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Multiple Omic Approaches Detail Mouse Gut Environment Changes Following Salmonella Infection

NEW YORK (GenomeWeb News) – A team of researchers from the US Department of Energy's Pacific Northwest National Laboratory studied the series of changes that occur in the mouse gut as mice are infected with Salmonella enterica. As they reported in PLOS One yesterday, S. enterica infection disrupts the commensal bacteria in the gut, further aiding the pathogen's establishment, and leads to metabolic changes.

By combining a number of approaches — metagenomics, proteomics, metabolomics, and more — researchers sought to determine how the host, pathogen, and commensal bacteria interact during infection with S. enterica serovar Typhimurium, a common cause of food poisoning, in a mouse model.

"Infection changes the populations of bacteria in the gut with resulting inflammation. We want to understand the interplay between these events," Josh Adkins, a team leader at PNNL, said in a statement.

During infection in the mouse gut, they reported, S. Typhimurium infection induced inflammation, which altered the established balance of bacteria, and the pathogen then thrived in the subsequent environment. In addition, infection led to changes in the gut environment as metabolites usually consumed by the missing or outnumbered bacteria accumulated. S. Typhimurium, the researchers added, which appeared to take advantage of the increased levels of one sugar, using it as a food source.

To watch Salmonella infections over time, Adkins and his team turned to a mouse model, infecting 10 mice with the pathogen, while 10 others were given a mock inoculation. They collected fecal samples from the mice prior to inoculation as well as at various time points through day 28.

Oral Salmonella infection, the researchers found, disrupted the established homeostasis in the gut. For example, liquid chromatography-mass spectrometry analysis of the mouse fecal samples showed that infection led to changes in expression of 22 host mouse proteins, 46 proteins derived from commensal bacteria, and more than 40 S. Typhimurium proteins. In particular, host innate immune response factors were more highly expressed.

In addition, 16S rDNA sequencing of the fecal samples over time indicated that changes to the microbial population structure occurred in response to infection. The researchers noted that the initial microbial communities were dominated by Bacteroides and Firmicutes, and then in infected mice, Proteobacteria and Enterococci proliferated.

The metabolomic profile of the mouse gut also shifted. By gas chromatography-mass spectrometry analysis, Adkins and his team saw that a number of sugar moieties, such as lactose, galactinol, melibose, and raffinose, built up in the gut. Both the mouse host and the Salmonella invader lacked the ability to digest those sugars.

However, the researchers found that S. Typhimurium expressed a number of sugar utilization proteins during the infection, including three fucose utilization proteins, FucI, FucU, and FucA. The researchers noted that FucA and FucU had rarely been detected in their previous proteomic studies of S. Typhimurium.

Following that, they examined glycans in the mouse fecal samples, finding that the total fucosylated glycan content increased during infection. The researchers hypothesized that such an increase was likely due to a combination of the loss of commensal organisms, immune function, and cell damage.

"Loss of commensal microbes (likely due in part to the host inflammatory response) and their associated functions is evident mid-way through infection, when metabolites such as fucose and other sugars normally utilized by commensal bacteria accumulate in the gut," the researchers noted.

At that point, they added, S. Typhimurium flourishes.

Their findings, they said, support the suspicion that S. Typhimurium metabolizes fucose in the gut, something that they did not anticipate. "We were taken completely by surprise with the fucose results," Adkins said in a statement. "By knowing what the bacteria eat, we can try to promote the good bacteria and throw off the battle" between the commensal bacteria and the pathogen."

Further studies, he and his colleagues wrote, will help untangle what factors lead to the S. Typhimurium metabolizing fucose in the gut.

"[T]his study demonstrates that the union of complementary omics technologies to an under-investigated biological system allows for concurrent monitoring of multiple factors during S. Typhimurium gut infection and development of a working model of these interactions," they wrote. "Host, commensal, and pathogen behavior in this complex environment, including known and novel factors, provide insights into the lifestyle of S. Typhimurium in the gut and the host response to infection."

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