Crosstalk Between Host Genetics and Intestinal Microbiota in Response to Dietary Alterations Regulates Host Metabolism
Authors: Surujon Defne , Simas Alexandra M. , Coston Alexandra N. , Greenberg Andrew S. 
Published: November 2023

The intake of carbohydrates such as fructose has been associated with an increased incidence of nonalcoholic fatty liver disease (NAFLD), increased serum cholesterol and insulin resistance (IR). Importantly, the genetic background of an individual has a significant effect on the genesis of these complications. The presence of these metabolic complications has been closely associated with alterations in the intestinal microbiota, implicating the microbiota as a modifier of metabolic disease risk. To examine the predictive potential of the microbiota in the early onset effects of a fructose‐rich diet, we selected four mouse strains; A/J is a common strain which is resistant to diet‐induced IR and obesity, C57BL6/J is on the other hand highly susceptible to diet‐induced obesity and IR. The sister strains C3H/HeJ and C3H/HeOuJ come from a similar genetic lineage, and C3H/HeJ (but not C3H/HeOuJ) has a mutation in the endotoxin response gene Tlr4, which has been implicated as a critical regulator of fructose‐induced steatosis. Age matched male mice (starting at 9 weeks of age) from the four common laboratory strains mentioned were fed either a 30% fructose (HFD) or a calorie‐matched no fructose (NFD) diet for four weeks. HFD feeding resulted in significant weight gain increase only in the C3H substrains, primarily due to increased adiposity. Surprisingly, C57BL6/J was the only strain completely protected against diet‐induced increase in body fat composition. Using 16S rDNA sequencing for microbiota composition analysis, we demonstrated that C57BL6/J is the only mouse strain that harbors the genus Akkermansia ‐ previously demonstrated to have protective effects on obesity ‐ along with a few other operational taxonomic units (OTUs). Also of interest, there was a wide range of variability across the four strains in serum cholesterol levels. In order to better understand the variability in the serum cholesterol and potential association with specific OTUs, we employed a generalized linear model with lasso shrinkage in order to identify influences of specific OTUs, and we established a robust relationship between the abundance of the genus Coprobacillaceae –both before, 2 weeks after, and 4 weeks after HFD or NFD feeding– and serum cholesterol. Correlations between this OTU and serum cholesterol have been observed in prior human and mouse studies from multiple groups. In response to the fructose diet, morphological examination of the distal jejunum reveals a dramatic increase in goblet cell secretion in C3H/HeOuJ, and a dramatic decrease in C3H/HeJ, possibly due to the lack of TLR4. In contrast, the goblet cell secretion of metabolically more stable strains A/J and C57BL6/J are unchanged. Our current studies are investigating potential links between the microbiota and intestinal and serum metabolites in promoting the observed phenotypic abnormalities. Possible future studies will aim to address the direction of causality in the associations presented here.Support or Funding InformationA.S.G. receives support from R01 DK098606‐02, T32 DK062032‐24, and ARS agreement no. 58‐1950‐7‐70