Salmonella exposure a risk for colon cancer

A new study published in the journal Cell Reports Medicine links exposure to salmonella bacteria to colon cancer risk.

The researchers, including a team led by Jun Sun from the University of Illinois Chicago, studied human colon cancer tissue samples and animal models and found that exposure to salmonella was linked with colon cancers that developed earlier and grew larger.

The study authors first looked at data from a Netherlands-based retrospective study of colon cancer patients that found tissue samples taken during routine colon cancer surgery with salmonella antibodies tended to be from people who had worse colon cancer outcomes.

Using salmonella strains isolated from these tissue samples, Sun and her U.S.-based team studied mice with colon cancer that had been exposed to the bacteria. They observed accelerated tumor growth and larger tumors in mice with salmonella exposure. They also saw that there was increased salmonella translocated to the tumors.

"During infection, salmonella hijacks essential host signaling pathways, and these molecular manipulations may cause oncogenic transformation. The current study tells us that more research is needed into the connection between salmonella exposure and colon cancer risk in the USA, and that simply by practicing safe food preparation, we can potentially help to protect ourselves," said Sun, UIC professor of medicine.

Sun's collaborators in the Netherlands also studied the bacteria in vitro. They combined human cancer cells and pre-cancer cells with the salmonella strain in the lab and measured any growth or changes in the tumor. They saw that even one infection caused transformation and that each salmonella infection exponentially increased the rate of cell transformation.

"The mouse and tissue culture experiments show that salmonella infection had a chronic effect to accelerate tumor growth," said Sun, who also is a member of the University of Illinois Cancer Center at UIC. "This evidence tells us that we need to look closer at salmonella exposure as an environmental risk factor for chronic diseases, such as colon cancer."

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Spaceflight: Microgravity analog culture profoundly affects microbial infection process in 3-D human tissue models

Infectious microbes have evolved sophisticated means to invade host cells, outwit the body's defenses and cause disease. While researchers have tried to puzzle out the complicated interactions between microorganisms and the host cells they infect, one facet of the disease process has often been overlooked -- the physical forces that impact host-pathogen interactions and disease outcomes.

In a new study, corresponding authors Cheryl Nickerson, Jennifer Barrila and their colleagues demonstrate that under low fluid shear force conditions that simulate those found in microgravity culture during spaceflight, the foodborne pathogen Salmonella infects 3-D models of human intestinal tissue at much higher levels, and induces unique alterations in gene expression.

This study advances previous work by the same team showing that physical forces of fluid shear acting on both the pathogen and host can transform the landscape of infection.

Understanding this subtle interplay of host and pathogen during infection is critical to ensuring astronaut health, particularly on extended space missions. Such research also sheds new light on the still largely mysterious processes of infection on earth, as low fluid shear forces are also found in certain tissues in our bodies that pathogens infect, including the intestinal tract.

While the team has extensively characterized the interaction between conventionally grown shake flask cultures of Salmonella Typhimurium and 3-D intestinal models, this study marks the first time that S. Typhimurium has been grown under the low fluid shear conditions of simulated microgravity and then used to infect a 3-D model of human intestinal epithelium co-cultured with macrophage immune cells, key cell types targeted by Salmonella during infection.

The 3-D co-culture intestinal model used in this study more faithfully replicates the structure and behavior of the same tissue within the human body and is more predictive of responses to infection, as compared with conventional laboratory cell cultures.

Results showed dramatic changes in gene expression of 3-D intestinal cells following infection with both wild-type and mutant S. Typhimurium strains grown under simulated microgravity conditions. Many of these changes occurred in genes known to be intimately involved with S. Typhimurium's prodigious ability to invade and colonize host cells and escape surveillance and destruction by the host's immune system.

"A major challenge limiting human exploration of space is the lack of a comprehensive understanding of the impact of space travel on crew health," Nickerson says. "This challenge will negatively impact both deep space exploration by professional astronauts, as well as civilians participating in the rapidly expanding commercial space market in low Earth orbit. Since microbes accompany humans wherever they travel and are essential for controlling the balance between health and disease, understanding the relationship between spaceflight, immune cell function, and microorganisms will be essential to understand infectious disease risk for humans."

