Karolinska Institutet

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Vaginal Delivery Induces “Good” Stress

A little more than a year ago, my son was born. And, just as the birth of my daughter had been, the delivery became an emergency caesarean section. Neither my first nor my second went all the way, despite hours even days of pain and contractions.

Why am I telling you this? Yes, believe it or not, but the stress induced by giving birth vaginally actually equivalates to a positive impact. At least for the child anyways.

Five years ago, my colleagues did an attention-grabbing study in which they looked epigenetically at how children are affected by vaginal birth compared to being born via caesarean section. This in light of previous studies that have shown that children born via a planned cesarean section have a higher risk of developing asthma, type 1 diabetes, obesity and gluten intolerance later in life. The reason for the connection is not fully established, but as planned caesarean deliveries have increased in many parts of the world, it is of increasing importance to look into this more closely.

In my study, my colleagues investigated epigenetic changes in stem cells from cell-sorted umbilical cord blood. Global epigenetic analysis was performed on 43 newborn infants, 18 of whom were delivered with planned caesarean section. Furthermore, DNA from twelve newborns (six planned cesarean sections) was analyzed for gene-specific epigenetic change throughout the genome.

The results show specific epigenetic differences between the groups at nearly 350 sites in the genome. The genes with different methylation patterns were involved, among other things, in processes that control the metabolism and the immune system.

The study provides support for the theory that the act of giving birth itself leaves imprints in the genome of the newborn baby’s stem cells. The discovery may be important to understand why people born with caesarean section are statistically at increased risk for immunological diseases. However, it is still unclear whether the so-called epigenetic change is temporary or persists for a long time. The biological mechanisms that predispose a fetus or newborn to diseases later in life are complex and depend on both inheritance as well as environment during the fetal stage and throughout adolescence (which I wrote about earlier).

But what could this “good” stress* be positive for?

One possible explanation is that during a vaginal delivery, the fetus is subjected to a progressively increasing and very strong stress onset, which here is positive for the child and prepares it for life outside the uterus. This stress is believed to activate the child’s defense system for adaptation to life after birth, which is absent in planned Caesarean sections where the work of labor never starts. However, it is important to remember that many immunological diseases, including those mentioned above, are a result of both inheritance and the environment, and that our epigenome is not static but is affected by our internal and external environment throughout our lives.

Finally, I sometimes can’t help but think that no matter how much advanced technology and knowledge we get, we often cannot circumvent biology. Maybe something to comfort yourself with the next time you think back on your (or your partner’s) labor. Or when you’re breathing through the pain of your upcoming labor. And to those who have had emergency C-sections: those hours of pain pre-cesarean were actually useful. So don’t despair!

(This post does not try to blame or act as a pointing stick. My view is that every woman decides over her own body and knows what it can and does best. For many, planned caesarean sections are a medical necessity. As I see it, knowledge is power to be able to make sensible decisions and change the world in a positive direction.)

* However, it should be clarified that the type of stress we are talking about here is not the same as chronic, long-term, stress. Which has on the contrary been shown to have negative health effects (which I do not go into here).

Louise Sjöholm has an education in molecular biology and a doctorate in depression genetics from Karolinska Institutet. She has been working as an epigeneticist for seven years and is researching the role of the gastrointestinal tract in autoimmune diseases, i.e., diseases in which the body’s immune system attacks its own tissue. She is also interested in understanding the epigenetics of bacteria and its connection to health and disease. The views in the chronicle are the writer’s own.



Karolinska Institutet

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Exercising the Patience Muscle, What it’s Like Working as a Researcher?

Time for an update on how things have gone for our SweMaMi study thus far, plus a look into what it’s like to be a researcher. As I wrote last autumn, our research group studies the relationship between pregnant women’s bacterial flora (with samples from the mouth, gut and vagina) and various pregnancy complications. We sync the data from the analyzed bacterial flora and the questionnaire about the woman’s pregnancy, lifestyle, health, eating habits, stress, bowel function and other things. In addition, we ask the parents to collect a sample from the diaper from the newborn baby and we then follow the child’s health for many years to come.

Today we have recruited about 2,300 pregnant women to the study, but fewer than 2000 have submitted samples. We had hoped to finish the recruitment now this summer, but due to the large drop-out we need to extend the recruitment time until we reach our goal of 2,500 women who have both filled in the surveys and submitted the samples to us. Then we need to wait until all SweMaMi babies are born to get the last samples before we start analyzing. You can see how this takes a lot of patience.

