Response of Germfree Mice to Colonization by Oxalobacter formigenes and Altered Schaedler Flora

Abstract

Colonization with Oxalobacter formigenes may reduce the risk of calcium oxalate kidney stone disease. To improve our limited understanding of host-O. formigenes and microbe-O. formigenes interactions, germfree mice and mice with altered Schaedler flora (ASF) were colonized with O. formigenes. Germfree mice were stably colonized with O. formigenes, which suggests that O. formigenes does not require other organisms to sustain its survival. Examination of intestinal material indicated no viable O. formigenes in the small intestine and ϳ4 ؋ 10 6 CFU O. formigenes per 100 mg contents in the cecum and proximal colon, with ϳ0.02% of total cecal O. formigenes cells being tightly associated with the mucosa. O. formigenes did not alter the overall microbial composition of ASF, and ASF did not affect the capacity of O. formigenes to degrade dietary oxalate in the cecum. Twentyfour-hour collections of urine and feces in metabolic cages in semirigid isolators demonstrated that the introduction of ASF into germfree mice significantly reduced urinary oxalate excretion. These experiments also showed that O. formigenes-monocolonized mice excreted significantly more urinary calcium than did germfree mice, which may be due to degradation of calcium oxalate crystals by O. formigenes and subsequent intestinal absorption of free calcium. In conclusion, the successful establishment of mouse models with defined flora and O. formigenes should improve our understanding of O. formigenes-host and O. formigenes-microbe interactions. These data support the use of O. formigenes as a probiotic that has limited impact on the composition of the resident microbiota but provides an efficient oxalate-degrading function. Oxalobacter formigenes is part of the bacterial flora in the large intestine of many humans and other mammalian species and is unique in that it is the only bacterium yet identified in the intestines of mammals that requires oxalate as both an energy source and a carbon source. Recent evidence suggests that a lack of colonization with this oxalate-degrading specialist is a risk factor for idiopathic recurrent calcium oxalate stone disease (1, 2). A review of worldwide data indicated that 38% to 77% of a normal population and only 17% of stone formers were colonized with O. formigenes (1). The ability to recolonize individuals lacking O. formigenes was previously addressed in a study in which two healthy adults not colonized with O. formigenes became colonized following the ingestion of cultured O. formigenes (3) and remained colonized for 9 months. However, studies in which O. formigenes was provided in either a lyophilized form in enteric coated capsules or as a frozen paste to patients suffering from primary hyperoxaluria resulted in only a minority of the patients remaining colonized posttreatment (4, 5). Therefore, although it seems quite possible that O. formigenes colonization of noncolonized stone formers may be an effective way to minimize the risk of recurrent calcium oxalate stone disease, a better understanding o...

The Use of Defined Microbial Communities To Model Host-Microbe Interactions in the Human Gut

“…In an older study, male mice were found to be more susceptible to death after C. botulinum infection, which could be explained by their coprophagic behavior or a more general higher susceptibility to disease (36). In contrast, other studies reported an absence of gender-specific effects on, for instance, levels of Oxalobacter formigenes colonizing ASF mice (20) or the assembly of a synthetic microbiota (43). Whereas some studies discussed here (Tables 1 to 3) reported the use of a mixed-gender population, others included only one gender (n ϭ 12 of 53 studies), in which male animals were more often used than female animals (nine versus three).…”

“…The applications of ASF in rodents varied from wild-type strains (mostly C57BL/6 but also C3H/HeN and Swiss Webster mice) to models prone to diseases, including irritable bowel disease (IBD) (15)(16)(17), type I diabetes (18), or colorectal cancer (19). The ASF lacks Proteobacteria, a phylum shared by mice and humans, whereas some researchers introduced Proteobacteria to ASF mice, such as Oxalobacter formigenes (20) and Escherichia coli (21). Other studies included only selected members of the ASF, because not all members were found to successfully colonize the murine cecum (18) or to test the levels of colonization resistance of different combinations of ASF members (22).…”

The role of the microbiome in kidney stone formation

“…Experiments showed that these mono-colonized mice had significantly reduced urinary oxalate excretion compared to germ free mice. This finding may play an important role in the development of Oxf as probiotic [30]. …”

Microbial contributions to oxalate metabolism in health and disease

“…Multiple gut microbes can degrade oxalate [22], including Oxalobacter formigenes, an oxalate autotroph [23][24][25][26][27]. When given to animals, O. formigenes has reduced host oxalate burden [28][29][30][31][32][33]. [44][45][46].…”