Does the gut microbiota have a role in type 1 diabetes? Early evidence from humans and animal models of the disease - PubMed (original) (raw)

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Does the gut microbiota have a role in type 1 diabetes? Early evidence from humans and animal models of the disease

M A Atkinson et al. Diabetologia. 2012 Nov.

Abstract

Despite years of appreciating the potential role of environment to influence the pathogenesis of type 1 diabetes, specific agents or mechanisms serving in such a capacity remain ill defined. This is exceedingly disappointing as the identification of factors capable of modulating the disease, either as triggers or regulators of the autoimmune response underlying type 1 diabetes, would not only provide clues as to why the disorder develops but, in addition, afford opportunities for improved biomarkers of disease activity and the potential to design novel therapeutics capable of disease abatement. Recent improvements in sequencing technologies, combined with increasing appreciation of the role of innate and mucosal immunity in human disease, have stirred strong interest in what is commonly referred to as the 'gut microbiota'. The gut (or intestinal) microbiota is an exceedingly complex microenvironment that is intimately linked with the immune system, including the regulation of immune responses. After evaluating evidence supporting a role for environment in type 1 diabetes, this review will convey current notions for contributions of the gut microbiota to human health and disease, including information gleaned from studies of humans and animal models for this autoimmune disorder.

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Figures

Fig. 1

Fig. 1

Development of the human immune system in relation to microbiota composition. Newborns have a limited capacity to initiate immune responses; both innate and adaptive immune responses are compromised. The kinetics of the maturation of the immune system varies for the different components. Dark blue, immature; medium blue, developing; light blue, adult levels. NK, natural killer. Modified from [89] with permission

Fig. 2

Fig. 2

Culture-independent genomic analysis of the human microbiome. Culture-independent techniques have advanced our capacity to survey complex microbial communities in human samples. Two sequencing approaches are utilised. As shown on the right of the figure, conserved and variable 16S rRNA genomic regions are amplified and subjected to pyrosequencing. The resulting sequences are then aligned, filtered and compared with publicly available databases of 16S rRNA sequences, enabling taxonomic classification of the bacteria present or absent in a given sample. Whole genome shotgun sequencing (on the left-hand side) provides information that enables identification of genes present and allows for subsequent comparison of enzymatic pathways and functions represented among different samples. Enzymatic databases are also available to assist in the identification of protein function, describing the richness and diversity of functional capacities provided by the analysed microbiome. Adapted by permission from Macmillan Publishers Ltd: Nat Rev Rheumatol [90], copyright 2011

Fig. 3

Fig. 3

A hypothetical model for how microbiota, based on genetic and environmental influences, may contribute to type 1 diabetes. In this model, the end result is the autoimmune destruction of pancreatic beta cells. However, for this to occur, there must be significant variations from the normal setting of development (i.e. healthy microbiota). Here, molecules produced by a given microbiota network, in response to a combination of environmental exposures and genetic susceptibility, influence proneness to type 1 diabetes. In a healthy microbiome, there is an optimal proportion of organisms, which provide signals to the developing immune system (controlled by genetic susceptibility and environmental events) that lead to a balance in immune regulatory activities that avoid, or provide susceptibility to, type 1 diabetes. At present, the list of potential means by which environment can influence microbiota development is large; with a variety of putative (i.e. unproven but previously noted) candidates listed. T1D, type 1 diabetes

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