Age and sex determine the effects of microbiota on rat metabolism

Microbiomes have assumed significant importance as producers and modulators of host metabolism and homeostatic machinery. In a new study, researchers at the University of Calgary, Canada, explored the metabolites of mice exposed to different types of microbes to understand the effects and possible influences of age and gender on these outcomes.

Study: Microbiota alter metabolite in an age- and sex-dependent manner in mice.  Image credit: Volodimir Zozulinskyi / Shutterstock

Stady: Microbiota alter metabolite in an age- and sex-dependent manner in the micH. Image credit: Volodimir Zozulinskyi / Shutterstock


The gut handles all ingested food for further digestion and assimilation. In addition, it contains a wealth of microbes that produce metabolic by-products with multiple effects on host physiology. Therefore, changes in the composition of the gut microbiome can alter the gut metabolite as well.

For example, microorganisms in the human gut produce a variety of vitamins, ferment carbohydrates, and undigested proteins to produce short-chain fatty acids (SCFAs), lactate, and bile acids, among other molecules, affecting the immune system and coagulation, as well as modulating the immune system network. Neuroendocrine influence on the gut-brain axis. These metabolic products may cause changes in the type and abundance of metabolites absorbed across the epithelial barrier.

The use of germ-free murine models (GFMM) is a recent advance in the study of microbial influences on gut metabolism. It enables them to separate it from the effects of the host’s metabolites. The current paper published in the journal Nature Communicationsbenefited gnotobiotic mouse models, along with GFMM and specific pathogen-free (SPF) mice.

Gnotobiotic mice (OMM12) were colonized with a selection of 12 symbionts from each of the five major divisions present in the mouse gut. These bacteria include Bacteroidota, Bacillota, Pseudomonadota, Actinomycetota, and Verrucomicrobiota.

The researchers studied the metabolites in the peritoneal fluid, serum, liver, spleen, and urine of rats of various ages, from just-weaned infants to adult males and females.

What did the study show?

The results show that host metabolite is specifically driven by body size, modulated by microbiota, age and sex, in that order.

The gut shows different regions with distinct metabolite signatures, with the most significant similarity between the upper gastrointestinal (GI) and lower GI tracts of GF mice versus colonized mice, respectively.

The upper gastrointestinal tract (GIT) contains higher concentrations of amino acids from the diet, such as tryptophan, leucine, and histidine, which are decreased downstream, possibly due to absorption. Polysaccharides, fatty acids, and nucleosides were abundant in the lower GI tract due to microbial degradation of proteins, carbohydrates, and nucleic acids. This was reflected in the significantly higher concentrations of these digestion products in GF mice, which lack any microbiota.

The most important factor determining differences in metabolite concentrations at each site within the gut was the microbiota.

a The estimated proportion of variance by microbiota, age, and sex at each sampled site based on PERMANOVA statistics is depicted. B Proportion of metabolites altered (PAdj < 0.05) by microbiome, age and sex at each site. c Partial R2 Show the relative contribution of age, germ, and sex in explaining the variance in metabolite abundance at each site. The metabolites shown are the 20 metabolites where most of the variance was explained by the three factors, and the full heatmap of all metabolites is shown in Supplementary Fig 1. Data represent n = 72 samples/site (equal representation of male and female mice, GF, OMM12 and SPF colonized mice and 3, 8 and 12-week-old mice). PF = peritoneal fluid. parts of fig. 2a Created with under license. Source data is provided as a source data file.

However, the effect of age was similar to that of germs in the variance of metabolites in serum, urine, and peritoneal fluid. Age played a prominent role in modulating the metabolite profile in the liver and spleen. Gender differences caused the small effect.

Metabolism in the three mouse models also showed an influence of microbial density and complexity. In the lower GI tract, the greatest effect was due to microbiota density, with OMM12 showing changes in approximately half of its metabolites. In contrast, SPF mice showed changes in more than 60% of the metabolites in the colon and more than half in the cecum.

Bacterial densities are highest in these regions, accounting for the significant contributions of microbes to the host metabolism. However, the entire gastrointestinal tract showed a significant effect on microbial metabolism.

The different bacterial composition was reflected in a diverse metabolite profile. In the upper GI tract, SPF and OMM12 mice had higher levels of taurocholate than GF mice, but only SPF mice had higher levels of taurocholate. Similarly, microbes in SPF mice used allantoin and raffinose in the lower intestine, producing glutamine, nicotine and guanine, but the OMM12 microbiota consumed only raffinose and produced only nicotine.

Raffinose consists of glucose, fructose, and galactose. The enzyme required for its degradation, α-galactosidase, has been found in microbes but not humans or mice. Nicotine is a vital micronutrient needed for the energy cycle of the cell and is derived from the amino acid tryptophan by microbes, regardless of its availability in the diet.

The abilities of the SPF microbiota and OMM12 to similarly affect the abundance of molecules such as raffinose and nicotinate suggest that these may be well-conserved metabolic pathways in bacteria, or that a specific member of the OMM12 consortium is able to normalize to murine SPF levels.. “

However, none of the 12 symbionts in OMM12 mice appear to produce tryptophanase.

Similar changes were also seen at sites other than the GI, indicating “Metabolic preferences of microbial communities, which have an effect on metabolite concentration. “

Effects of age on microbiota-induced metabolite profiles were also notable, although this was also modulated by the local microbiome. GF mice showed higher levels of uridine and histidine, among others, in the lower GI tract at eight weeks, compared to three weeks. This was not the case when comparing mice with different microbiota, such as SPF and GF mice.

This indicates that the influence of the bacterium on host metabolism varies with the stage of development. Some metabolites also showed significant variation with sex in OMM12 or SPF mice but not in GF mice, showing metabolic differences influenced by sex hormones in adult mice mediated by the microbiome.

The study helps understand more about how gut microbes interact with the host via metabolites and could aid future research. For example, it shows the significant effect of a specific GI site on a metabolite, which is mainly determined by the microorganism.

The absence of multiple metabolic pathways in GF mice underscores the significant contribution of the microbiome to human metabolism.

What are the effects?

Leveraging microbe-metabolite-host interactions toward personalized medicine holds great promise for improving health and preventing disease.. “

The study showed that microbes differentially alter levels of certain metabolites depending on the presence of particular taxa. In addition, age and sex modulate the effects of the microbiome on metabolism.

While the study was able to identify differences in 140 metabolites using semi-targeted methods, this is only the tip of the iceberg. Multiple orders of magnitude of metabolites remain that are not identified by these methods. Thus the study may provide a pattern for future microbiome studies regarding these modifiers.

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