New research shows that having aberrant bacteria and viruses in the gut is strongly associated with anorexia and suggests that a disrupted gut microbiota locks down the brain biology of young women with anorexia nervosa in an unhealthy autonomic state.
Disrupted gut microbiota is strongly associated with anorexia.
This is the conclusion of a major 9-year research project with the most extensive in-depth analysis to date of how the composition and function of gut microbiota affect the health of affected individuals.
The research indicates that changes in the gut microbiota are not just associated with the development of anorexia but probably also keep girls and young women in the iron grip of this eating disorder.
The leading researcher behind the study says that the results may pave the way for randomised controlled trials to change the gut microbiota of people with anorexia and thereby perhaps help to save them from a life-threatening condition that affects not only the body but also the mind.
“Our study justifies hope that the code to unlock the highly disrupted gut microbiota may eventually be found by resetting it with antibiotics followed by weekly faecal transplants from healthy siblings over several months. Anorexia should not just be portrayed as a mental disorder but also as a metabolic disorder in which an altered gut microbiota seems to be involved,” explains Oluf Borbye Pedersen, Professor and Research Leader, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen and Center for Clinical Metabolic Research, Herlev and Gentofte Hospital.
The research has been published in Nature Microbiology.
Girls and young women comprise 90% of anorexia cases
About 1% of young people develop anorexia, and 20% have a chronic and often life-threatening trajectory. Girls and young women account for about 90% of anorexia cases worldwide, and they often develop it in adolescence.
The researchers wanted to elucidate how the gut microbiota, with its ecosystem of billions of bacteria and viruses, influences the development of anorexia. They therefore thoroughly mapped the gut microbiome of 77 women with anorexia in Denmark and 70 matched healthy women controls.
They also examined many of the metabolites in the blood that are either produced or modified by the gut microbiota and examined the participants for 12 personality traits.
Gut microbiota strongly associated with anorexia
The results showed that both the composition and the function of the gut bacteria differed greatly between people with anorexia and healthy people.
The gut microbiota of those affected with anorexia had greater capacity to break down gut microbiota–derived signalling compounds that affect the brain.
The researchers also found that the disrupted bacterial ecology was associated with secondary bile acids and certain breakdown products of amino acids. These substances are produced or changed by gut bacteria and are known to affect hunger and satiety.
The researchers used in-depth statistical analysis to show associations between changes in gut bacteria, changes in the concentration of bacterial substances in the blood and personality traits such as low self-esteem, fear of adulthood and refusal to eat.
“In anorexia cases, we found changes in the concentration of secondary bile acids and breakdown products of the amino acid tryptophan, which are known to affect the brain,” says Oluf Borbye Pedersen.
The researchers comprehensively analysed the genes of the individual bacteria and found thousands of DNA changes that were also linked to the participants’ personality traits.
The loss of many genes in a common commensal gut bacterium called Bacteroides uniformis especially attracted the researchers’ attention. One of these lost bacterial genes is necessary for bacteria to produce vitamin B1 (thiamine). Thiamine deficiency can lead to reduced appetite, gastrointestinal symptoms and anxious and isolating social behaviour.
Viruses can eradicate healthy gut bacteria
The mapping of the gut microbiota also revealed that cases with anorexia had markedly altered composition of viruses.
“No one knows how many viruses reside in the gut, but there are an estimated 10 times as many viruses as bacteria. There is a complex interaction between viruses and bacteria in the gut, and some of this dynamic interaction was also missing among women with anorexia,” explains Oluf Borbye Pedersen.
The research team also made another thought-provoking observation about the gut viruses.
Many gut viruses are lytic bacteriophages that kill bacteria as they divide. An overrepresentation of certain types of bacteriophages in the gut can reduce the number of gut bacteria and thus also the bacterial products that people need to stay healthy and well.
The gut of women with anorexia had many more lytic bacteriophages than did healthy controls, and the composition of viruses were also more diverse.
The researchers especially noticed that there were more of the type of bacteriophage that kills Lactobacillus bacteria, and some strains of Lactobacillus are considered to be part of the healthy gut microbiota.
Fecal microbiota from women with anorexia transplanted into mice
To investigate whether the associations are potentially causal, the researchers transplanted the gut microbiota of cases with anorexia and of healthy people into germ-free mice, which are born sterile and have therefore never been in contact with microbes. The bacteria in the transplanted faeces colonised the gut of the mice to a certain extent.
This part of the study showed that the mice that received the transplants from women with anorexia had more difficulty gaining weight than the mice with fecal transplants from the healthy controls.
In addition, the expression of several of the genes controlling fat combustion was elevated in fat tissue of mice receiving stools from women with anorexia. The researchers also examined the brains of the mice that had received fecal transplants from cases with anorexia and found altered expression of some of the key genes in the hypothalamus regulating hunger and satiety.
“The fact that the mice had suppressed hunger in the brain and had increased fat metabolism in the adipose tissue may partly explain why they gained less weight,” says Oluf Borbye Pedersen.
Adjuvant treatment for anorexia still a long way off
Oluf Borbye Pedersen hypothesises that the way to unlock the brains of people with anorexia may be to reboot healthy gut microbiota.
He advocates investigating whether randomised controlled fecal transplantation trials involving young healthy siblings can break the vicious circle into which the abnormal gut microbiota has whirled people with anorexia.
He has drawn inspiration from experiences of using fecal transplantation for people with the life-threatening disorder caused by Clostridioides difficile, in which fecal transplantation is the only effective cure.
Oluf Borbye Pedersen also mentions that a pilot experiment with combined initial antibiotics and subsequent weekly faecal transplantation over several months improved mental and intestinal symptoms for up to 2 years among children and adolescents with autism spectrum disorder.
“The current treatment of women with anorexia includes psychotherapy, changing diet and exercise and family counselling. In future randomised controlled trials, in addition to the conventional treatment, clinicians will probably test whether an adjuvant treatment with repeated fecal transplantation, thiamine and Lactobacilllus from, for example, kefir, which contains 13 different Lactobacilllus strains, can improve the prognosis of this terrible disorder affecting young people,” concludes Oluf Borbye Pedersen.
