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Probiotic normalization of systemic inflammation in siblings of Type 1 diabetes patients

ABSTRACT: BACKGROUND. The incidence of Type 1 Diabetes (T1D) has significantly increased in recent decades and coincides with lifestyle changes that have likely altered the composition of the gut microbiota. Dysbiosis and gut barrier dysfunction are associated with T1D, and notably, our studies have identified an inflammatory state in T1D families that is consistent microbial antigen exposure. METHODS. We conducted a 6-week, single-arm, open-label trial to investigate whether daily multi-strain probiotic (Bifidobacteria, Lactobacillus, and Streptococcus) supplementation could reduce the familial inflammatory state in 25 unaffected siblings of diabetes patients. RESULTS. Probiotic supplementation was found safe and well-tolerated; there were no adverse events and participant adherence was 93%. Bacterial 16S rDNA gene sequencing of stool revealed that community alpha and beta diversity were not altered between the pre- and post-supplement samplings. LEfSe analyses identified post-supplement enrichment of the family Lachnospiraceae, producers of the anti-inflammatory short chain fatty acid butyrate. Systemic inflammation was measured by plasma induced transcription and quantified with a gene ontology-based composite inflammatory index (I.I.com). After supplementation, I.I.com was reduced (p=0.017), and pathway analysis predicted inhibition of IL17A, lipopolysaccharide, NFkB, IL1B, and TNF (Z-score≤-2.0) and activation of IL10RA (Z-score=2.0). Post-supplement plasma levels of IL12p40, IL-13, IL-15, IL-18, CCL2, CCL24 were reduced (p<0.05), while butyrate levels trended 2.4-fold higher (p=0.06). CONCLUSION. There is a substantial need for safe, broadly applicable therapies to reduce T1D susceptibility. This study indicates that investigations of prebiotic and probiotic strategies are warranted as they may be efficacious either alone or in combination with other therapeutic agents.

ORGANISM(S): Homo sapiens

PROVIDER: GSE162622 | GEO | 2022/03/01

REPOSITORIES: GEO

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Project description:Type 1 diabetes (T1D) is an autoimmune disease characterized by destruction of the pancreatic β-cells. T1D pathogenesis has a strong genetic basis. However, in recent decades, the prevalence of high-risk HLA haplotypes among new diagnoses has declined, the age of onset has decreased, and T1D incidence has increased. These changes are consistent with increased environmental pressure and coincide with introduction of the Western diet, widespread antibiotic use and reduced breast feeding. These factors are thought to drive intestinal dysbiosis, increased gut permeability and systemic inflammation. Notably, our studies of T1D families and the BioBreeding (BB) rat have identified a peripheral inflammatory state associated with diabetes susceptibility that is consistent with microbial antigen exposure and pattern recognition receptor ligation. Lactiplantibacillus plantarum 299v (Lp299v), a probiotic strain, is reported to increase plasma and stool levels of anti-inflammatory short chain fatty acids (SCFA) and promote IL-10 signaling in colonic derived macrophages and T-cells. Here we investigated the effect of Lp299v supplement on T1D progression and inflammatory phenotypes in diabetes prone BB DRlyp/lyp rats. Rats were weaned at 21 days onto a normal cereal diet (ND) or a gluten-free hydrolyzed casein diet (HCD), with and without daily Lp299v supplementation. All DRlyp/lyp ND rats developed T1D by day 83 (mean time to onset of 62.8+/-7.9 days). DRlyp/lyp ND+Lp299v rats exhibited an insignificant delay in T1D onset (62.6+/-6.5 days), however 8% remained diabetes-free to day 130. Providing DRlyp/lyp rats HCD prevented T1D in 17% of rats (to age 130 days) and significantly delayed onset (mean time to onset 72.8+/-7.3 days, p<0.001). Providing DRlyp/lyp rats HCD+Lp299v prevented T1D in 25% of rats and more robustly delayed onset (mean time to onset 84.9 +/-14.3 days, p<0.001). While multiplex ELISA failed to detect significantly altered plasma cytokine/chemokine levels at 40 days of life, plasma induced transcription revealed greatest normalization of systemic inflammation in the HCD+Lp299v group. Plasma SCFA levels (propionate and butyrate, p<0.01) were elevated in the HCD+Lp299v group compared to the ND group. Global gene expression analysis of pancreatic islets was conducted at 40 days, prior to insulitis. Endoplasmic reticulum (ER) stress has been implicated in the formation of islet neoantigens that may underlie the initial loss of immune tolerance in T1D. Under one or both diets, Lp299v favorably modulated islet expression levels of pathways and transcripts related to inflammation and innate immunity (Cxcl9, Cxcl10), oxidative stress (Gsta1, Gsta4, Gstp1, Gstk1), as well as ER stress and unfolded protein response (Cirbp, Edem1, Hspa1a, Atf4). These ongoing studies add to a growing understanding that inherited susceptibility can be modulated by diet and microbiota.

Project description:A need exists for biomarkers in T1D that can 1) sensitively and specifically detect disease-related immune activity prior to, and independent of, measurement of auto-antibodies towards islet cell antigens; 2) define immunopathological mechanisms; and 3) monitor changes in the inflammatory state associated with disease progression or response to therapeutic intervention. In an effort to fill this gap, we have applied a novel bioassay to both human and BB rat T1D whereby the complex milieu of inflammatory mediators present in plasma can be indirectly detected through their ability to drive transcription in peripheral blood mononuclear cells (PBMCs) drawn from healthy, unrelated donors. The resultant gene expressions are comprehensively measured with a microarray. In our human studies, we find that plasma of recent-onset T1D patients induces expression of a pro-inflammatory signature consisting in part of many interleukin-1 (IL-1) regulated genes related to immunological activation and immunocyte chemotaxis compared to unrelated healthy controls. This signature has been found to resolve in long-standing T1D subjects (>10 years post-onset), thus associating it with active autoimmunity. Importantly, this signature has been detected in pre-onset samples of progressors to T1D years prior to onset and prior to development of auto-antibodies directed towards islet antigens. In applying this approach to the BN rat, we observed that samples collected from both sub-strains at 60 days of age induced transcription of genes encoding cytokines, immune receptors, and signaling molecules consistent with a their shared susceptibility and immune activation. The DRlyp/lyp signature was differentiated from that of the DR+/+ by more robust induction of many interleukin (IL)-1M-bM-^@M-^Sregulated genes. Treatment of DRlyp/lyp rats with IL-1 receptor antagonist (IL-1RN) delayed onset and, in part, normalized the signature, suggesting that this approach may prove useful in monitoring the effect of therapeutic interventions in human T1D. Consistent with the presence of TREG cells in DR+/+ rats, we observed induction of a signature possessing negative regulators of transcription and inflammation. Fresh PBMCs of healthy Brown Norway (BN) rats (~180 days old males, to avoid variation introduced by estrous or pubertal status) were isolated by density gradient centrifugation. Transcription was induced by culturing PBMCs for 6 h at 37M-BM-0C in 5% CO2 with 20% allogeneic BN (healthy-unrelated control), DRlyp/lyp, or DR+/+ plasma [PMID 18209091]. DRlyp/lyp and DR+/+ Plasma was pooled at various ages (30, 40, 50, 60 days old) to represent timepoints prior to onset in the DRlyp/lyp strain.

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Probiotic normalization of systemic inflammation in siblings of Type 1 diabetes patients

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