Foxp3+ regulatory T cells (Tregs) control inflammation. Foxp3 loss-of-function mutations cause a severe multi-organ autoimmune and inflammatory disorder in humans (IPEX syndrome) and in mice (Scurfy, sf). Treg-deficient sf mice generally die of a lymphoproliferative syndrome with severe multi-organ inflammation at 21-28 days old. Lactobacillus reuteri (LR) has beneficial effects in several human diseases such as necrotizing enterocolitis (NEC), rotavirus diarrhea, infant colic and atopic dermatitis. Our preliminary studies demonstrated that feeding LR strain DSM17938 (LR17938) for 3 weeks significantly prolonged the survival of sf mice.
Specific Aims are to (1-1) test the effects of 1-,2-, and 3-week LR feeding regimens on the survival of sf mice; (1-2) test whether the therapeutic effect is specific to LR17938 compared with other probiotics; and (2-1) investigate the immunological changes in sf mice produced by LR17938 and another probiotic; (2-2) characterize the fecal microbial community and metabolome of sf mice, and the effects of LR17938. The impact of the proposed studies will (1) provides preclinical data for potential LR treatment of autoimmune diseases, focusing on IPEX syndrome. (In theory, LR treatment could prolong survival prior to bone marrow transplantation); and (2) provide insights into how the probiotic LR modulates the immune system. The studies may lead to future clinical trials for IPEX syndrome and possibly other autoimmune and inflammatory disorders.
Evidence is emerging that probiotics (health-promoting bacteria, including Lactobacillus reuteri) have a positive impact on human intestinal diseases, including the prevention of neonatal necrotizing enterocolitis (NEC), which has a prevalence of 7% in low birth weight infants and a mortality rate of >20% 1, and other autoimmune-related diseases, including atopic dermatitis2. Our human studies of Lactobacillus reuteri have included human trials of safety and biomarkers (Phase I Adult Safety RCT (U01 AT003519 under IND) and Phase I in infants with colic (R34 AT006727)). Our laboratory studies using rat and mouse models have provided a framework which will allow us to establish a central mechanism by which Lactobacillus reuteri protects from inflammatory diseases. We are studying an autoimmune disease due to deficiency of regulatory T cells which produces severe dermatitis and early death with inflammation in multiple organs. We propose to test if Lactobacillus reuteri prevents this disease from causing early death, and identify the key anti-inflammatory white blood cell type(s) (including dendritic cells and T cells) in the intestine, intestinal lymph nodes spleen, and blood. We will examine bacterial communities in stool which may be affected by Lactobacillus reuteri. The study will provide information that will hopefully lead to clinical trias of Lactobacillus reuteri in certain autoimmune and inflammatory diseases. References 1. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011; 364:255-264. 2. Rosenfeldt V, Benfeldt E, Valerius NH et al. Effect of probiotics on gastrointestinal symptoms and small intestinal permeability in children with atopic dermatitis. J Pediatr 2004; 145:612-616.
|He, Baokun; Hoang, Thomas K; Tran, Dat Q et al. (2017) Adenosine A2A Receptor Deletion Blocks the Beneficial Effects of Lactobacillus reuteri in Regulatory T-Deficient Scurfy Mice. Front Immunol 8:1680|
|He, Baokun; Hoang, Thomas K; Wang, Ting et al. (2017) Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency-induced autoimmunity via adenosine A2A receptors. J Exp Med 214:107-123|
|Liu, Yuying; Hoang, Thomas K; Wang, Ting et al. (2016) Circulating L-selectin expressing-T cell subsets correlate with the severity of Foxp3 deficiency autoimmune disease. Int J Clin Exp Pathol 9:899-909|