Abstract
Dietary heme can be used by colonic bacteria equipped with heme-uptake systems as a growth factor and thereby impact on the microbial community structure. The impact of heme on the gut microbiota composition may be particularly pertinent in chronic inflammation such as in inflammatory bowel disease (IBD), where a strong association with gut dysbiosis has been consistently reported. In this study we investigated the influence of dietary heme on the gut microbiota and inferred metagenomic composition, and on chemically induced colitis and colitis-associated adenoma development in mice. Using 16S rRNA gene sequencing, we found that mice fed a diet supplemented with heme significantly altered their microbiota composition, characterized by a decrease in α-diversity, a reduction of Firmicutes and an increase of Proteobacteria, particularly Enterobacteriaceae. These changes were similar to shifts seen in dextran sodium sulfate (DSS)-treated mice to induce colitis. In addition, dietary heme, but not systemically delivered heme, contributed to the exacerbation of DSS-induced colitis and facilitated adenoma formation in the azoxymethane/DSS colorectal cancer (CRC) mouse model. Using inferred metagenomics, we found that the microbiota alterations elicited by dietary heme resulted in non-beneficial functional shifts, which were also characteristic of DSS-induced colitis. Furthermore, a reduction in fecal butyrate levels was found in mice fed the heme supplemented diet compared to mice fed the control diet. Iron metabolism genes known to contribute to heme release from red blood cells, heme uptake, and heme exporter proteins, were significantly enriched, indicating a shift toward favoring the growth of bacteria able to uptake heme and protect against its toxicity. In conclusion, our data suggest that luminal heme, originating from dietary components or gastrointestinal bleeding in IBD and, to lesser extent in CRC, directly contributes to microbiota dysbiosis. Thus, luminal heme levels may further exacerbate colitis through the modulation of the gut microbiota and its metagenomic functional composition. Our data may have implications in the development of novel targets for therapeutic approaches aimed at lowering gastrointestinal heme levels through heme chelation or degradation using probiotics and nutritional interventions.
Highlights
Availability of nutrients within the gut is a major driver of the microbial community structure (Kamada et al, 2013)
To investigate the effects of heme iron on gut microbiota composition, we analyzed microbiota in stool samples from mice fed a diet containing 50 ppm as iron-sulfate or 50 ppm of iron as heme, and compared to mice fed with the control diet while subjected to dextran sodium sulfate (DSS)-induced colitis, which causes gastrointestinal bleeding
Principal Coordinate Analysis (PCoA) (Figure 1B) showed that mice fed the control diet clustered separately from mice fed the heme-supplemented diet, indicating that heme iron substantially altered the composition of the gut microbiota
Summary
Availability of nutrients within the gut is a major driver of the microbial community structure (Kamada et al, 2013). Bacterial iron acquisition systems include direct contact between the bacterium and exogenous iron sources as well as more sophisticated systems that rely on molecules synthesized and released by bacteria into the extracellular medium to scavenge iron or heme from various sources. These include high-affinity iron-siderophore and heme acquisition systems, which enable bacteria to compete for iron (Wandersman and Delepelaire, 2004). Intestinal luminal iron availability is highly dependent on dietary components and/or iron supplementation and holds the potential to directly affect microbial composition
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