, and Selected Gut Bacteria

Etiology of diabetes mellitus

TL1A regulates TCRγδ⁺ intraepithelial lymphocytes and gut microbial composition

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Promotion of Autoimmune Diabetes by Cereal Diet in the Presence or Absence of Microbes Associated With Gut Immune Activation, Regulatory Imbalance, and Altered Cathelicidin Antimicrobial Peptide

Cited by 51 publications

References 53 publications

Cathelicidin Antimicrobial Peptide: A Novel Regulator of Islet Function, Islet Regeneration, and Selected Gut Bacteria

Cathelicidin Antimicrobial Peptide: A Novel Regulator of Islet Function, Islet Regeneration, and Selected Gut Bacteria

Etiology of diabetes mellitus

TL1A regulates TCRγδ+ intraepithelial lymphocytes and gut microbial composition

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TL1A regulates TCRγδ⁺ intraepithelial lymphocytes and gut microbial composition