In the meantime, we have begun to analyze the questionnaire responses from the first 2000 pregnant women in the study. We are pleased to see that we have received data from almost all of Sweden, about 60% of the studies participants come from areas outside of Stockholm. In addition, the age distribution seems to be representative of pregnant women in Sweden as well. When it comes to education and work, we mainly reach women with college education and full-time jobs, which unfortunately does not represent all pregnant women in Sweden. This will limit our ability to generalize our findings to the entire population.

So far, about 650 babies have been born by mothers who are part of the study, and for the first 444 participants, we have evaluated the questionnaire responses regarding eating habits as well as the reports of depression after childbirth. There seems to be a link between unhealthy eating habits and the onset of depression, especially when it comes to high consumption of sweetened beverages and low consumption of vegetables. Perhaps not quite unexpected, but an important finding that we will analyze further considering that the connection between the intestinal flora and our mental health is a hot research area. Studies in mice show that intestinal bacteria can affect brain development and animal behavior. But when it comes to people, there are no studies that show the connection between the bacterial flora and our mind. Above all, it is uncertain what is cause and what is effect. The connection may be due to several things, such as the fact that it is common to eat sweets as a form of self comforting, but it could also be that the diet affects mental health via a change in the bacteria. We do not yet know how the bacteria in the mouth, intestine and vagina interact with each other in our bodies, hence why our study is so important.

Our research team tries to collect all the knowledge available on pregnancy and bacterial flora, but at present it cannot make any recommendations on specific pre- or probiotics that could prevent miscarriage, premature birth or depression in expectant mothers. Sometimes it may feel a little frustrating, but the more understanding we get for the complexity of the interaction between our bodies and the trillions of microbes that live in and on us, the harder it will be to make cross-proof statements about which we should add. Unfortunately, many unscientific advice is being disseminated by self-proclaimed media experts. Science as of today can only recommend a Mediterranean style diet and a lifestyle with a lot of physical activity to avoid the bacterial flora adversely affecting pregnancy and fetal development.

So more patience is required, but if every women who is pregnant (earlier than week 19) and finds herself residing in Sweden could imagine participating in the SweMaMi study, then, we can together come a bit further in our understandings. Help us spread the information about the study and base the recommendations given to pregnant women on scientific facts.

Subscribe to our study at www.swemami.se. You are also welcome to follow us on Facebook and Instagram: SweMaMi.

Ina Schuppe Koistinen is an Associate Professor at Karolinska Institutet and works at the Center for Translational Microbiome Research to study the role of bacterial flora in inflammatory bowel diseases and women’s health. In addition to her research, she is passionate about yoga and guiding people to a healthier lifestyle. She is also active as an artist with watercolor as a medium. The views in the chronicle are the writer’s own.

Watercolor: Ina Schuppe Koistinen



Karolinska Institutet

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Twins – An Important Epigenetic Tool

An important part of my work is to carefully plan my studies so that we actually measure what we intend on measuring and nothing else. Maybe this sounds straightforward but it’s not quite that easy.

As an epigeneticist, I study the impact of the environment on the genome (read more here). What makes it all difficult is that our epigenome is not static, but constantly exposed to changes from our environment. For example, if we discover an epigenetic difference between sick and healthy people, we cannot say whether the difference seen  is the cause of the disease or a consequence of it. In most cases we are studying people who are already sick. And, to make things all the more complicated, most diseases are the result of a combination of heritage and the environment.

So how do we get around around this? There are a few different ways to design a study to filter out the noise of unwanted signals, and clarify what is cause and effect. One way to sort out the noise from our genes and just study the environmental impact is to use twins. Identical twins have the same genome and to some extent a common environment, however, the older they get the more separated their living environment and habits tend to become. And this is what we benefit from when studying twins where only one twin has suffered from a particular disease.

In one of our studies, we studied epigenetic changes and rheumatic disease with the help of identical twins from the Swedish Twin Registry. And to find out more about the onset of the disease, and not just the effect, we also studied “healthy” twins who have not yet been affected by rheumatism, but who are likely to develop the disease as they have a certain type of antibody in their blood that is associated with rheumatism (antibodies against ACPA).

With this approach, we were able to identify methylation differences that were not dependent on the interference of the genes. But why do you want to do this? Well, in the vast majority of studies that investigate rheumatism, a certain group of genes pop up, the so-called HLA genes. These genes encode proteins that help our immune system talk about what is body-like or body-foreign.

