Studying the body’s defence against bacteria’s arsenal

Mikael Sellin holds up the miniature organs, or organoids, used in their lab work. They are produced using stem cells and stored in liquid nitrogen.

White smoke billows out as Mikael Sellin lifts out the samples. It’s in this tank, which maintains a temperature of –175 degrees, that the tissue samples are kept. They are known as organoids and are the focus of the lab’s work. They are grown out of stem cells taken from real human intestines.

“This technology is a breakthrough that allows us to grow human tissue that resembles your gut or your lung. This means that we can conduct experiments under conditions that better resemble the body,” explains Sellin, associate professor at the Department of Medical Biochemistry and Microbiology, head of the Sellin lab and SciLifeLab group leader. 

Filming invasion of the gut

For five years now, they have been using organoids to study what happens when gut bacteria, such as Salmonella and Shigella, attack the gut. Using microscopes and a thin layer of cultivated intestine, they are able to document what happens when the bacteria are added. For example, they have been able to film in real time Salmonella bacteria locating their points of attack, thanks to the advanced microscope built by a colleague, Jens Eriksson.

“The Salmonella bacteria can swim around with help from ‘swimming fins’ known as flagella. When they reach the lining of the gut, they search over the surface, and when they find a weak spot they work their way in,” continues Sellin.

Salmonella and Shigella are examples of invasive bacteria, which means they attack our tissue. However, the body has developed methods to try and prevent the bacteria’s progress. In the lab, they have managed to film the process whereby the gut manages an attack.

“There’s a system in the surface cells, or the intestinal epithelium, which recognises this invasion. When the cell realises it has been attacked, it commits suicide and is then squeezed out by its neighbours. This way the gut removes the potential risk of the bacteria spreading to the sterile tissue.”

Antibiotics ineffective

There are around 500 million bacterial gut infections across the globe each year. Most people affected make a recovery, but there are also many cases that prove fatal. Antibiotics are used in acute cases, but they are not particularly effective in treating these types of infection. This is partly due to the fact that antibiotics cause the normal flora in the gut to crash, and partly because the bacteria can lie dormant and thus survive the treatment.

“This is something we need to understand better – what enables them to lie dormant? And can we wake them up so that the antibiotic treatment can detect them?”

Sellin explains how they have now slowly begun to study the process whereby antibiotics enter tissue and tackle bacteria. By using organoids instead of culture plates, they hope to obtain a better picture of the true inner workings of the actual intestine.

Plans to study bacteria’s arsenal 

Late last year, Sellin was awarded a consolidation grant from the Swedish Research Council totalling SEK 10 million. Thanks to this funding, the lab – which currently consists of 10 researchers – can expand to recruit another post-doctoral researcher. They will also attempt to map the genes of the invasive gut bacteria. They are particularly interested in the genes that describe how the bacteria produce their weapons.

“These invasive gut bacteria resemble the body’s normal flora, but they have an arsenal of weapons. One example is a type of machine gun that it can place on its surface. The bacteria use it to push into the surface of the cell and fire in small bacterial toxins that order the host cell to do as the bacterial cell wants.”

By using a method that randomly knocks out the bacteria's genes and then studying what happens to their ability to attack the intestinal lining, the researchers hope to find out which genes control the bacteria's weapon production. His colleague, Maria Letizia Di Martino, has just made this powerful method work.

“If we know which weapons there are, we can develop pharmaceuticals, antibodies and vaccines against those specific weapons. This gives us better specificity than if we use an antibiotic that knocks out multiple types of bacteria.”

The method used by the gut bacteria to attack tissue is not unique; it can be found among other dangerous bacteria. Greater knowledge about how the machine guns function is thus vital for understanding and, in the long term, being able to treat serious infections.  

“It’s not the case that the gut infections we are studying are the most serious that can affect us; there are also lung and urinary tract infections that are even more problematic. But what we are doing in these experimental systems can also be applied to them,” notes Sellin, before continuing:

“Naturally, it’s a researcher’s dream for our findings to not only prove important for our minor research area, but to also be significant in a broader context.”