Explained: gut bacteria can program digestive genes

Explained: gut bacteria can program digestive genes

The bacteria in your gut do more than just break down prebiotic fibers into important substances, they can even influence how genes work.

Gut health is all the rage, and the microbiome is an important part of that. Yet, the powers of our bacteria extend far beyond manufacturing substances for wellbeing. They’re even involved in our circadian rhythm, the 24-hour clock that regulates the entire spectrum of our bodily functions.

This week’s edition of Science Bites caters to our two favourite subjects, genes and gut bacteria, as we dissect a study on how the activity of bacteria can turn up or down the work of genes in the cells of the small intestine.

Table of contents

This research was conducted in mice, not humans, who were created for this purpose. Some had gut microbiomes, others had sterile insides. Some had specific genes, and others didn’t. This ultimately allowed the scientists to assess the function of genes and compare it with the activities of bacteria.

Mice share many genetic similarities with humans, and the study of living creatures is a necessary step in the investigation of human health. So, let’s dive in and see what they found.

Circadian rhythm 101

Before we bring you up to speed on this research, let’s review some basics about the circadian rhythm and how genes work.

In this study, researchers looked at gene expression, the process by which the instructions in our DNA are converted into functional products called proteins. Our genes don’t function all the time, instead they increase or decrease their expression depending on the time of day.

This translates into very practical applications. For example, your body’s insulin system that directs the storage of energy is more efficient in the morning, and its activity wanes as day progresses to night.

The timing of these essential functions is regulated by clock genes, whose sole job is to tell your genes when to work, and when to leave the playing field to other genes. If we take the example of the digestive system, it primes them for breaking down your daily meals, but also leaves time for maintenance and repairs.

Your clock genes work on (roughly) a 24-hour cycle, but they depend on external stimuli to regulate the body’s functions. This cycle is determined on exposure to light, which lets the body know what to do during the day and at night.

Genes in your small gut

While much microbiome research focuses on bacteria in the colon, there are also microbes in your small intestine. This is where the researchers looked for answers.

Read the original publication here

The researchers chose to analyse activity in the small intestine, the organ that extracts and absorbs most nutrients and energy from our food, and see if and how bacteria could influence the circadian rhythm.

They started with chromatin, a substance found in cells that helps regulate the circadian rhythm. It periodically takes in proteins called histones when it wants to turn off gene expression. That’s how gene activity is regulated to work at specific times of the day.


Your cells contain genes and gut bacteria can influence their work

So, these scientists decided to see whether bacteria in the small intestine could influence aspects of our digestion (like energy extracted from macronutrients) by acting on the genes in the cells of the gut lining, called epithelial cells.

The genes investigated were responsible for important metabolic functions: nutrient uptake and lipid metabolism. The researchers hypothesised that, if these genes were deregulated by microbial activities, they could influence a person’s weight and disease risk.

In order to measure changes in the daily circadian cycle of these gene activities, they collected epithelial cells of the lining of the small intestine from 2 sets of mice over a period of 24 hours.

One group of mice were conventional: their microbiome had developed normally. The other mice were germ-free, meaning they had no microbiota and lived in a sterile environment.

The microbiome programs digestive genes

When the scientists compared the level of gene activity in the collected cells over the 24-hour period, they found some interesting results.

The cells of conventional mice showed that gene expression for specific functions rose and declined rhythmically (a term called “oscillation”). In contrast, the gene expression of germ-free mice remained higher, and didn’t vary a lot throughout the 24-hour period.

This indicated that gut bacteria likely influence the circadian rhythm of digestive cells by affecting histone production. Remember, when histones are released by cells, they inhibit gene activity, which is probably why gene expression in the germ-free mice was consistently high in both cell samples.

There are several different histone deacetylase (HDAC - this protein’s full name), and the study found that one specific type was particularly affected by the absence (or indeed, presence of microbiota). It is called histone deacetylase 3 (#HDAC3).

In essence, the researchers found that gut bacteria are able to program the daily rhythm of small intestine activities by inducing the production of HDAC3 (which periodically turns off gene activity). Without it, the genes remain active throughout the day.

This is not ideal, as we’re going to see in the next part - because HDAC3 plays a role in turning on and off lipid absorption and nutrient uptake, so disrupting this process could be linked to diseases like obesity and diabetes type II.