The HLA genes are involved in one way or another in rheumatism, and also in many other autoimmune diseases. But, with the help of identical twins, we could identify other genes involved in addition to the HLA genes. The PCDHB14 gene was found to be differently methylated in both the “healthy” twins with ACPA antibodies in their blood and the diseased twins, suggesting that this gene is involved in the actual development of the disease.

PCDHB14 belongs to a large complex gene family that is mainly expressed in the brain and which has been reported to be involved, just like the HLA genes, in sensing what is own and body foreign. Super interesting! In the mentioned study, we could not point out which environmental risk factor or factors could possibly be behind the development of the disease, but we gained knowledge about which biological systems could be involved in rheumatism. One puzzle piece at a time!

In another study, we focused instead on one of the most common risk factors for many autoimmune diseases, namely smoking. We wanted to investigate how smoking affected MS patients and then looked at smokers, former smokers and MS patients who had never smoked. But I’ll tell you more about this in my next post here at Food Pharmacy.

Louise Sjöholm has a education in molecular biology and a doctorate in depression genetics from Karolinska Institutet. She has been working as an epigeneticist for seven years and is researching the role of the gastrointestinal tract in autoimmune diseases, i.e., diseases in which the body’s immune system attacks its own tissue. She is also interested in understanding the epigenetics of bacteria and its connection to health and disease. The views in the chronicle are the writer’s own.

Photo by Sharon McCutcheon on Unsplash




Karolinska Institutet

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Saving the Antibiotic for Future Generations

World Health Organization (WHO) has classified the global issue of antibiotic resistance as a major threat to public health. In just Europe alone, approximately 30,000 deaths per year occur from infections with resistant bacteria and this figure is expected to have doubled in the next ten years.

In some countries, when there is risk of infection of such bacteria, the risk alone is causation enough to cancel a scheduled operation. Should we just give up then or is there light at the end of the tunnel? Well, first of all, we must change our behavior and not use antibiotics unnecessarily. Antibiotics should, in principle, be used to save lives and not for banal viral infections or colds. But if we want to save the antibiotic for future generations, new alternative treatments for infections with resistant bacteria must also be tested. These such trials are what is currently ongoing at the Center for Translational Microbiome Research, CTMR.

An alternative that seems promising is to compete the resistant bacteria in the intestinal flora with a “good microbiome” i.e., good intestinal flora. Currently ongoing in the laboratory is an experiment where resistant bacteria are supplied with a disturbed intestinal flora in test tubes and we then add “healthy intestinal flora” from a healthy donor. It is the same principle used in so-called fecal transplantation (FMT) where patients with diarrhea caused by certain antibiotics are cured with a healthy donor intestinal flora. We hope to be able to identify healthy donors whose intestinal flora can, in the future, help to compete with resistant bacteria in the intestinal flora of people who unknowingly carry. In this way, we can also reduce the risk of spreading resistant bacteria outside the body.

Another way to kill disease-causing resistant bacteria is phage therapy. Here, target-seeking viruses are used to eliminate the desired bacteria, usually with great precision. Phage therapy has long existed as a treatment option in Georgia and other post-Soviet states, but when the antibiotic entered the scene about 60 years ago the technique has not developed or advanced, as many thought antibiotics were the solution to all infectious problems. Now the researchers are beginning to realize that phage can be a good alternative when antibiotics cannot be used. Phage therapy also has the advantage that it does not interfere with the intestinal flora, which has proven to be a problem in antibiotic treatment, where even “good” bacteria are eliminated as well.

At our center, several trials are now underway. One of which we use test tubes containing good intestinal flora, then we add resistant bacteria and lastly the phages that kill them. Our results show that the phages do not disturb the intestinal flora at all and that the number of resistant bacteria decreases markedly in the test tube. The next step is to transfer this principle to humans. Today, there are occasional reports of successful treatment in patients where antibiotics did not work and where the patient’s life was rescued thanks to phages who did the job instead. A combination of phages therapy as well as supplying a dose of good intestinal flora could also be tested in some patients.

If we can prevent the spread of resistant bacteria by changing our behavior while developing new alternative treatments for infections with resistant bacteria then hope is not out. Then future generations can also use antibiotics when needed, i.e., to save lives.

Lars Engstrand is a doctor and professor at Karolinska Institute and leads the work at the Center for Translational Microbiome Research. He has been studying microorganisms in the gastrointestinal tract for over 30 years and is one of the pioneers in studying the role of the gut flora in health and disease.