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Image: Salmonella bacteria, shutterstock

Salmonella: Intestinal flora as reason for asymptomatic disease progression

August 2, 2021 | Bärbel Zierl

Salmonella infections can result in a broad spectrum of illnesses. According to the latest research findings, one reason why some cases are harmless while others are very severe lies in the intestinal flora.

An infection with Salmonella can have very different consequences. While some infected people do not notice the infection with the bacteria at all – this is called an asymptomatic progression – others suffer from severe gastrointestinal complaints. In extreme cases, Salmonella infections can even lead to death. Until recently, it was largely unknown why the disease varies so much in severity.

Now microbiologist Alyson Hockenberry, a postdoc in Prof. Martin Ackermann's Environmental Microbiology research department at Eawag, has discovered a possible cause: the infected person's natural intestinal flora and its metabolic products. Together with other researchers from the Eawag Water Research Institute and ETH Zurich, she has discovered that short-chain fatty acids, which are produced by bacteria resident in the intestine, can have a decisive influence on the course of the infection.

Tricks played by Salmonella

Salmonella usually enters the digestive tract through contaminated food. In order to displace the natural intestinal flora as quickly as possible and colonise the intestine themselves, the pathogens have a few tricks up their sleeve. "One trick is to form different cell-types in populations of genetically identical bacteria," says Hockenberry. "Each cell-type specialises in a particular task. This has advantages because the cooperation of the different cell types increases the ability of Salmonella to cause disease."

One cell-type, for example, specialises in causing inflammation in the intestinal mucosa. On the one hand, such inflammations increase the availability of nutrients for Salmonella; on the other hand, they lead to the breakdown of the natural intestinal flora. This opens up niches for the invading pathogens to colonise. A second cell-type, in turn, specialises in growing rapidly and thus occupying the vacated niches as quickly as possible. The interaction between the two cell-types gives Salmonella a clear advantage. Within a few hours, they can displace the bacteria of the natural intestinal flora and proliferate.
 

Salmonella cells growing inside a microfluidic device.  Left: without short-chain fatty acids, right: with short-chain fatty acids. Green cells: Cell type specialised in causing inflammation. Grey cells: Cell type specialised to grow rapidly. The experiment shows that the short-chain fatty acids slow the growth of inflammation-inducing Salmonella cells.

The intestinal flora strikes back

However, the intestinal flora is not defenceless. Through experiments and stochastic simulations, the research team led by Alyson Hockenberry was able to show that short-chain fatty acids, i.e. the metabolic products of the natural intestinal flora, slow down the growth of the cell type that causes inflammation. The higher the concentration of the fatty acids, the more growth was inhibited. "Our results suggest that the metabolic products can influence the cooperation of the cell-types and thereby weaken the spread of Salmonella," says Hockenberry.

Possible explanation for asymptomatic courses of the disease.

This may explain why people react so differently to Salmonella infections. Every person is host to a very individual composition of bacteria in their intestine. One reason for this is, in particular, individual dietary habits. So while one person's intestinal flora is capable of completely preventing the spread of Salmonella, another person's intestinal flora can do little or nothing to counteract the pathogens. The disease takes its individual course, influenced by the intestinal flora.

"We hope that the new findings will give us a better understanding of how asymptomatic infections generally develop," says Alyson Hockenberry. "After all, infections without symptoms often play an important role in the transmission of diseases, as we are currently seeing with the Corona pandemic."

Cover picture: Salmonella-Bakterien, shutterstock

Original publication

Microbiota-derived metabolites inhibit Salmonella virulent subpopulation development by acting on single-cell behaviors

Salmonella spp. express Salmonella pathogenicity island 1 Type III Secretion System 1 (T3SS-1) genes to mediate the initial phase of interaction with their host. Prior studies indicate short-chain fatty acids, microbial metabolites at high concentrations in the gastrointestinal tract, limit population-level T3SS-1 gene expression. However, only a subset of Salmonella cells in a population express these genes, suggesting short-chain fatty acids could decrease T3SS-1 population-level expression by acting on per-cell expression or the proportion of expressing cells. Here, we combine single-cell, theoretical, and molecular approaches to address the effect of short-chain fatty acids on T3SS-1 expression. Our in vitro results show short-chain fatty acids do not repress T3SS-1 expression by individual cells. Rather, these compounds act to selectively slow the growth of T3SS-1–expressing cells, ultimately decreasing their frequency in the population. Further experiments indicate slowed growth arises from short-chain fatty acid–mediated depletion of the proton motive force. By influencing the T3SS-1 cell-type proportions, our findings imply gut microbial metabolites act on cooperation between the two cell types and ultimately influence Salmonella’s capacity to establish within a host.
Hockenberry, A. M.; Micali, G.; Takács, G.; Weng, J.; Hardt, W. D.; Ackermann, M. (2021) Microbiota-derived metabolites inhibit Salmonella virulent subpopulation development by acting on single-cell behaviors, Proceedings of the National Academy of Sciences of the United States of America PNAS, 118(31), e2103027118 (7 pp.), doi:10.1073/pnas.2103027118, Institutional Repository

Funding

NCCR Microbiomes

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