Nickerson, who co-directed the new study with Jennifer Barrila, is a researcher in the Biodesign Center for Fundamental and Applied Microbiomics and is also a professor with ASU's School of Life Sciences. The research appears in the current issue of the journal Frontiers in Cellular and Infection Microbiology

Life-altering force

Life on earth has diversified into an almost incomprehensibly vast array of forms, evolving under wildly dissimilar environmental conditions. Yet one parameter has remained constant. Throughout the 3.7-billion-year history of life on earth, all living organisms evolved under, and respond to, the pull of Earth's gravity.

For more than 20 years, Nickerson has been a pioneer in exploring the effects of the reduced microgravity environment of spaceflight on a range of pathogenic microbes and the impact on interactions with human cells and animals they infect. She and her colleagues have doggedly pursued this research in both land-based and spaceflight settings, the results of which helped lay the foundation for the rapidly growing research field, mechanobiology of infectious disease, the study of how physical forces impact infection and disease outcomes.

Among their important findings is that the low fluid shear conditions associated with the reduced gravity environment of spaceflight and spaceflight analog culture are similar to those encountered by pathogens inside the infected host, and that these conditions can induce unique changes in the ability of pathogenic microbes like Salmonella to aggressively infect host cells and exacerbate disease, a property known as virulence.

The infectious agent explored in the new study, Salmonella Typhimurium, is a bacterial pathogen responsible for gastrointestinal disease in humans and animals. Salmonella is the leading cause of death from food-borne illness in the United States. According to the CDC, Salmonella bacteria cause about 1.35 million infections, 26,500 hospitalizations, and 420 deaths in the United States each year. Foods contaminated by the bacteria are the primary source for most of these illnesses.

Salmonella infection typically causes diarrhea, fever, and stomach cramps, beginning 6 hours to 6 days after infection. Illness from the disease usually lasts 4 to 7 days. In severe cases, hospitalization may be required.

'Shear' probability?

Cells in mammalian organisms, including humans, as well as the bacterial cells that infect them, are exposed to extracellular fluid flowing over their outer surfaces. Just as a gentle downstream current will affect the pebbles in the underlying streambed differently than a raging torrent, so the force of fluid gliding over cell surfaces can cause changes to affected cells. This liquid abrasion of cell surfaces is known as fluid shear.

Since spaceflight experiments are rare and access to the space research platform is currently limited, researchers often simulate the low fluid shear conditions that microbes encounter during culture in spaceflight by growing cells in liquid growth media within a device known as a rotating wall vessel bioreactor or RWV. As the cylindrical reactor rotates, cells are maintained in suspension, gently and continuously tumbling in their surrounding culture medium. This process mimics the low fluid shear conditions of microgravity that cells experience during culture in spaceflight.

The team has also shown that this fluid shear level is relevant to conditions that microbial cells encounter in the human intestine and other tissues during infection, triggering changes in gene expression that can help some pathogens better colonize host cells and evade the immune system's efforts to destroy them.

Portrait of an intruder

The study found significant changes in both gene expression and ability to infect 3-D intestinal models by Salmonella bacteria cultured in the RWV bioreactor. These experiments involved two S. Typhimurium strains, one unaltered or wild type strain and one mutant strain.

The mutant strain was otherwise identical to the wild type but lacked an important protein known as Hfq, a major stress response regulator in Salmonella. In earlier research, Nickerson and her team discovered that Hfq acts as a master regulator of Salmonella's infection process in both spaceflight and spaceflight analog culture. They later discovered additional pathogens that also use Hfq to regulate their responses to these same conditions.

Unexpectedly, in the current study, the hfq mutant strain was still able to attach, invade into, and survive within 3-D tissue models at levels comparable to the wild type strain. In agreement with this finding, many genes responsible for Salmonella's ability to colonize human cells, including those associated with cell adherence, motility, and invasion were still activated in the mutant strain under simulated microgravity conditions, despite the removal of Hfq.

From the host perspective, the 3-D intestinal co-culture model responded to Salmonella infection by upregulating genes involved in inflammation, tissue remodeling, and wound healing at higher levels when the bacteria were grown under simulated microgravity conditions prior to use in infection studies. This was observed for both wild type and hfq mutant strains of the pathogen.

