Summary Short-chain fatty acids (SCFAs) are metabolites produced by the fermentation of fibers by bacteria in the gut and play an important role in the maintenance of health and disease prevention in a variety of disorders, including metabolic, autoimmune, and neurological diseases. The sufficient production of SCFAs in the gut and their efficient absorption by intestinal epithelial cells and transport into systemic circulation are important for disease prevention. Although the effect of prebiotics and probiotics on the production of SCFAs in the gut has been extensively studied, their effect on the absorption and transport of SCFAs has not been well studied. Low-grade intestinal inflammation is one of the causes of reduction in the expression of SCFAs-transporter genes and the transport of SCFAs into the systemic circulation. We found that the levels of intestinal inflammation biomarker are increased in MS patients compared to healthy donors (HDs), and the levels of the SCFA acetate are lower in the blood but higher in fecal samples in MS patients compared to HDs, suggesting insufficient absorption and transport of SCFA acetate in MS patients. We hypothesize that MS-associated gut dysbiosis may trigger and/or exacerbate the inflammation in the gut and subsequently reduce the expression of SCFAs-transporter genes and their transport into the system circulation. To examine this hypothesis, germfree mice will be transplanted with fecal samples collected from MS patients and HDs, and examined for the expression of SCFA-transporters and tight junction proteins, intestinal permeability, and concentration of SCFAs in fecal and blood samples. Further, we will examine the development of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in the human microbiota-transplanted mice in Aim-1. We found that the abundance of B. massiliensis was significantly associated with increased levels of acetate, butyrate, and propionate in the blood. B. massiliensis is a newly isolated bacterium from healthy human fecal samples, and its effect on health has not been explored yet. Of interest, the culture supernatant of B. massiliensis and its outer membrane vesicles (OMVs) up-regulated the expression of SCFAs-transporter genes. We also found that A. hallii, SCFA-producing bacterium, is reduced in the gut of MS patients and that intake of high-fiber diets (HFD) can increase the colonization of SCFAs-producing bacteria. Therefore, we hypothesize that treatment with A. hallii or HFD can increase the production of SCFAs in the gut and increased colonization of B. massiliensis could promote the transport of SCFAs into the blood circulation. We will test this hypothesis in Aim-2. In this study, we will elucidate a novel mechanism of how the gut microbiome impacts health and modulates disease, and identify a synbiotic intervention with HFD and B. massiliensis as a beneficial treatment for autoimmune diseases including MS.