Salmonella enterica subspecies 1 serovar Typhimurium is a principal cause of human enterocolitis. For unknown reasons, in mice serovar Typhimurium does not provoke intestinal inflammation but rather targets the gut-associated lymphatic tissues and causes a systemic typhoid-like infection. The lack of a suitable murine model has limited the analysis of the pathogenetic mechanisms of intestinal salmonellosis. We describe here how streptomycin-pretreated mice provide a mouse model for serovar Typhimurium colitis. Serovar Typhimurium colitis in streptomycin-pretreated mice resembles many aspects of the human infection, including epithelial ulceration, edema, induction of intercellular adhesion molecule 1, and massive infiltration of PMN/ CD18 ؉ cells. This pathology is strongly dependent on protein translocation via the serovar Typhimurium SPI1 type III secretion system. Using a lymphotoxin ␤-receptor knockout mouse strain that lacks all lymph nodes and organized gut-associated lymphatic tissues, we demonstrate that Peyer's patches and mesenteric lymph nodes are dispensable for the initiation of murine serovar Typhimurium colitis. Our results demonstrate that streptomycin-pretreated mice offer a unique infection model that allows for the first time to use mutants of both the pathogen and the host to study the molecular mechanisms of enteric salmonellosis.Salmonella spp. are gram-negative enterobacteria that cause diseases ranging from a self-limiting enterocolitis to systemic infection (typhoid fever). Salmonella enterica serovar Typhimurium evokes a common form of nonsystemic enterocolitis in humans and cattle, whereas mice are intrinsically resistant to serovar Typhimurium enterocolitis (68,81). Although resistant to intestinal salmonellosis, certain susceptible mouse strains that carry mutations in the NRAMP gene develop a disease similar to typhoid fever (30,75).After oral infection of susceptible mice, serovar Typhimurium does not replicate efficiently in the intestine but penetrates the epithelial barrier by invasion of M cells (12,41,64) or (less efficiently) by transport via CD18 ϩ /dendritic cells (67, 80) and possibly by penetration of enterocytes (72). After penetration of the epithelial barrier, Salmonella spp. colonize Peyer's patches and mesenteric lymph nodes and then spread to the liver and spleen, and the mice finally succumb to systemic infection (10,35,75,81). However, mice show few signs of the intestinal inflammation observed in cattle or humans.Due to the lack of a versatile animal model, much less is known about the mechanisms of the enteric salmonellosis (21,33,62,75,81). To overcome these limitations, the pathogenesis of enteric salmonellosis has been studied by extrapolating data from tissue culture (review by Galan [26]) or from intestinal organ culture (1) or by infection of ligated murine and rabbit ileal loops (11,12,20,41,63,64). However, it remains unclear how these results relate to enteric salmonellosis.For this reason, bovine infection models with serovar Typhimurium (and serovar D...

Postnatal colonization of the body with microbes is assumed to be the main stimulus to postnatal immune development. By transiently colonizing pregnant female mice, we show that the maternal microbiota shapes the immune system of the offspring. Gestational colonization increases intestinal group 3 innate lymphoid cells and F4/80(+)CD11c(+) mononuclear cells in the pups. Maternal colonization reprograms intestinal transcriptional profiles of the offspring, including increased expression of genes encoding epithelial antibacterial peptides and metabolism of microbial molecules. Some of these effects are dependent on maternal antibodies that potentially retain microbial molecules and transmit them to the offspring during pregnancy and in milk. Pups born to mothers transiently colonized in pregnancy are better able to avoid inflammatory responses to microbial molecules and penetration of intestinal microbes.

The lower intestine of adult mammals is densely colonized with non-pathogenic (commensal) microbes. Gut bacteria induce protective immune responses, which ensure host-microbial mutualism. The continuous presence of commensal intestinal bacteria has made it difficult to study mucosal immune dynamics. Here we report a reversible germ-free colonization system in mice that is independent of diet or antibiotic manipulation. A slow (>14 days) onset of a long-lived (t1/2>16 weeks), highly specific anti-commensal IgA response in germ-free mice was observed. Ongoing commensal exposure in colonized mice rapidly abrogated this response. Sequential doses lacked a classical prime-boost effect seen in systemic vaccination, but specific IgA induction occurred as a stepwise response to current bacterial exposure, such that the antibody repertoire matched the existing commensal content.

Mammals harbor a dense commensal microbiota in the colon. Regulatory T (Treg) cells are known to limit microbe-triggered intestinal inflammation and the CD4+ T cell compartment is shaped by the presence of particular microbes or bacterial compounds. It is, however, difficult to distinguish whether these effects reflect true mutualistic immune adaptation to intestinal colonization or rather idiosyncratic immune responses. To investigate truly mutualistic CD4+ T cell adaptation, we used the altered Schaedler flora (ASF). Intestinal colonization resulted in activation and de novo generation of colonic Treg cells. Failure to activate Treg cells resulted in the induction of T helper 17 (Th17) and Th1 cell responses, which was reversed by wild-type Treg cells. Efficient Treg cell induction was also required to maintain intestinal homeostasis upon dextran sulfate sodium-mediated damage in the colon. Thus, microbiota colonization-induced Treg cell responses are a fundamental intrinsic mechanism to induce and maintain host-intestinal microbial T cell mutualism.