Is the origin of type 1 diabetes in the gut?

Abstract

In type 1 diabetes, insulin-producing beta-cells in the pancreas are destroyed by immune-mediated mechanisms. The manifestation of the disease is preceded by the so-called pre-diabetic period that may last several years and is characterized by the appearance of circulating autoantibodies against beta-cell antigens. The role of the gut as a regulator of type 1 diabetes was suggested in animal studies, in which changes affecting the gut immune system modulated the incidence of diabetes. Dietary interventions, alterations in the intestinal microbiota and exposure to enteric pathogens, regulate the development of autoimmune diabetes in animal models. It has been demonstrated that these modulations affect the gut barrier mechanisms and intestinal immunity. Because the pancreas and the gut belong to the same intestinal immune system, the link between autoimmune diabetes and the gut is not unexpected. The gut hypothesis in the development of type 1 diabetes is also supported by the observations made in human type 1 diabetes. Early diet could modulate the development of beta-cell autoimmunity; weaning to hydrolysed casein formula decreased the risk of beta-cell autoimmunity by age 10 in the infants at genetic risk. Increased gut permeability, intestinal inflammation with impaired regulatory mechanisms and dysregulated oral tolerance have been observed in children with type 1 diabetes. The factors that contribute to these intestinal alterations are not known, but interest is focused on the microbial stimuli and function of innate immunity. It is likely that our microbial environment does not support the healthy maturation of the gut and tolerance in the gut, and this leads to the increasing type 1 diabetes as well as other immune-mediated diseases regulated by intestinal immune system. Thus, the interventions, aiming to prevent or treat type 1 diabetes in humans, should be targeting the gut immune system. Keywords: beta-cell autoimmunity; enteral infections; gut microbiota; intestinal permeabilityThe present concept of the pathogenesis of type 1 diabetes (T1D) is that T-cell-mediated immune mechanisms destroy the pancreatic insulin-producing beta cells. 1 CD8 T cells have been suggested to be responsible for the beta-cell killing, but there is also accumulating evidence showing that cytokines, such as IFN-gamma, IL-1beta and IL-17 released by T cells could cause beta-cell apoptosis. 2,3 The association of T1D with HLA DQB1*0302 and 02 alleles supports the role of antigen-specific T cells in the pathogenesis, however. In most patients, a pre-diabetic phase lasting several years characterized by the appearance of circulating beta-cell autoantibodies is seen, which further supports the involvement of (auto)immune mechanisms (in the majority of the cases). It is likely that infection etiology has a role in beta-cell destruction, but the available data suggest that a direct virus-induced beta-cell death might be important only in a minority of cases. Infection of beta cells may trigger autoimmunity or potentiate the destructi...

The gut microbiota and inflammatory noncommunicable diseases: Associations and potentials for gut microbiota therapies

“…Increased gut permeability and intestinal inflammation with impaired immune-regulatory mechanisms have been shown in children with allergic disease 55 , and also in children with type 1 diabetes 56 . Consistent with reports of dysbiosis in children with allergic manifestations, an aberrant gut microbiome has been associated with type 1 diabetes 57,58 .…”

Стан Мікробіоти Порожнини Товстого Кишечника У хворих На цукровий Діабет 1-Го Типу Залежно Від Тяжкості Клінічного Перебігу

“…У будь-якому біоценозі, у тому числі у товстій киш-ці, домінують представники автохтонної облігатної мікрофлори, якій відведена провідна роль у підтрим-ці симбіотичних відношень між організмом людини та мікрофлорою, а також у регуляції міжмікробних від-ношень, ця мікрофлора є ключовою складовою мікро-біоценозу [6][7][8]10].…”

“…При зниженні у кишковому біо-ценозі рівня бактерій роду Bifidobacterium і Lactobacillus та їх біологічної активності порушуються процеси всмоктування поживних речовин, засвоєння мікроеле-ментів та екзогенних вітамінів, знижується активність ряду ферментів і біологічно активних речовин, суттє-во знижується колонізаційна резистентність слизових оболонок шлунково-кишкового тракту, що сприяє роз-витку інфекційно-запальних захворювань [2,3,7,8].…”

“…Перераховане вище свідчить про необхідність ви-вчення якісного та кількісного складу мікрофлори товстої кишки хворих на ЦД 1-го типу з метою вдоско-налення діагностики та лікувальної тактики не тільки основного, а також супутніх захворювань (запальних процесів лор-органів) [3,8].…”

GUT-the Trojan Horse in Remote Organs’ Autoimmunity

“…In contrast, host-derived hormones increase the bacterial proliferative capacity and pathogenicity. In the gut lumen, this type of cross-talk between microorganisms and the host is presumed to be performed continually through various kinds of luminal molecules [65,66]. Dopamine, norepinephrine, nitric oxide and the inhibitory transmitter GABA are few examples of our own gut microbiota generating compound that interact with our own endocrine system and can be called the microbial endocrinology [64][65][66].…”