Does Gut Microbiota Influence Lipid Metabolism in the Sexes?

Background:

Differences between human males and females can be large or small; one of our largest problems in the more recent years may be influenced by a very small thing, or things rather. It turns out that the microbes living in our gut can affect our metabolism of fats (Eldin et al, 2016), impacting fat storage and digestion in the body.

In the paper by Baars et al (2018), the authors investigated the differences in male and female lipid (fat) metabolism, responsible for the breakdown and storage of fats (Goldberg, 2018),  by looking at their gut microbes. These authors are researching this difference in lipid metabolism based on the previous study done by Sugiyama, M. G. and L. B. Agellon (2012) that suggested that microbes and host sex can influence the metabolism. In this study, the authors are testing whether or not the bacteria in our gut has an effect on the lipid metabolism in our bodies, specifically between males and females.

Baars et al (2018) explore the extent that the microbes in our gut influence the lipid metabolism in males and females. The impact of gut microbes was tested by looking at functions of the metabolism in males and females, differences in the product of the lipid metabolism (bile acids) produced, and differences in the microbial gut communities.

They looked at differences between the sexes in gut microbes and metabolism, trying to find a link between microbial presence and changes in the lipid metabolism. Using mouse models, Baars et al (2018) were able to say that gut microbial activity does have an impact on lipid metabolism and affects males and females differently. In this study, they were not able to identify why males and females showed differences in the lipid metabolism or in their bile acids. However, the results do open up interesting questions about how the microbes in our gut can impact our bodies.

The central question in the study:

Baars et al (2018) asked the question: How do the microbes in our gut affect fat metabolism differently in males and females? This question can help us understand the differences in metabolism between men and women, as well as help with possible predictions on personal health and weight gain.

Evidence for the conclusions:

In order to prove that gut microbiota has different effects on the lipid metabolism of men and women, they first need to prove that the microbes themselves instead of another factor are causing a change. To help support the hypothesis, a lab experiment identified the top 1000 most variable genes of groups of mice with a microarray analysis. Mice were tested in two sets, conventional male/female or normal mice without any alterations, and germ-free male/female, which are mice that have no microbes on or in them. When both sets are grouped together on the principal coordinate plot (PC Plot) in Figure 1A, we can see there are distinct groupings between males and females, concluding that lipid metabolism in males and females are different from one another. This also tells us that the variable genes in each sex are more closely related to each other than the other sex.

A coordinate plot showing the difference between gene expression of the lipid metabolism in males and females.
Figure 1A. This PC plot shows the variance in gene expression between the lipid metabolism of males and females in the two test groups. (Figure from Baars et al, 2018)

Top biologic functions were examined between the two groups (conventional and germ-free). The Lipid metabolism was ranked as a primary function in germ-free mice, as the top biologic function, and ranked twenty-ninth in conventional mice. Overall, germ-free mice showed top biologic pathways in the lipid metabolism relating to fatty acid metabolism. Whereas in the conventional mice, the lipid metabolism was related to cholesterol, lipid, and the fatty acid metabolism.

These differences show that there are different gene expressions occurring in conventional and germ-free mice lipid metabolisms. Male and female mice also exhibited differences in the bile acid metabolism (A subset of lipid metabolism responsible for liquid digestion absorption and cholesterol mediation (Lefebvre, 2009)). From the microarray data, results show bile acids transporters and receptors were increased in male mice (Abcc3 Transporter and LDL Receptors) whereas female mice had increased bile acid binding proteins (Fabp6)

Looking further into the metabolism of bile acids, differences were found in microbial communities in the different sexes. The authors tested the contribution of gut microbes to the differences they found in bile acid homeostasis. Bile acid samples were taken from each group (conventional and germ-free) and tested for content. In both conventional and germ-free female groups, bile acids (both primary and secondary) were found to be more abundant than in males. Primary bile acids are those that are made by the liver, and secondary bile acids are made by bacterial metabolism in the intestines. Conventional females had comparatively lower hydrophobicity and 2.5 times the amount of secondary bile acids in comparison to males.

Using the V1 and V2 regions of the commonly sequenced 16s rRNA gene, an analysis was done of mice microbial gut communities. Males showed higher microbial diversity than females. Female mice showed a higher abundance of Firmicutes than males and a higher ratio of Firmicutes to Bacterioidetes than males. Additionally, there were several taxa,  Clostridies, Ruminococcus, and Rikenallanaeae that were higher in abundance in conventional females. This microbial analysis of the gut microbiota indicated that there was a difference in gut microbiota between the two sexes, that affected the lipid and bile acid metabolism.

In conclusion,  the authors found that gut microbes contribute to differences in lipid metabolism between females and males. Differences were found in the top 1000 most variable genes of the mice used (Figure 1A.), the bile acid metabolism, the amount of bile acids present and the ratio of Firmicutes to Bacterioidetes in males and females. More research is needed to solidify the relationship between gut microbial activity and lipid metabolism. Additional research will also be necessary to find the mechanism causing the differences present between the sexes.  But, this study does provide us with some interesting questions and future directions to look into. 

My Questions:

  1. This study was done using a single type of autoclaved rat/mouse maintenance V153X R/M-H diet food. What differences would be apparent if the same study was done using this food as a control while implementing a high, and low fat on different groups? Would lipid metabolism increase?
  2. When the study mentions the bile acid metabolism, I found it interesting that in male mice transporters and receptors of bile acids were increased. Whereas, in females, binding proteins were increased. What is happening in the male bile acid metabolism that requires more acid transport and reception? Additionally, what is occurring in females that call for increased binding? I think this would be an interesting topic to explore in the future, delving into the molecular differences in the bile metabolism, and how they affect the host.
  3. When looking at microbial crosstalk with the host lipid metabolism, how much of the lipid metabolism is affected by microbes communicating with our metabolism? Does this “crosstalk” occur between bacteria in our gut and other aspects of our metabolism?
  4. What Could be causing the difference in expression of bile acids in males versus females? Females have 2.5 times the amount of secondary bile acids present in samples, would this indicate a more productive gut or a higher quantity of microbes?

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