Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.

Alcohol consumption is a consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown. Here we show that alcohol and its metabolite acetate alter the functional state of T follicular helper (T_FH) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice have reduced Bcl6 and PD-1 expression as well as IL-21 production by T_FHcells, preventing proper spatial organization of T_FHcells to form T_FH:B cell conjugates in germinal centers. This effect is associated with impaired autoantibody formation, and mitigates experimental autoimmune arthritis. By contrast, T cell independent immune responses and passive models of arthritis are not affected by alcohol exposure. These data clarify the immune regulatory and tolerance-inducing effect of alcohol consumption.

Benefits and harms of different components of human diet have been known for hundreds of years. Alcohol is one the highest consumed, abused, and addictive substances worldwide. Consequences of alcohol abuse are increased risks for diseases of the cardiovascular system, liver, and nervous system, as well as reduced immune system function. Paradoxically, alcohol has also been a consistent protective factor against the development of autoimmune diseases such as type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis (RA). Here, we focused on summarizing current findings on the effects of alcohol, as well as of its metabolites, acetaldehyde and acetate, on the immune system and RA. Heavy or moderate alcohol consumption can affect intestinal barrier integrity, as well as the microbiome, possibly contributing to RA. Additionally, systemic increase in acetate negatively affects humoral immune response, diminishing T_FH cell as well as professional antigen-presenting cell (APC) function. Hence, alcohol consumption has profound effects on the efficacy of vaccinations, but also elicits protection against autoimmune diseases. The mechanism of alcohol’s negative effects on the immune system is multivariate. Future studies addressing alcohol and its metabolite acetate’s effect on individual components of the immune system remains crucial for our understanding and development of novel therapeutic pathways.

Lin28 is a family of RNA binding proteins and microRNA regulators. Two members of this family have been identified: Lin28A and Lin28B, which are encoded by genes localized in different chromosomes but share a high degree of sequence identity. The role of Lin28B in androgen-independent prostate cancer (AIPC) is not well understood. Lin28B is expressed in all grades of prostatic carcinomas and prostate cancer cell lines, but not in normal prostate tissue. In this study we found that Lin28B co-localized in the nucleus and cytoplasm of the DU145 AIPC. The expression of Lin28B protein positively correlated with the expression of the c-Myc protein in the prostate cancer cell lines and silencing of Lin28B also correlated with a lower expression of the c-Myc protein, but not with the downregulation of c-Myc messenger RNA (mRNA) in the DU145 AIPC cells. We hypothesized that Lin28B regulates the expression of c-Myc protein by altering intermediate c-Myc suppressors. Therefore, a microRNA profile of DU145 cells was performed after Lin28B siRNA silencing. Nineteen microRNAs were upregulated and eleven microRNAs were downregulated. The most upregulated microRNAs were miR-212 and miR-2278. Prior reports have found that miR-212 is suppressed in prostate cancer. We then ran TargetS can software to find potential target mRNAs of miR-212 and miR-2278, and it predicted Lin28B mRNA as a potential target of miR-212, but not miR-2278. TargetScan also predicted that c-Myc mRNA is not a potential target of miR-212 or miR-2278. These observations suggest that Lin28B:miR-212 may work as a regulatory loop in androgen-independent prostate cancer. Furthermore, we report a predictive 2-fold symmetric model generated by the superposition of the Lin28A structure onto the I-TASSER model of Lin28B. This structural model of Lin28B suggests that it shows unique microRNA binding characteristics. Thus, if Lin28B were to bind miRNAs in a manner similar to Lin28A, conformational changes would be necessary to prevent steric clashes in the C-terminal and linker regions between the CSD and ZNF domains.

Chronic inflammatory diseases like rheumatoid arthritis (RA) have been described to cause CNS activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota–derived histamine as such a factor. We showed that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord, and restore homeostatic microglia, thereby reducing inflammation in the joints. We found that elective histamine 3 receptor (H3R) signaling in the intestine was critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist–induced pro-resolving effects on arthritis. Moreover, therapeutic supplementation of the short-chain fatty acid propionate revealed one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut/CNS/joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS.

Alcohol is among the most widely consumed dietary substances. While excessive alcohol consumption damages the liver, heart and brain, clinical observations suggest that alcohol has strong immunoregulatory properties. Mechanisms by which alcohol undermines immune cell functions during autoimmunity and vaccination are currently elusive. Herein, we show that acetate, the main metabolite of alcohol, effectively inhibits the migratory capacity of T cells through acetylation of cortactin, a protein which stabilizes and promotes branching of filamentous actin. Acetate-induced cytoskeletal changes effectively inhibited activation, proliferation, and immune synapse formation in T cells at tissue concentrations reached by alcohol consumption. In summary, these data show that acetate inhibits T cell-mediated immune responses by modulating the T cell cytoskeletal biomechanics. One-Sentence Summary Exposure to elevated acetate concentrations change T cell biomechanics, reducing cell migration and immune synapse formation.