This is Drosophila intestine associated with lactobacilli bacteria, seen in red. The green GFP-positive tissue on the edges is a measure of the upregulation of Nrf2-responsive cytoprotection genes. Credit: Rheinallt Jones
A helpful subset of the intestinal microbiome, lactobacilli, stimulates the cytoprotective Nrf2 pathway in both flies and mice. The findings could potentially lead to advances in the use of bacteria to treat intestinal diseases or mitigate the effects of radiation therapy for cancer. “The body’s response to bacteria is often seen through the lens of the immune system,” says Prof. Andrew Neish, MD. “The pathway we’ve identified is not inflammatory or immunoregulatory; rather, it’s cytoprotective.”
While many types of bacteria that live in our intestines are inert or even harmful to intestinal cells, a small subset – lactobacilli – can stimulate increased motility, proliferation and ability to withstand stress, Neish says. “Lactobacilli are present in yogurt, and they’re also the first kind of bacteria that will colonize a baby’s system after the baby is born,” he says.
Only lactobacilli could protect previously “germ free” fruit flies from paraquat, a toxic herbicide. Similarly, feeding lactobacilli, but not other types of bacteria, to germ-free mice could protect them from weight loss and death after exposure to radiation. In intestinal tissues in both flies and mice, the lactobacilli turned on a series of genes in a pattern that indicates that the Nrf2 pathway is involved. If the flies or the mice had a mutation disabling Nrf2, the protective effect from the bacteria was not seen.
Nrf2 is a cellular pathway involved in protecting cells against external stresses such as toxins and carcinogens, and it is activated by reactive oxygen species or ROS. Both paraquat and radiation generate ROS. “It looks like a little bit of ROS helps cells get ready to withstand stress,” Jones says. “This is an example of the concept of hormesis, where limited exposure to something that is harmful protects an organism from more of it later.”
Previously, Jones and Neish have shown that lactobacilli stimulate intestinal epithelial cells to produce ROS, which are a key signal for wound healing. When enzyme Nox1, which makes ROS in response to bacteria, is removed from the intestines in mice, the radioprotective effect of lactobacilli is lost.
While it is not the only regulatory circuit stimulated by beneficial bacteria, Jones and Neish say their findings suggest Nrf2 is more highly conserved than other bacterially-induced signals, and that it likely evolved as a mechanism for higher organisms to co-exist with bacteria. Common genetic signatures of various types of bacteria that stimulate ROS and Nrf2 are being investigated, allowing sorting of ones may have therapeutic benefits, and possibly how to mimic the bacteria with synthetic agents. http://www.eurekalert.org/pub_releases/2015-08/ehs-hbb081215.php
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