Calcinaro F, Dionisi S, Marinaro M, Candeloro P, Bonato V, Marzotti S et al.. Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse. Diabetologia 48: 1565-1575

Department of Internal Medicine, University of Perugia, Italy.
Diabetologia (Impact Factor: 6.88). 09/2005; 48(8):1565-75. DOI: 10.1007/s00125-005-1831-2
Source: PubMed

ABSTRACT Recent observations suggest the involvement of the gastrointestinal tract in the pathogenesis of islet autoimmunity. Thus, the modulation of gut-associated lymphoid tissue may represent a means to affect the natural history of the disease. Oral administration of probiotic bacteria can modulate local and systemic immune responses; consequently, we investigated the effects of oral administration of the probiotic compound VSL#3 on the occurrence of diabetes in non-obese diabetic (NOD) mice.
VSL#3 was administered to female NOD mice three times a week starting from 4 weeks of age. A control group received PBS. Whole blood glucose was measured twice a week. IFN-gamma and IL-10 production/expression was evaluated by ELISA in culture supernatants of mononuclear cells isolated from Peyer's patches and the spleen, and by real-time PCR in the pancreas. Insulitis was characterised by immunohistochemistry and histomorphometric studies.
Early oral administration of VSL#3 prevented diabetes development in NOD mice. Protected mice showed reduced insulitis and a decreased rate of beta cell destruction. Prevention was associated with an increased production of IL-10 from Peyer's patches and the spleen and with increased IL-10 expression in the pancreas, where IL-10-positive islet-infiltrating mononuclear cells were detected. The protective effect of VSL#3 was transferable to irradiated mice receiving diabetogenic cells and splenocytes from VSL#3-treated mice.
Orally administered VSL#3 prevents autoimmune diabetes and induces immunomodulation by a reduction in insulitis severity. Our results provide a sound rationale for future clinical trials of the primary prevention of type 1 diabetes by oral VSL#3 administration.

