SUMMARY To understand how different diets, the consumers’ gut microbiota and the enteric nervous system (ENS) interact to regulate gut motility, we developed a gnotobiotic mouse model that mimics short-term dietary changes that happen when humans are traveling to places with different culinary traditions. Studying animals transplanted with the microbiota from humans representing each cuisine and fed a sequence of diets representing those of all donors, we find that correlations between bacterial species abundances and transit times are diet-dependent. However, the levels of unconjugated bile acids - reflecting microbial bile salt hydrolase activity - correlate with faster transit across diets, including a Bangladeshi diet. Mice harboring a consortium of sequenced bacterial strains from the Bangladeshi donor’s microbiota and fed a Bangladeshi diet revealed that the commonly used spice, turmeric, slows transit times. Turmeric affects gut motility via bacterial bile acid deconjugation and modulation of Ret signaling in the ENS. These results demonstrate how a single food ingredient interacts with a functional microbiota trait to regulate host physiology.

To model how interactions among enteropathogens and gut microbial community members contribute to undernutrition, we colonized gnotobiotic mice fed representative Bangladeshi diets with sequenced bacterial strains cultured from the fecal microbiota of two 24-month-old Bangladeshi children: one healthy, the other underweight. The undernourished donor’s bacterial collection contained an enterotoxigenic Bacteroides fragilis strain (ETBF), whereas the healthy donor’s bacterial collection contained two nontoxigenic strains of B. fragilis (NTBF). Analyses of mice harboring either the unmanipulated culture collections or systematically manipulated versions revealed that ETBF was causally related to weight loss in the context of its native community, but not when introduced into the healthy donor’s community. This phenotype was transmissible from the dams their offspring and was associated with derangements in host energy metabolism manifest by impaired tricarboxylic acid cycle activity and decreased acyl-CoA utilization. NTBF reduced ETBF’s expression of its enterotoxin and mitigated the effects of ETBF on the transcriptomes of other healthy donor community members. These results illustrate how intraspecific (ETBF-NTBF) and interspecific interactions impact the effects of harboring B. fragilis..

In the above article, we show that changes in diet composition affect gut motility in a microbiota-dependent manner. While describing the rationale for re-deriving Ret +/À mice as germ free on page 103, right column, lines 6-9, we erroneously indicated that conventionally raised wild-type (Ret +/+ ) mice have slower transit times than their heterozygous (Ret +/À ) littermates. The correct sentence should have stated, ''We found that conventionally raised wild-type (Ret +/+ ) mice have significantly lower transit times (faster motility) than their conventionally raised heterozygous (Ret +/À ) littermates (p = 0.05, one-tailed Student's t test; as shown in Table S2F).'' The published results of this experiment were correct, and this textual error does not affect the conclusions of the paper. The online version of the paper has been corrected to reflect this change. We apologize for any confusion that it may have caused.

Abstract:The myelodysplastic syndromes (MDS) are clonal stem cell disorders, characterized by ineffective and dysplastic hematopoiesis. The genetic and epigenetic pathways that determine disease stage and progression are largely unknown. In the current study we used gene expression microarray methodology to examine the gene expression differences between normal hematopoietic cells and hematopoietic cells from patients with MDS at different disease stages, using both unselected and CD34+ selected cells. Signifi cant differences between normal and MDS hematopoietic cells were observed for several genes and pathways. Several genes promoting or opposing apoptosis were dysregulated in MDS cases, most notably MCL1 and EPOR. Progression from RA to RAEB(T) was associated with increased expression of several histone genes. In addition, the RAR-RXR pathway, critical for maintaining a balance between self-renewal and differentiation of hematopoietic stem cells, was found to be deregulated in hematopoietic cells from patients with advanced MDS compared to patients with refractory anemia. These fi ndings provide new insights into the understanding of the pathophysiology and progression of MDS, and may guide to new targets for therapy. Taken together with previous published data, the present results also underscore the considerable complexity of the regulation of gene expression in MDS.