Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells

Abstract

Background Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder with a high prevalence, especially in industrialized countries. Dysbiosis of the intestinal microbiota has been observed in RA patients. For instance, new-onset untreated RA (NORA) is associated with the underrepresentation of the Clostridium cluster XIVa, including Lachnospiraceae, which are major butyrate producers, although the pathological relevance has remained obscure. Follicular regulatory T (T FR ) cells play critical regulatory roles in the pathogenesis of autoimmune diseases, including RA. Reduced number of circulating T FR cells has been associated with the elevation of autoantibodies and disease severity in RA. However, the contribution of commensal microbe-derived butyrate in controlling T FR cell differentiation remains unknown. Methods We examined the contribution of microbe-derived butyrate in controlling autoimmune arthritis using collagen-induced arthritis (CIA) and SKG arthritis models. We phenotyped autoimmune responses in the gut-associated lymphoid tissues (GALT) in the colon and joint-draining lymph nodes in the CIA model. We developed an in vitro CXCR5 + Bcl-6 + Foxp3 + T FR (iT FR ) cell culture system and examined whether butyrate promotes the differentiation of iT FR cells. Findings Microbe-derived butyrate suppressed the development of autoimmune arthritis. The immunization of type II collagen (CII) caused hypertrophy of the GALT in the colon by amplifying the GC reaction prior to the onset of the CIA. Butyrate mitigated these pathological events by promoting T FR cell differentiation. Butyrate directly induced the differentiation of functional T FR cells in vitro by enhancing histone acetylation in T FR cell marker genes. This effect was attributed to histone deacetylase (HDAC) inhibition by butyrate, leading to histone hyperacetylation in the promoter region of the T FR -cell marker genes. The adoptive transfer of the butyrate-treated iT FR cells reduced CII-specific autoantibody production and thus ameliorated the symptoms of arthritis. Interpretation Accordingly, microbiota-derived butyrate serves as an environmental cue to enhance T FR cells, which suppress autoantibody production in the systemic lymphoid tissue, eventually ameliorating RA. Our findings provide mechanistic insights into the link between the gut environment and RA risk. Funding This work was supported by (16gm1010...

Associations of serum short-chain fatty acids with circulating immune cells and serum biomarkers in patients with multiple sclerosis

“…In MS, fewer circulating functional Tfr have been implicated in the emergence of autoreactive B-cells, breakdown of self-tolerance and the emergence of ectopic germinal centre-like structures within the meninges 38 . In mouse models, butyrate and propionate supplementation have induced maturation of Tfr from Tregs via histone acetylation in Tfr marker genes 39 . Therefore, lower propionate levels in the serum from CIS/MS patients could result in decreased regulation of germinal centre activity.…”

Symbiotic polyamine metabolism regulates epithelial proliferation and macrophage differentiation in the colon

“…The ions were monitored at m/z 117 for acetic acid, m/z 131 for propionic acid, m/z 145 for butyric acid and isobutyric acid, m/z 159 for valeric acid and isovaleric acid, m/z 173 for 2-EB, m/z 261 for lactic acid, and m/z 289 for succinic acid. The extraction and derivatization rates were standardised using 2-EB acid and quantified using the corresponding external calibration curves 65,66 .…”

Functional modulation of T follicular cells in vivo enhances antigen-specific humoral immunity

“…The microbiota is well established to play a critical role in maintenance of immunological homeostasis and tolerance. Studies have identified metabolites produced by the microbiota, and induction of regulatory T cells as mechanisms through which the immune system is regulated by the microbiota (Takahashi et al, 2020, Maslowski et al, 2009). Our results uncovered a surprising role in this regard, where the microbiota set the balance of cells intimately involved in IgG responses, and specifically IgG affinity, including T FH , T FR , and GC B cells.…”

“…Further, the microbiota influences the immune system and its responses through multiple non-mutually exclusive mechanisms. Microbiota-derived metabolites, including short-chain fatty acids (SFCA), have been shown to promote T regulatory cells (Chinen et al, 2010, Atarashi et al, 2011, Marino et al, 2017) and also T FR cells (Takahashi et al, 2020). Furthermore, depletion of the microbiota revealed exacerbated or harmful immune responses, generally attributed to T regulatory deficiencies or deficits (Atarashi et al, 2011, Belkaid and Harrison, 2017, Chinen et al, 2010, Honda and Littman, 2016, Marino et al, 2017, Maslowski et al, 2009, Rakoff-Nahoum et al, 2004, Rooks and Garrett, 2016).…”