Innate lymphoid cells (ILCs) and CD4⁺ T cells produce IL-22, which is critical for intestinal immunity. The microbiota is central to IL-22 production in the intestines; however, the factors that regulate IL-22 production by CD4⁺ T cells and ILCs are not clear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4⁺ T cells and ILCs through G-protein receptor 41 (GPR41) and inhibiting histone deacetylase (HDAC). SCFAs upregulate IL-22 production by promoting aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor 1α (HIF1α) expression, which are differentially regulated by mTOR and Stat3. HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding to the Il22 promoter through histone modification. SCFA supplementation enhances IL-22 production, which protects intestines from inflammation. SCFAs promote human CD4⁺ T cell IL-22 production. These findings establish the roles of SCFAs in inducing IL-22 production in CD4⁺ T cells and ILCs to maintain intestinal homeostasis.

Composition of the gut microbiota has profound effects on intestinal carcinogenesis. Diet and host genetics play critical roles in shaping the composition of gut microbiota. Whether diet and host genes interact with each other to bring specific changes in gut microbiota that affect intestinal carcinogenesis is unknown. Ability of dietary fibre to specifically increase beneficial gut microbiota at the expense of pathogenic bacteria in vivo via unknown mechanism is an important process that suppresses intestinal inflammation and carcinogenesis. Free fatty acid receptor 2 (FFAR2 or GPR43) is a receptor for short-chain fatty acids (acetate, propionate and butyrate), metabolites of dietary fibre fermentation by gut microbiota. Here, we show FFAR2 is down modulated in human colon cancers than matched adjacent healthy tissue. Consistent with this, Ffar2^−/− mice are hypersusceptible to development of intestinal carcinogenesis. Dietary fibre suppressed colon carcinogenesis in an Ffar2-dependent manner. Ffar2 played an essential role in dietary fibre-mediated promotion of beneficial gut microbiota, Bifidobacterium species (spp) and suppression of Helicobacter hepaticus and Prevotellaceae. Moreover, numbers of Bifidobacterium is reduced, whereas those of Prevotellaceae are increased in human colon cancers than matched adjacent normal tissue. Administration of Bifidobacterium mitigated intestinal inflammation and carcinogenesis in Ffar2^−/− mice. Taken together, these findings suggest that interplay between dietary fibre and Ffar2 play a key role in promoting healthy composition of gut microbiota that stimulates intestinal health.

The IRE1α/XBP1 branch of unfolded protein response (UPR) pathway has a critical function in endoplasmic reticulum (ER) expansion in plasma cells via unknown mechanisms; interestingly, another UPR branch, PERK, is suppressed during plasma cell development. Here we show that Ufbp1, a target and cofactor of the ufmylation pathway, promotes plasma cell development by suppressing the activation of PERK. By contrast, the IRE1α/XBP1 axis upregulates the expression of Ufbp1 and ufmylation pathway genes in plasma cells, while Ufbp1 deficiency impairs ER expansion in plasma cells and retards immunoglobulin production. Structure and function analysis suggests that lysine 267 of Ufbp1, the main lysine in Ufbp1 that undergoes ufmylation, is dispensable for the development of plasmablasts, but is required for immunoglobulin production and stimulation of ER expansion in IRE1α-deficient plasmablasts. Thus, Ufbp1 distinctly regulates different branches of UPR pathway to promote plasma cell development and function.