Nutrient absorption

To check how the microbiome could influence our digestive functions via HDAC3 production, the researchers created mice without this protein and recorded what happened.

Indeed, the study used special mice which had no HDAC3 gene in their gut epithelial cells (so they couldn’t make HDAC3), and they confirmed what they found in germ-free mice: gene expression is continually activated. And this isn’t a good thing.

Bubbly Bubbles 2
It's not just what you eat, but what the body and bacteria do with it

HDAC3 inhibits the activity of genes that transport specific nutrients in the small intestine, and by doing so, it regulates when and how much the body absorbs. In mice without HDAC3, their nutrient uptake did not fluctuate as it did in conventional mice.

From this comparison, the researchers concluded that gut microbes likely influence nutrient uptake in the small intestine too, via this same pathway. In particular, HDAC3 was shown to influence tyrosine (an amino acid), inositol (a vitamin-like substance), and vitamin B2 (riboflavin) uptake.

Nutrients Function
Tyrosine Aromatic amino acid found in many foods, including cheese.
Inositol Vitamin-like substance found in the brain and other tissues.
Riboflavin (B2) Vitamin used for energy supply and to break down macronutrients

This builds on previous findings that gut microbes can influence nutrient levels in the body. And in some cases, they act directly. Indeed, beneficial bacteria are known to produce over a dozen different vitamins (Bs and K).

They can also act indirectly by breaking down compounds and making them into substances that are used by the body like making butyrate from prebiotic dietary fibers. They can even turn antioxidant polyphenols into active substances that the body can absorb.

Lipid metabolism

HDAC3 activity turns up and down the activity of 35 different genes in small intestinal cells with positive and not-so-positive consequences.

HDAC3 is involved in regulating the activity of several genes involved in lipid metabolism, from absorption to storage. In fact, mice without HDAC3 didn’t have the trademark oscillation in lipid metabolism.

In mice genetically designed without HDAC3, 17 genes for lipid oxidation and lipid biosynthesis had higher overall expression, meaning that without HDAC3 to regulate gene activity, the body made more fat (biosynthesis) and broke down more fat (oxidation).

However, 18 other fat-related genes actually displayed less activity in mice with no HDAC3. This affected genes responsible for transporting fats into the body and processing them. So after eating, more fat left the gut in their stool, and less entered the body.

When they fed conventional and HDAC3-free mice a high-fat diet, only the conventional mice gained weight. The researchers explained it like this: HDAC3 probably enabled obesity in these mice by enhancing intestinal lipid absorption.

Simply put, without HDAC3 to regulate gene expression, it was harder for the mice to absorb fat. And they confirmed this finding in germ-free mice, proving the concept that gut bacteria have the ability to influence body weight and obesity by the HDAC3 pathway.

Many studies have already identified links between body weight and the gut microbiome of the colon. For example, Akkermansia muciniphila and Christensenella minuta are two microbes associated with lean body mass, which researchers suggest have a protective role against obesity.

This study confirms such suspicions, and add another clue to the mystery of how, why, and is it possible to manage and manipulate these interactions in the interests of human health.

Conclusions

The gut microbiome doesn’t just act directly on our health by maintaining the gut environment and making nutrients, it influences our genes too.

While more research is required to identify exactly how gut microbes affect HDAC3 production, this study shows that they can by comparing what happens in mice with and without a microbiome, and then evaluating the role of HDAC3 in mice that produce it and those that didn’t.

In particular, the researchers highlighted that a high-fat diet in mice (with a gut microbiome) can enhance lipid absorption and contribute to weight gain and obesity, especially when confronted with disruptions to their daily circadian rhythm (by simulating jetlag).

Relatively little is known about the activities of bacteria in the small intestine (with the exception of Small Intestinal Bacterial Overgrowth) because it is much harder to measure and analyse them without directly penetrating into this organ.

However, this study will likely spur interest into this lesser-known colony of gut bacteria in the small intestine, and may reveal interesting findings that build on current research.

It is already known that some bacteria play a role in maintaining lean body mass. Who knows, maybe the next piece in this jigsaw puzzle was right under our noses, in the organ above our colon?

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Leigh Stewart
Leigh Stewart Head of Atlas Biomed content, trained chef and avid fermenter of edible bacteria.

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