New thesis shows that the gut microbiome is not gender-neutral

What is the main focus of your thesis?

Colorectal cancer is becoming more common, and here's something curious: men get it more often than women — at least until women reach menopause. That age-related pattern suggests female sex hormones, especially estrogens, might be protecting the gut somehow.

This thesis digs into that question. It focuses on a protein called ERβ, which acts like a receiver for estrogen signals in the gut. The goal was to understand what happens when that receiver is switched off — and whether it matters more for men or women when the gut gets inflamed.

Which are the most important results?

The microbiome isn't gender-neutral. During intestinal inflammation (for example, triggered by a high-fat diet), male and female mice recruited different communities of bacteria. Estrogen treatment was able to influence this response with a couple of specific bacterial species, which could be considered markers of inflammation

Men's immune systems react more dramatically to gut inflammation. In one of the projects, we mapped out immune cells through the entire length of the mouse colon. Under inflammation, males showed much bigger shifts in their immune response, especially in cells that are supposed to calm inflammation down.  When ERβ was removed from the intestinal cells, immune response to colitis was more intense overall, and male response pattern to inflammation started resembling that of females, suggesting that this receptor is part of what makes male and female gut respond so differently in the first place. 

Inflammation throws off the gut's internal clock — and sex matters here too. Our cells run on daily biological rhythms, and inflammation throws that rhythm off. We found that males were more affected by this disruption than females. ERβ turned out to play a role in here too, helping regulate BMAL1 — one of the master components driving this biological clockwork.

How can this new knowledge contribute to the improvement of people’s health?

This work gives a clearer picture of how sex shapes the body’s response to gut disease. Historically, all medical research was largely conducted on male subjects, with findings assumed to apply to everyone. We now know this is not the case. Therefore, accounting for sex in gut disease research — and potentially targeting ERβ in treatments — could be an important step toward more personalized and effective therapies. 

What are your future ambitions? 

I would love to continue working in experimental oncology and try to unravel the complex network of causes and consequences that drive disease progression. 

Dissertation

Friday 5 June, at 09:30, Rockefeller, Nobels väg 11, Campus Solna / Online

Thesis

Influence of molecular sex differences and estrogen signaling on colorectal cancer