A set of coordinated interactions between gut microbiota and the immune cells surveilling the intestine play a key role in shaping local immune responses and intestinal health. Gpr109a is a G protein–coupled receptor expressed at a very high level on innate immune cells and previously shown to play a key role in the induction of colonic regulatory T cells. In this study, we show that Gpr109a^−/−Rag1^−/− mice exhibit spontaneous rectal prolapse and colonic inflammation, characterized by the presence of an elevated number of IL-17–producing Rorγt⁺ innate lymphoid cells (ILCs; ILC3). Genetic deletion of Rorγt alleviated the spontaneous colonic inflammation in Gpr109a^−/−Rag1^−/− mice. Gpr109a-deficient colonic dendritic cells produce higher amounts of IL-23 and thereby promote ILC3. Moreover, the depletion of gut microbiota by antibiotics treatment decreased IL-23 production, ILC3, and colonic inflammation in Gpr109a^−/−Rag1^−/− mice. The ceca of Gpr109a^−/−Rag1^−/− mice showed significantly increased colonization by members of Bacteroidaceae, Porphyromonadaceae, Prevotellaceae, Streptococcaceae, Christensenellaceae, and Mogibacteriaceae, as well as IBD-associated microbiota such as Enterobacteriaceae and Mycoplasmataceae, compared with Rag1^−/− mice, housed in a facility positive for Helicobacter and murine norovirus. Niacin, a Gpr109a agonist, suppressed both IL-23 production by colonic DCs and ILC3 number in a Gpr109a-dependent manner. Collectively, our data present a model suggesting that targeting Gpr109a will be potentially beneficial in the suppression of IL-23–mediated immunopathologies.

Periodontitis (PD) is a common dysbiotic inflammatory disease that leads to local bone deterioration and tooth loss. PD patients experience low-grade bacteremias with oral microbes implicated in the risk of heart disease, cancer, and kidney failure. Although Th17 effectors are vital to fighting infection, functional imbalance of Th17 effectors and regulatory T cells (Tregs) promote inflammatory diseases. In this study, we investigated, in a small pilot randomized clinical trial, whether expansion of inflammatory blood myeloid dendritic cells (DCs) and conversion of Tregs to Th17 cells could be modulated with antibiotics (AB) as part of initial therapy in PD patients. PD patients were randomly assigned to either 7 d of peroral metronidazole/amoxicillin AB treatment or no AB, along with standard care debridement and chlorhexidine mouthwash. 16s ribosomal RNA analysis of keystone pathogen Porphyromonas gingivalis and its consortium members Fusobacterium nucleatum and Streptococcus gordonii confirmed the presence of all three species in the reservoirs (subgingival pockets and blood DCs) of PD patients before treatment. Of the three species, P. gingivalis was reduced in both reservoirs 4–6 wk after therapy. Further, the frequency of CD1C⁺CCR6⁺ myeloid DCs and IL-1R1 expression on IL-17A⁺FOXP3⁺CD4⁺ T cells in PD patients were reduced to healthy control levels. The latter led to decreased IL-1β–stimulated Treg plasticity in PD patients and improvement in clinical measures of PD. Overall, we identified an important, albeit short-term, beneficial role of AB therapy in reducing inflammatory DCs and Treg–Th17 plasticity in humans with PD. Key Points •AB therapy in PD patients ablated P. gingivalis from oral and hematogenous reservoirs. •This reduced inflammatory blood mDCs and IL-1R expression on Tregs in PD patients. •A favorable clinical response was related with P. gingivalis ablation and a decrease in Treg→Th17.

Carbidopa is a drug that blocks conversion of levodopa to dopamine outside of central nervous system (CNS) and thus inhibits unwanted side effects of levodopa on organs located outside of CNS during management of Parkinson’s Disease (PD). PD is associated with increased expression of inflammatory genes in peripheral and central nervous system (CNS), infiltration of immune cells into brain, and increased numbers of activated/memory T cells. Animal models of PD have shown a critical role of T cells in inducing pathology in CNS. However, the effect of carbidopa on T cell responses in vivo is unknown. In this report, we show that carbidopa strongly inhibited T cell activation in vitro and in vivo. Accordingly, carbidopa mitigated myelin oligodendrocyte glycoprotein peptide fragment 35–55 (MOG-35-55) induced experimental autoimmune encephalitis (EAE) and collagen induced arthritis in animal models. The data presented here suggest that in addition to blocking peripheral conversion of levodopa, carbidopa may inhibit T cell responses in PD individuals and implicate a potential therapeutic use of carbidopa in suppression of T cell mediated pathologies.