Writing in Science, the team behind the new study reveal the probiotic strain Lactobacillus reuteri is linked to the occurrence of specific immune cells in the gut – and that these immune cells are only triggered when both the bacterial strain and tryptophan are present.
"We established a link between one bacterial species -- Lactobacillus reuteri -- that is a normal part of the gut microbiome, and the development of a population of cells that promote tolerance," said senior author Professor Marco Colonna, MD, from the Washington University School of Medicine in St. Louis. "The more tryptophan the mice had in their diet, the more of these immune cells they had."
If such findings hold true for people, it would suggest that the combination of L. reuteri and tryptophan (or a tryptophan-rich diet) could help foster a more tolerant, less inflammatory gut environment, which could mean relief for people with the abdominal pain and diarrhoea associated with inflammatory bowel disease, said the team.
They noted that humans have been shown to have the same tolerance-promoting cells – known as CD4+CD8αα+ double-positive intraepithelial T lymphocytes (DP IELs) – as mice. Furthermore, it has been established that most people harbour L. reuteri in our gastrointestinal tracts.
It is not yet known whether the tryptophan by-products from L. reuteri induce the cells to develop in people as they have been shown to in the current mouse study, said the team. However, they did note that defects in genes related to tryptophan have previously been linked to people with inflammatory bowel disease (IBD).
"The development of these cells is probably something we want to encourage since these cells control inflammation on the inner surface of the intestines," said study first author Dr Luisa Cervantes-Barragan.
"Potentially, high levels of tryptophan in the presence of L. reuteri may induce expansion of this population."
Cervantes-Barragan was studying DP IELs when she discovered that one group of study mice had such cells, while a second group of study mice that were the same strain of mice but were housed far apart from the first group did not have such cells.
Although the mice were genetically identical, they had been born and raised separately, indicating that an environmental factor influenced whether the immune cells developed, said the team.
The team then began to sequence DNA from the intestines of the two groups of mice – finding that six bacterial species present in the mice with the immune cells but absent from the mice without them.
Using mice that had lived under sterile conditions since birth, the team then worked to identify which of the six species was involved in inducing the immune cells.
They found that when L. reuteri was introduced to the germ-free mice, the immune cells occured.
To understand how the bacteria affected the immune system, Cervantes-Barragan and colleagues then grew L. reuteri in liquid and then transferred small amounts of the liquid - without any bacteria - to immature immune cells isolated from mice.
The immune cells developed into the tolerance-promoting cells.
After further analysis, the active component was identified to be a by-product of tryptophan metabolism known as indole-3-lactic acid.
When the team then doubled the amount of tryptophan in the mice's feed, the number of such cells rose by about 50%. When tryptophan levels were halved, the number of cells dropped by half.
“The complete reliance of DP IELs on a single species, L. reuteri, and its tryptophan metabolites for their final maturation may provide a basis for the use of L. reuteri as a probiotic and tryptophan-rich food to treat disorders that are modifiable by DP IELs, such as inflammatory bowel diseases,” they concluded.
Published online ahead of print, doi: 10.1126/science.aah5825
“Lactobacillus reuteri induces gut intraepithelial CD4+CD8αα+ T cells”
Authors: Luisa Cervantes-Barragan, et al