Regulation of CD4+ and CD8+ T Cell Biology by Short-Chain Fatty Acids and Its Relevance for Autoimmune Pathology

Abstract

The gut microbiota encodes a broad range of enzymes capable of synthetizing various metabolites, some of which are still uncharacterized. One well-known class of microbiota-derived metabolites are the short-chain fatty acids (SCFAs) such as acetate, propionate, butyrate and valerate. SCFAs have long been considered a mere waste product of bacterial metabolism. Novel results have challenged this long-held dogma, revealing a central role for microbe-derived SCFAs in gut microbiota-host interaction. SCFAs are bacterial signaling molecules that act directly on host T lymphocytes by reprogramming their metabolic activity and epigenetic status. They have an essential biological role in promoting differentiation of (intestinal) regulatory T cells and in production of the anti-inflammatory cytokine interleukin-10 (IL-10). These small molecules can also reach the circulation and modulate immune cell function in remote tissues. In experimental models of autoimmune and inflammatory diseases, such as inflammatory bowel disease, multiple sclerosis or diabetes, a strong therapeutic potential of SCFAs through the modulation of effector T cell function was observed. In this review, we discuss current research activities toward understanding a relevance of microbial SCFA for treating autoimmune and inflammatory pathologies from in vitro to human studies.

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders

“…Epigenetic processes are a crucial aspect of 'autoimmunity' in many of its manifestations [26], including the following: (i) histone acetyltransferase (HAT) and histone deacetylase (HDAC), which regulate histone acetylation and alter histone spatial structure, thereby impacting on transcription. The gut microbiome influence on 'autoimmunity' includes variations in the levels of gut microbiome-derived butyrate, an HDAC inhibitor (HDACi), and regulator of the immune response in a number of 'autoimmune' conditions [27], including via enhanced Treg differentiation [28]; (ii) miRNAs, long non-coding RNAs (lncRNAs) and circular RNAs (CircRNA). miRNAs and the RNA-induced silencing complex (RISC) suppress mRNA transcription via binding to the mRNA 3 UTR region, including via complex formation.…”

“…The m 6 A methyltransferase METTL3 leads to mitochondrial dysfunction via mRNA modification of the 'master mitochondrial regulator', peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α [35]. HDAC regulates a number of autoimmune disorders, with its inhibition by butyrate optimizing mitochondrial function [27]. Autoimmunity-associated suboptimal mitochondrial function can drive oxidative and nitrosative stress (O&NS) that induces miRNAs and lncRNAs, shown to be significant aspects of SLE pathophysiology [36], whilst a number of miRNAs increased in T1DM are strongly associated with suboptimal mitochondrial function [37].…”

Diet-gut microbial interactions influence cancer immunotherapy

“…However, the level of SCFAs seems to be very important in inducing its function. Evidence shows that the anti-inflammatory effect of SCFAs is dose-dependent (117). Qi Hui et al (118) found that when butyrate concentration is 20 mmol, the levels of IL-6 and IL-1bwere significantly reduced, while the concentration was 2 mmol has no effect.…”

The impact of microbiome dysbiosis on T cell function within the tumor microenvironment (TME)

“…Effector molecules such as CD25, IFN-γ, and TNF-α were then elevated in these treated cells, demonstrating enhanced cytotoxic activity and potential for pentanoate and C4 as supplements to cancer treatment for some malignancies (Figure 2D). (Schiweck et al, 2022).…”