Gut bacteria changes likely side effect, not driver, of CLN2 disease
Mouse study finds disease progression driven by genes, not gut dysregulation
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The composition of bacteria living in the gut is altered in people with late infantile Batten disease, but these changes are likely secondary consequences of the disease rather than drivers of disease activity, according to a study done in mice.
“Our data suggest the previously documented dysregulation of the microbiome in [late infantile Batten disease] mice, is likely a secondary effect of altered gut motility or other impacts of [the disease] upon the bowel, rather than these microbiota alterations contributing significantly to [the disease],” the researchers wrote.
An early-access version of the study, “Antibiotic treatment reveals the contributions of the gut microbiome to CLN2 disease in the central and enteric nervous system,” was published in Scientific Reports.
Late infantile Batten disease, also known as CLN2 disease, is caused mainly by mutations in the gene that provides instructions to make the protein TPP1. Deficiency of this protein leads to widespread neurological problems, though the mechanisms underlying these effects are not fully understood.
Most research on CLN2 disease focuses on its effects on the brain. But there’s emerging evidence that the disease also affects other systems, including the digestive tract. Previous research has suggested that the disease also affects the enteric nervous system (ENS), the network of nerves that controls the gut. In CLN2 disease, ENS degeneration may contribute to digestive symptoms in patients, but the biological mechanisms remain obscure.
Scientists induce changes to mice’s gut microbiota
The digestive system is home to billions of bacteria and other microscopic organisms, collectively known as the gut microbiome. These microscopic cohabitants of our bodies have profound effects on bodily health, including the health of the ENS and brain, that are only beginning to be understood.
A previous study done in a mouse model of CLN2 disease indicated that the gut microbiome is dysregulated in the disease. But it wasn’t clear whether these changes were a consequence of disease activity or if microbiome changes might be directly contributing to nerve damage.
To address this question, a team led by U.S. scientists conducted a series of experiments in which they fed CLN2 mice a cocktail of powerful antibiotics to deplete their gut microbiome. “Our goal was to assess the extent to which [antibiotic]-induced gut microbial changes may influence disease progression in both the bowel and brain of [CLN2] mice,” the researchers wrote.
They found that the antibiotic cocktail had almost no effect on CLN2 disease processes. In both the ENS and the brain, nerve cells showed little difference between mice given the antibiotics and those not given them. Overall, the intestinal structure was also not substantially altered. The researchers noted that this contrasts with healthy mice, in which this type of antibiotic cocktail leads to ENS and intestinal damage.
“Collectively, our observations suggest that the primary driver of gastrointestinal and neurological dysfunction in CLN2 disease is most likely the underlying TPP1 mutation, rather than being driven primarily by alterations in the gut microbiota,” the scientists wrote.
There were only two minor ways in which the antibiotic cocktail appeared to affect CLN2 mice. In the ileum (the backmost part of the small intestine), CLN2 mice showed slightly increased nerve cell density, suggesting that the antibiotic treatment had a small protective effect on this specific population of nerve cells. And in the brain, the antibiotic treatment led to a small decrease in microglial levels, the brain’s resident immune cells, which can become hyperactivated in Batten disease and promote brain inflammation.
The scientists said it’s not clear whether these small changes would affect clinical manifestations of the disease, highlighting the need for further study.
“Our data reveal isolated examples of restricted benefit of modulating the gut microbiome upon selected features of both bowel and brain [disease activity] that will need to be defined in larger more properly powered studies to determine how these effects are mediated and if they provide any therapeutic benefit,” the scientists concluded.
