Th17 Cell-Derived Amphiregulin Promotes Colitis-Associated Intestinal Fibrosis Through Activation of mTOR and MEK in Intestinal Myofibroblasts.

Background & Aims: Intestinal fibrosis is a significant complication of Crohn's disease (CD). Gut microbiota reactive Th17 cells are crucial in the pathogenesis of CD; however, how Th17 cells induce intestinal fibrosis is still not completely understood.

Methods: In this study, T-cell transfer model with wild-type (WT) and Areg Th17 cells and dextran sulfate sodium (DSS)-induced chronic colitis model in WT and Areg mice were used.

Glucose promotes regulatory T cell differentiation to maintain intestinal homeostasis.

Glucose, the critical energy source in the human body, is considered a potential risk factor in various autoimmune diseases when consumed in high amounts. However, the roles of glucose at moderate doses in the regulation of autoimmune inflammatory diseases and CD4 T cell responses are controversial. Here, we show that while glucose at a high concentration (20% w/v) promotes intestinal inflammation, it suppresses colitis at a moderate dose (6% w/v), which increases the proportion of intestinal regulatory T (Treg) cells but does not affect effector CD4 T cells.

MicroRNA-10a Negatively Regulates CD4 T Cell IL-10 Production through Suppression of Blimp1.

An uncontrolled CD4 T cell response is a critical hallmark of autoimmune diseases. IL-10, which can be produced by both effector and regulatory CD4 T cells, plays an essential role in the inhibition of autoimmunity. MicroRNAs are key molecules involved in regulating immune responses.

L-lactate promotes intestinal epithelial cell migration to inhibit colitis.

Lactate, one of the most common primary metabolites of bacteria and human cells, has been shown to play essential roles in the regulation of inflammatory diseases, including inflammatory bowel diseases. However, whether and how host-derived lactate affects intestinal epithelial homeostasis is still not completely understood. Here, we investigated how L-lactate, mainly produced by host cells, regulates intestinal epithelial cell (IEC) migration to promote intestinal wound healing.

Propionate Enhances Cell Speed and Persistence to Promote Intestinal Epithelial Turnover and Repair.

Background And Aims: Gut bacteria-derived short-chain fatty acids (SCFAs) play crucial roles in the maintenance of intestinal homeostasis. However, how SCFAs regulate epithelial turnover and tissue repair remain incompletely understood. In this study, we investigated how the SCFA propionate regulates cell migration to promote epithelial renewal and repair.

STING controls intestinal homeostasis through promoting antimicrobial peptide expression in epithelial cells.

Stimulator of interferon genes (STING) has been shown to play a critical role in orchestrating immune responses to various pathogens through sensing cyclic dinucleotides. However, how STING regulates intestinal homeostasis is still not completely understood. In this study, we found that STING mice were more susceptible to enteric infection with Citrobacter rodentium compared to wild-type (WT) mice evidenced by more severe intestinal inflammation and impaired bacterial clearance.

Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity.

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).

IL-21 Promotes Intestinal Memory IgA Responses.

The role of IL-21, produced mainly by Th17 cells and T follicular helper cells, has been intensively investigated in B cell differentiation and Ab class switch. However, how IL-21 regulates memory IgA B cell development and memory IgA responses in the intestines is still not completely understood. In this study, we found the total IgA B cells as well as CD38CD138IgA memory B cells were significantly increased in intestinal lamina propria (LP) of TCRβxδ mice after transfer of microbiota Ag-specific Th17 cells but not Th1 cells.

Gut microbiota metabolite regulation of host defenses at mucosal surfaces: implication in precision medicine.

The gut microbiota has a well-established role in the regulation of host homeostasis. Multiple factors control the composition and function of the microbiota. The westernization of diet, a shift away from nutrient-dense foods toward diets high in saturated fats, has been implicated in the rise of chronic inflammatory diseases such as inflammatory bowel disease (IBD).

Microbiota Metabolite Short-Chain Fatty Acids Facilitate Mucosal Adjuvant Activity of Cholera Toxin through GPR43.

The gut microbiota has been shown critical for mucosal adjuvant activity of cholera toxin (CT), a potent mucosal adjuvant. However, the mechanisms involved remain largely unknown. In this study, we report that depletion of gut bacteria significantly decreased mucosal and systemic Ab responses in mice orally immunized with OVA and CT.

Serine Threonine Kinase 17A Maintains the Epithelial State in Colorectal Cancer Cells.

Serine threonine kinase 17A (STK17A) is a ubiquitously expressed kinase originally identified as a regulator of apoptosis; however, whether it functionally contributes to colorectal cancer has not been established. Here, we have analyzed STK17A in colorectal cancer and demonstrated decreased expression of STK17A in primary tumors, which is further reduced in metastatic lesions, indicating a potential role in regulating the metastatic cascade. Interestingly, changes in STK17A expression did not modify proliferation, apoptosis, or sensitivity of colorectal cancer cell lines to treatment with the chemotherapeutic 5-fluorouracil.

Neutrophils Promote Amphiregulin Production in Intestinal Epithelial Cells through TGF-β and Contribute to Intestinal Homeostasis.

Neutrophils are the first responders to sites of inflammation when the intestinal epithelial barrier is breached and the gut microbiota invade. Despite current efforts in understanding the role of neutrophils in intestinal homeostasis, the complex interactions between neutrophils and intestinal epithelial cells (IECs) is still not well characterized. In this study, we demonstrated that neutrophils enhanced production of amphiregulin (AREG), a member of the EGFR ligand family, by IECs, which promoted IEC barrier function and tissue repair.

GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3.

The antimicrobial peptides (AMP) produced by intestinal epithelial cells (IEC) play crucial roles in the regulation of intestinal homeostasis by controlling microbiota. Gut microbiota has been shown to promote IEC expression of RegIIIγ and certain defensins. However, the mechanisms involved are still not completely understood.