FFAR from the Gut Microbiome Crowd: SCFA Receptors in T1D Pathology

Abstract

The gut microbiome has emerged as a novel determinant of type 1 diabetes (T1D), but the underlying mechanisms are unknown. In this context, major gut microbial metabolites, short-chain fatty acids (SCFAs), are considered to be an important link between the host and gut microbiome. We, along with other laboratories, have explored how SCFAs and their cognate receptors affect various metabolic conditions, including obesity, type 2 diabetes, and metabolic syndrome. Though gut microbiome and SCFA-level changes have been reported in T1D and in mouse models of the disease, the role of SCFA receptors in T1D remains under explored. In this review article, we will highlight the existing and possible roles of these receptors in T1D pathology. We conclude with a discussion of SCFA receptors as therapeutic targets for T1D, exploring an exciting new potential for novel treatments of glucometabolic disorders.

The Specificity and Broad Multitarget Properties of Ligands for the Free Fatty Acid Receptors FFA3/GPR41 and FFA2/GPR43 and the Related Hydroxycarboxylic Acid Receptor HCA2/GPR109A

“…Our findings generally agree with the recent publications about multitarget pleiotropic drugs including 1,4-DHPs [55] and their usefulness as modulators for GPCR (especially anti-inflammatory SCFA receptors) for the treatment of Diabetes mellitus (T1D) [56].…”

“…The observed inhibition of proinflammatory cytokines in macrophages by the studied compounds can be mediated via inactivation of NF-κB; however, the precise mechanism should be further elucidated. Our findings generally agree with the recent publications about multitarget pleiotropic drugs including 1,4-DHPs [55] and their usefulness as modulators for GPCR (especially anti-inflammatory SCFA receptors) for the treatment of Diabetes mellitus (T1D) [56].…”

The Intersection between Bacterial Metabolism and Innate Immunity

“…Propionate was found to enhance cytokine production in sebocytes through epigenetic regulation of histones 8 and 9 [36, 37]. This regulatory process activates the free fatty acid receptors, which sense SCFAs, thereby regulating the immune response based on the metabolic status of the cell [38]. Free fatty acid receptors 2 and TLR2 are increased upon propionate stimulation, suggesting the elevated cytokine response is mediated, at least in part, through TLR2 activation [36, 39].…”

Probiotics of Lacticaseibacillus paracasei SD1 and Lacticaseibacillus rhamnosus SD11 attenuate inflammation and β-cell death in streptozotocin-induced type 1 diabetic mice

“…Among all probiotic strains, Lactobacillus is one of the most commonly used and studied bacteria in humans, and two main mechanisms have been proposed to modulate gut microbiota balance and the host immune system in T1D: 1) by suppressing the innate immune response via Toll-like receptors (TLRs). Specifically, the consumption of selected probiotic strains has been found to decrease the level of proinflammatory cytokines, including IL-6, IL-1β, and TNF-α, while increasing that of anti-inflammatory cytokines, such as IL-10 and TGF-β [ 9 , 10 ] and/or 2), by upregulating FFAR 2/3 via the production of short-chain fatty acids (SCFAs), which could enhance the production of glucagon-like peptide-1 (GLP-1) from intestinal L-cells, thereby lowering blood glucose levels [ 11 ]. This evidence highlights the potential of probiotics as a promising intervention to combat autoimmune destruction of β-cells in T1D by restoring homeostasis of the gut microbiota-immune axis, granting host health benefits.…”