A commensal strain of Escherichia coli was able to protect mice from the wasting syndrome cachexia, giving both new insights into how the microbiome contributes to health, and a possible new way of fighting, if not infections themselves, then their sequelae.

During both intestinal and lung infections, E. coli O21/H+ was able to move from the gut into fat tissue and counteract signaling cascades that can set off wasting during serious infections.

When intestinal bacteria show up beyond the gut, this is usually a both a sign of leaky intestines and itself a serious health problem.

"To my knowledge, this is the first time it's been shown that a component of the intestinal microbiome can promote damage control mechanisms to fight infectious diseases" by moving to a site outside of the intestines, Janelle Ayres told BioWorld Today.

Ayres is assistant professor at the Salk Institute for Biological Studies and the corresponding author of the study, which appeared in the Oct. 30, 2015, issue of Science.

Ayres' lab is focused on so-called tolerance mechanisms – the ways in which infected organisms try to minimize the damage that is done by the infection.

"Rather than find mechanisms that kill pathogens, we look for mechanisms that alleviate the pathology," Ayres explained.

Unlike targeting the bacteria themselves, focusing on secondary problems will not inevitably drive resistance.

At the same time, the infection itself can be a more manageable problem than sequelae such as cachexia or sepsis. In extreme cases, such follow-on problems can cause the patient to succumb to disease despite the infection's being brought under control by antibiotics.

One such pathology is the wasting syndrome cachexia, a syndrome that includes weight loss, muscle wasting and fatigue.

"It's very well known in cancer," Ayres said. "But people have forgotten that it is a very serious pathology in the context of infectious diseases as well."

In the time before antiretroviral therapy became available, for example, AIDS-related wasting was what ultimately killed many HIV-infected individuals. But other infections, including tuberculosis, can also cause cachexia. And in weakening the patient, cachexia further complicates their fight against the disease.

The work now published in Science is part of a larger effort to identify the role of the microbiome in tolerance mechanisms, based on mathematical prediction and evolutionary theory suggesting that commensal microbes should have evolved beneficial effects.

To identify microbiome members that might be protective against cachexia, the team compared the response of C57Bl/6 mice from two different colonies.

"This is a twist on what a geneticist would do," Ayres explained. Rather than looking at different strains of mice to understand the role of genes that differed between them, the team compared animals that were the same strain, but had different microbiomes due to being raised in different environments.

They found that mice that had been raised at UC Berkeley showed less wasting in a model of Crohn's disease than those that came from the Jackson Laboratory. Through a detailed comparison of the two groups' microbiomes, Ayres and her colleagues identified E. coli O21/H+ as a strain that was present in the Berkeley animals but normally absent in the Jackson Laboratory ones.

When Jackson Laboratory mice, as well as other mouse strains were first treated with E. coli O21/H+, they were protected against cachexia in several models of infection, whether those infections led to a leaky gut or not.

The team also found that the effect was dependent on E. coli's moving from the gut to the fat, attracted by an as-yet unknown signal, where it activated the inflammasome and insulin-related growth factor 1 (IGF-1). During infection, there is normally a drop in IGF-1 signaling, and that drop contributes to cachexia. E. coli O21/H+ prevented that drop.

Ayres and her team are currently looking for the molecular signal that lures E. coli O21/H+ to fat tissues during infections. They are also testing whether the strain could be protective in cachexia caused by other conditions, such as cancer or failure to thrive, a pediatric condition where children fail to gain weight at normal levels, often for mysterious reasons.