An analysis of the role of the indigenous microbiota in cholesterol gallstone pathogenesis.
OBJECTIVE
Cholesterol gallstone disease is a complex process involving both genetic and environmental variables. No information exists regarding what role if any the indigenous gastrointestinal microbiota may play in cholesterol gallstone pathogenesis and whether variations in the microbiota can alter cholesterol gallstone prevalence rates.


METHODS
Genetically related substrains (BALB/cJ and BALB/cJBomTac) and (BALB/AnNTac and BALB/cByJ) of mice obtained from different vendors were compared for cholesterol gallstone prevalence after being fed a lithogenic diet for 8 weeks. The indigenous microbiome was altered in these substrains by oral gavage of fecal slurries as adults, by cross-fostering to mice with divergent flora at <1 day of age or by rederiving into a germ-free state.


RESULTS
Alterations in the indigenous microbiome altered significantly the accumulation of mucin gel and normalized gallbladder weight but did not alter cholesterol gallstone susceptibility in conventionally housed SPF mice. Germ-free rederivation rendered mice more susceptible to cholesterol gallstone formation. This susceptibility appeared to be largely due to alterations in gallbladder size and gallbladder wall inflammation. Colonization of germ-free mice with members of altered Schaedler flora normalized the gallstone phenotype to a level similar to conventionally housed mice.


CONCLUSIONS
These data demonstrate that alterations in the gastrointestinal microbiome may alter aspects of cholesterol gallstone pathogenesis and that in the appropriate circumstances these changes may impact cholesterol cholelithogenesis.
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Jacqueline J
JJ
Fremont-Rahl
Zhongming
Z
Ge
Carlos
C
Umana
Mark T
MT
Whary
Nancy S
NS
Taylor
Sureshkumar
S
Muthupalani
Martin C
MC
Carey
James G
JG
Fox
Kirk J
KJ
Maurer
D000818:Animals; D000831:Animals, Newborn; D001646:Bile / Q000737:chemistry; D002769:Cholelithiasis / Q000209:etiology; D002784:Cholesterol / Q000737:chemistry*; D004195:Disease Models, Animal; D005260:Female; D042882:Gallstones / Q000737:chemistry* / Q000209:etiology*; D041981:Gastrointestinal Tract / Q000382:microbiology*; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D064307:Microbiota; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D015995:Prevalence
D009077:Mucins; D002784:Cholesterol