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Available from: Francesco Dotta, Sep 02, 2015
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    • "It has been hypothesized that beneficial microbes or probiotics can protect against diabetes ( Neu et al . , 2010 ) . VSL#3 has been shown to prevent diabetes in NOD mice when administered after weaning ( Calcinaro et al . , 2005 ) . Yet , admin - istration to germ - free NOD neonatal mice shows no effect ( Yurkovetskiy et al . , 2013 ) . Although NOD mice were deficient in several beneficial microbes present in the probiotic VSL#3 , we found that the administration of VSL#3 failed to protect against accelerated diabetes in NOD mice . Despite VSL#3 being adminis"
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    ABSTRACT: Accumulating evidence supports that the intestinal microbiome is involved in Type 1 diabetes (T1D) pathogenesis through the gut-pancreas nexus. Our aim was to determine whether the intestinal microbiota in the non-obese diabetic (NOD) mouse model played a role in T1D through the gut. To examine the effect of the intestinal microbiota on T1D onset, we manipulated gut microbes by: (1) the fecal transplantation between non-obese diabetic (NOD) and resistant (NOR) mice and (2) the oral antibiotic and probiotic treatment of NOD mice. We monitored diabetes onset, quantified CD4+T cells in the Peyer's patches, profiled the microbiome and measured fecal short-chain fatty acids (SCFA). The gut microbiota from NOD mice harbored more pathobionts and fewer beneficial microbes in comparison with NOR mice. Fecal transplantation of NOD microbes induced insulitis in NOR hosts suggesting that the NOD microbiome is diabetogenic. Moreover, antibiotic exposure accelerated diabetes onset in NOD mice accompanied by increased T-helper type 1 (Th1) and reduced Th17 cells in the intestinal lymphoid tissues. The diabetogenic microbiome was characterized by a metagenome altered in several metabolic gene clusters. Furthermore, diabetes susceptibility correlated with reduced fecal SCFAs. In an attempt to correct the diabetogenic microbiome, we administered VLS#3 probiotics to NOD mice but found that VSL#3 colonized the intestine poorly and did not delay diabetes. We conclude that NOD mice harbor gut microbes that induce diabetes and that their diabetogenic microbiome can be amplified early in life through antibiotic exposure. Protective microbes like VSL#3 are insufficient to overcome the effects of a diabetogenic microbiome.The ISME Journal advance online publication, 14 August 2015; doi:10.1038/ismej.2015.114.
    The ISME Journal 08/2015; DOI:10.1038/ismej.2015.114 · 9.27 Impact Factor
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    • "Multiple low dose streptozotocin induced lymphocyte infiltration in islets of all groups. The degree of infiltration was determined by blinded analysis of insulitis grading [34]. Control and hydrocortisone treated mice showed no signs of lymphocyte infiltration (Figure 6B). "
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    ABSTRACT: Role of GLP-1 and GIP in beta cell compensatory responses to beta cell attack and insulin resistance were examined in C57BL/6 mice lacking functional receptors for GLP-1 and GIP. Mice were treated with multiple low dose streptozotocin or hydrocortisone. Islet parameters were assessed by immunohistochemistry and hormone measurements were determined by specific enzyme linked immunoassays. Wild-type streptozotocin controls exhibited severe diabetes, irregularly shaped islets with lymphocytic infiltration, decreased Ki67/TUNEL ratio with decreased beta cell and increased alpha cell areas. GLP-1 and GIP were co-expressed with glucagon and numbers of alpha cells mainly expressing GLP-1 were increased. In contrast, hydrocortisone treatment and induction of insulin resistance increased islet numbers and area, with enhanced beta cell replication, elevated mass of beta and alpha cells, together with co-expression of GLP-1 and GIP with glucagon in islets. The metabolic responses to streptozotocin in GLP-1RKO and GIPRKO mice were broadly similar to C57BL/6 controls, although decreases in islet numbers and size were more severe. In contrast, both groups of mice lacking functional incretin receptors displayed substantially impaired islet adaptations to insulin resistance induced by hydrocortisone, including marked curtailment of expansion of islet area, beta cell mass and islet number. Our observations cannot be explained by simple changes in circulating incretin concentrations, suggesting that intra-islet GLP-1 and GIP make a significant contribution to islet adaptation, particularly expansion of beta cell mass and compensatory islet compensation to hydrocortisone and insulin resistance.
    PLoS ONE 06/2014; 9(6):e101005. DOI:10.1371/journal.pone.0101005 · 3.23 Impact Factor
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    • "VSL#3 has been also shown to reduce the depletion of hepatic natural killer cells and minimize the activation of NFkB in wild-type male C57BL6 mice fed a high fat diet [105]. A study investigating the effects of VSL#3 on the occurrence of diabetes in non-obese diabetic mice showed this probiotic mixture has impaired the development of T1D via three major pathways: 1) supressing both inflammation and pancreatic β cell death, 2) increasing the production of IL-10 from Peyer’s patches, a component of the gut-associated lymphoid tissue, and 3) increasing the IL-10 expression in the pancreas [106]. IL-10 is an anti-inflammatory cytokine which inhibits antigen presentation and proinflammatory cytokine production [107], whereas depletion of hepatic natural killer cells is linked to the development of hepatic insulin resistance [108]. "
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    ABSTRACT: Diabetes is a condition of multifactorial origin, involving several molecular mechanisms related to the intestinal microbiota for its development. In type 2 diabetes, receptor activation and recognition by microorganisms from the intestinal lumen may trigger inflammatory responses, inducing the phosphorylation of serine residues in insulin receptor substrate-1, reducing insulin sensitivity. In type 1 diabetes, the lowered expression of adhesion proteins within the intestinal epithelium favours a greater immune response that may result in destruction of pancreatic beta cells by CD8+ T-lymphocytes, and increased expression of interleukin-17, related to autoimmunity. Research in animal models and humans has hypothesized whether the administration of probiotics may improve the prognosis of diabetes through modulation of gut microbiota. We have shown in this review that a large body of evidence suggests probiotics reduce the inflammatory response and oxidative stress, as well as increase the expression of adhesion proteins within the intestinal epithelium, reducing intestinal permeability. Such effects increase insulin sensitivity and reduce autoimmune response. However, further investigations are required to clarify whether the administration of probiotics can be efficiently used for the prevention and management of diabetes.
    Nutrition Journal 06/2014; 13(1):60. DOI:10.1186/1475-2891-13-60 · 2.64 Impact Factor
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