Modulation of the diet and gastrointestinal microbiota normalizes systemic inflammation and β-cell chemokine expression associated with autoimmune diabetes susceptibility

Abstract

Environmental changes associated with modern lifestyles may underlie the rising incidence of Type 1 diabetes (T1D). Our previous studies of T1D families and the BioBreeding (BB) rat model have identified a peripheral inflammatory state that is associated with diabetes susceptibility, consistent with pattern recognition receptor ligation, but is independent of disease progression. Here, compared to control strains, islets of spontaneously diabetic BB DRlyp/lyp and diabetes inducible BB DR+/+ weanlings provided a standard cereal diet expressed a robust proinflammatory transcriptional program consistent with microbial antigen exposure that included numerous cytokines/chemokines. The dependence of this phenotype on diet and gastrointestinal microbiota was investigated by transitioning DR+/+ weanlings to a gluten-free hydrolyzed casein diet (HCD) or treating them with antibiotics to alter/reduce pattern recognition receptor ligand exposure. Bacterial 16S rRNA gene sequencing revealed that these treatments altered the ileal and cecal microbiota, increasing the Firmicutes:Bacteriodetes ratio and the relative abundances of lactobacilli and butyrate producing taxa. While these conditions did not normalize the inherent hyper-responsiveness of DR+/+ rat leukocytes to ex vivo TLR stimulation, they normalized plasma cytokine levels, plasma TLR4 activity levels, the proinflammatory islet transcriptome, and β-cell chemokine expression. In lymphopenic DRlyp/lyp rats, HCD reduced T1D incidence, and the introduction of gluten to this diet induced islet chemokine expression and abrogated protection from diabetes. Overall, these studies link BB rat islet-level immunocyte recruiting potential, as measured by β-cell chemokine expression, to a genetically controlled immune hyper-responsiveness and innate inflammatory state that can be modulated by diet and the intestinal microbiota.

Recent Advances on Microbiota Involvement in the Pathogenesis of Autoimmunity

“…A growing number of studies have supported the striking linking of altered microbiota composition with the onset of several different autoimmune disorders (Table 1). These include Type I diabetes (T1D) [16,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53]; rheumatoid arthritis (RA) [54,55,56,57,58,59,60,61,62]; systemic lupus erythematosus (SLE) [63,64,65,66,67]; inflammatory bowel disease (IBD) encompassing Crohn’s disease (CD) and ulcerative colitis (UC) [68,69,70,71,72,73,74,75,76,77,78]; Behcet’s disease (BD) [79,80,81,82]; autoimmune skin conditions including vitiligo [83], psoriasis vulgaris [84,85,86,87,88], and atopic dermatitis [89,90,91,92,93,…”

“…Recently, Henschel [50] reported that the peripheral inflammatory state correlated with autoimmune diabetes susceptibility was kept under control following modulation of the diet and gastrointestinal microbiota. More specific, spontaneous diabetic BB DR lyp / lyp and diabetes inducible BB DR + / + weanings fed with a standard cereal diet presented a considerable pro-inflammatory transcriptional expression consistent with microbial antigen exposure.…”

“…Moreover, the introduction of gluten to HCD reverted these effects. The sequencing of bacterial 16S rRNA gene highlighted that diet changes or antibiotic treatments disrupt ileal and cecal microbiota, with an enhancement in Firmicutes / Bacteriodetes ratio and in the relative abundances of lactobacilli and butyrate producing taxa [50]. A recent study of Mullaney et al [52] found that specific gut microbial imbalance were linked to T1D susceptibility alleles in mice.…”

Changes in insulin, glucagon and ER stress precede immune activation in type 1 diabetes

“…These studies frequently use non-physiological concentrations of pro-inflammatory cytokines to mimic the autoimmune attack on isolated islets. However, there are only a few studies on the natural course of pancreas gene expression in prediabetes (Crevecoeur et al 2017, Henschel et al 2018.…”

Co-morbidity of type 1 diabetes and endometriosis: bringing a new paradigm into focus

“…Collectively, the results suggest that current clinical management of ENDO may compromise women with accompanying T1DM and thus, advocate for physicians to recognize patients with ENDO and T1DM co-morbidities for provision of appropriate and optimal care. Given increasing support for the role of specific diets in the promotion of a pro-inflammatory state that is associated with T1DM (Vaarala 2011, Knip et al 2012, van Bussel et al 2013 and ENDO (Saguyod et al 2018, it is prudent to consider dietary changes, which can significantly impact the intestinal microbiota, for management of co-morbid ENDO and T1DM (Henschel et al 2018). Similarly, the use of metformin for targeting co-morbid T1DM and ENDO may have value, given recent evidence for its efficacy in reducing T1DM (Bjornstad et al 2018, Cree-Green et al 2019 and hindering the progression of ENDO lesions and associated signaling pathways (Takemura et al 2007, Yilmaz et al 2010.…”