High-risk genotypes for type 1 diabetes are associated with the imbalance of gut microbiome and serum metabolites

Abstract

BackgroundThe profile of gut microbiota, serum metabolites, and lipids of type 1 diabetes (T1D) patients with different human leukocyte antigen (HLA) genotypes remains unknown. We aimed to explore gut microbiota, serum metabolites, and lipids signatures in individuals with T1D typed by HLA genotypes.MethodsWe did a cross-sectional study that included 73 T1D adult patients. Patients were categorized into two groups according to the HLA haplotypes they carried: those with any two of three susceptibility haplotypes (DR3, DR4, DR9) and without any of the protective haplotypes (DR8, DR11, DR12, DR15, DR16) were defined as high-risk HLA genotypes group (HR, n=30); those with just one or without susceptibility haplotypes as the non-high-risk HLA genotypes group (NHR, n=43). We characterized the gut microbiome profile with 16S rRNA gene amplicon sequencing and analyzed serum metabolites with liquid chromatography-mass spectrometry.ResultsStudy individuals were 32.5 (8.18) years old, and 60.3% were female. Compared to NHR, the gut microbiota of HR patients were characterized by elevated abundances of Prevotella copri and lowered abundances of Parabacteroides distasonis. Differential serum metabolites (hypoxanthine, inosine, and guanine) which increased in HR were involved in purine metabolism. Different lipids, phosphatidylcholines and phosphatidylethanolamines, decreased in HR group. Notably, Parabacteroides distasonis was negatively associated (p ≤ 0.01) with hypoxanthine involved in purine metabolic pathways.ConclusionsThe present findings enabled a better understanding of the changes in gut microbiome and serum metabolome in T1D patients with HLA risk genotypes. Alterations of the gut microbiota and serum metabolites may provide some information for distinguishing T1D patients with different HLA risk genotypes.

Gut microbiome and blood glucose control in type 1 diabetes: a systematic review

“…All the authors found not significant differences in alpha diversity between T1D and healthy groups. Nevertheless, this result is not in agreement with that of other similar studies, not included in this review, in which a significantly different alpha diversity was registered, both by 16S ( 35 , 36 ) and shotgun ( 37 ) sequencing, comparing T1D and healthy subjects. In all the studies selected in this review, the beta diversity of gut microbiota was estimated.…”

Early-life exposures to specific commensal microbes prevent type 1 diabetes

“…In these studies some microbes are associated with higher risk of autoimmunity while others are associated with lower risk of disease (5,6). Intriguingly, Parabacteroides distasonis has, in some studies (6,53,54,71), been associated with a higher risk of developing T1D, yet was associated with protecIon in our findings. One potenIal explanaIon is that Iming of exposure to immunomodulatory microbes such as P. distasonis influences the trajectory of immune development toward tolerance or autoimmunity.…”

“…Another powerful feature of the PedsCom gnotobioIc model is the ability to determine the impact of specific microbes by reconstrucIng the community without those microbes. Since P. distasonis, AnaerosFpes sp., and C. intesFnale induced pTregs, did not induce systemic anIbodies, and are epidemiologically associated with T1D (6,(51)(52)(53)(54), we hypothesized that one or more of these three microbes is necessary for the PedsCom consorIum to protect from diabetes. To directly test this hypothesis, we generated a new six-member community, PedsCom-6, that lacks P. distasonis, AnaerosFpes sp., and C. intesFnale (Fig.…”

Important denominator between autoimmune comorbidities: a review of class II HLA, autoimmune disease, and the gut

“…These relationships are unsurprising when considering the common risk-associated HLA haplotypes by autoimmunities. For example, Prevotella copri is more abundant in RA, JIA, and T1D patients compared to controls and is also associated HLA DR3-DQ2 and DR4-DQ8 ( 98 , 99 , 120 , 131 ). This pattern makes sense when considering that HLA DR4-DQ8 is a risk-associated genotype for both RA and T1D.…”

“…Future research could benefit from analyzing risk haplotypes against each other to verify their similarities and differences in influence over the microbiome. Compared to low-risk or neutral haplotypes, high-risk HLA DR3-DQ2 and DR4-DQ8 are associated with higher abundance of Prevotella copri at the species level, Agathobacter, Bacteroides, Blautia, Dorea, Enterococcus, Intestinimonas, Klebsiella, Veillonella at the genus level, and Enterobacteriaceae, which includes Klebsiella, Lachnospiraceae, which includes Agathobacter, Blautia, and Dorea, and Ruminococcaceae, which includes Intestinimonas, at the family level (36,(129)(130)(131)(132). Bifidobacterium and Lactobacillus stand out as either negatively associated or in lower abundance in DR3-DQ2 and DR4-DQ8 compared to protective or neutral alleles (36,39,133,134).…”