Early life gut flora may play a role in juvenile idiopathic arthritis

More than ten years before being diagnosed with child rheumatism, children who developed the disease had a gut flora differing in several ways from that of children who remained healthy. This is shown by researchers from Linköping University and the University of Florida in a study published in eBioMedicine. This is the first study pointing to the role of early life gut flora in developing child rheumatism, the cause of which is not yet known.

Child rheumatism is the most common joint inflammatory disease in children. As there is no cure for this disease, it is instead treated with medical drugs that suppress the immune system, often for many years. The disease is also known as juvenile idiopathic arthritis, JIA. This is an autoimmune disease, which means that the immune system attacks the person's own body, resulting in inflammation in, for instance, the joints. It is still not known why the immune system launches this civil war in the body. As this is an autoimmune disease, it is of great interest to understand what factors impact the development of the immune system and what might cause JIA.

The development of the immune system is greatly impacted by the types and amount of bacteria in our guts. The composition of the gut flora depends on many factors, such as what the children eat, and genetic factors. Infections that disrupt the gut flora, and bactericidal antibiotics, may also have a huge role in this.

Many changes in gut flora take place in a baby's first year. Previous studies investigating gut flora composition in relation to JIA were conducted on patients who already have the disease when samples are taken. It has therefore not been possible to determine whether the differences observed between patients and healthy control groups were there from the beginning and maybe contributed to the disease, or whether these differences occurred later.

The current study is the first to investigate gut flora, as well as lifestyle and environmental factors, many years before the onset of the disease. The stool samples analysed were taken when the children were one year old, and those who developed JIA were diagnosed on average twelve years later.

"Some bacteria are almost completely lacking in the individuals who later developed juvenile idiopathic arthritis, compared with the healthy controls in our study. Interestingly enough, we see a connection with lifestyle. Antibiotics courses risk harming the gut flora and causing an imbalance, and we see this very clearly in our study. Breastfeeding for at least a few months, on the other hand, is linked to a reduced risk of developing the disease," says Johnny Ludvigsson, professor of pediatrics at Linköping University, who led the study together with Professor Eric Triplett at the University of Florida.

The researchers found bacteria whose presence was linked to an increased risk of JIA, as well as other bacteria that could have a protective effect. The presence of proinflammatory bacteria, such as Parabacteroides distasonsis, was linked to increased likelihood of developing JIA. The researchers believe that this bacteria may act as a trigger for autoimmunity. Conversely, several bacterial species known to produce butyrate, short-chain fatty acids or in other ways promote a healthy gut lining, such as the bacteria Akkermansia, were notably reduced or totally absent in 1-year-olds who later developed JIA. Similar findings have been noted in earlier cross-sectional studies of juvenile idiopathic arthritis.

What is unique about our study is that the reduced proportion of these butyric acid-producing bacteria in the child's gut flora was observed many years prior to the diagnosis of the disease. This suggests that this microbial signature precedes the onset of JIA, or could serve as a very early marker."

Angelica Ahrens, postdoctoral associate, University of Florida

The study is part of the ABIS (All Babies in Southeast Sweden) study led by Johnny Ludvigsson. This study, launched in the 1990s for the purpose of studying autoimmune diseases, includes 17,000 children born in 1997-1999. Of the children who were later diagnosed with JIA, twelve had provided stool samples at the age of one, on average twelve years prior to diagnosis. The researchers have analysed gut flora in these stool samples and compared it with that of children who remained healthy. The researchers also analysed the children's tissue type, or HLA type, where certain variants are linked to a genetically determined increased risk of disease. The study also includes survey data on a large number of lifestyle and environmental factors, such as breastfeeding, diet and antibiotics treatment.

"Our goal is to enhance the lives of children affected by JIA and pave the way for personalised interventions. Ideally, we aim to identify and intervene before a child enters a disease state. However, our findings may also inform complementary therapies for those who already have the disease, for instance, targeting specific bacteria, improving gut health, or promoting certain beneficial host microbes," says Angelica Ahrens.

Erik Kindgren, consultant at Skaraborg Hospital in Skövde, Sweden, who recently defended his thesis at Linköping University, also participated in the study. The research was funded by, among others, the Swedish Child Diabetes Foundation, the Swedish Council for Working Life and Social Research, the Swedish Research Council and the Joanna Cocozza Foundation for Paediatric Research at Linköping University.