Data from this new spaceflight analog study reinforces previous findings from the team's 2006, 2008 and 2010 Space Shuttle experiments. In particular, the 2010 flight experiment conducted aboard Space Shuttle Discovery, called STL-IMMUNE, used the same wild type strain of S. Typhimurium to infect a 3-D model of human intestinal tissue made from the same epithelial cells used in the new study.

Several commonalities were observed between host cell responses to infection in the new spaceflight analog study and those previously reported when infections took place in true spaceflight during the STL-IMMUNE experiment. These results further reinforce the RWV as a predictive ground-based spaceflight analogue culture system that mimics key aspects of microbial responses to true spaceflight culture.

"During STL-IMMUNE, we discovered that infection of a human 3-D intestinal epithelial model by Salmonella during spaceflight induced key transcriptional and proteomic biosignatures that were consistent with enhanced infection by the pathogen," Barrila says. "However, due to the technical challenges of performing in-flight infections, we could not quantify whether the bacteria were actually attaching and invading into the tissue at higher levels. The use of the RWV bioreactor as a spaceflight analog culture system in our current study has been a powerful tool which allowed us to explore this experimental question at a deeper level."

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Fasting may help ward off infections, study in mice suggests

Fasting before and during exposure to Salmonella enterica bacteria protects mice from developing a full-blown infection, in part due to changes in the animals' gut microbiomes,according to new research published in PLOS Pathogens by Bruce Vallance and colleagues at University of British Columbia, Canada.

When people or animals develop an infection, they often lose their appetite. However it remains controversial whether fasting protects a host from infection, or increases their susceptibility. In the new study, mice were fasted for 48 hours before and during oral infection with the bacteria Salmonella enterica serovar Typhimurium, a common cause of foodborne illness in people.

Fasting decreased the signs of bacterial infection compared to fed mice, including nearly eliminating all intestinal tissue damage and inflammation. When fasted animals were re-fed for a day after their fast, there was a dramatic increase in Salmonella numbers and invasion into the intestinal walls, although the associated inflammation was still attenuated compared to normal. The results did not hold true when mice were exposed to Salmonella intravenously instead of orally, and analyses of the microbiomes of mice showed significant changes associated with fasting and protection against infection. Moreover, fasting did not fully protect germ-free mice -- bred to lack a normal microbiome -- from Salmonella, suggesting that some of the protection was due to fasting's effect on the microbiome. Experiments using the bacteria Campylobacter jejuni confirmed that the effect of fasting was not limited to Salmonella, with similar results seen.

"These data suggest that therapeutic fasting or calorie restriction has the potential to beneficially modulate infectious and potentially non-infectious gastrointestinal diseases," the researchers conclude.

The researchers add, "Our research highlights the important role that food plays in regulating interactions between the host, enteric pathogens and the gut microbiome. When food is limited, the microbiome appears to sequester the nutrients that remain, preventing pathogens from acquiring the energy they need to infect the host. While more research is needed, fasting or otherwise adjusting food intake could be exploited therapeutically to modulate infectious diseases in the future."

From Science Daily

The nature of salmonella is changing -- and it's meaner

Salmonella is acting up in Michigan, and it could be a model for what's happening in other states, according to a new Michigan State University study.

The study, appearing in Frontiers in Medicine, documents a substantial uptick in antibiotic resistant strains, and consequently, longer hospital stays as doctors work to treat the increasing virulent pathogens.

"If you get a salmonella infection that is resistant to antibiotics today, you are more likely to be hospitalized longer, and it will take you longer to recover," said Shannon Manning, MSU Foundation professor in the Department of Microbiology and Molecular Genetics and senior author of the study. "We need better detection methods at the clinical level to identify resistant pathogens earlier so we can treat them with the right drugs the first time."

Losing a day or more to misdiagnosis or improper treatment allows symptoms to get worse. Doctors might kill off a subpopulation of bacteria that are susceptible, but the ones that are resistant grow stronger, she added.

Salmonella is a diverse group of bacterial pathogens that causes foodborne infections. Infected patients often develop diarrhea, nausea, vomiting and abdominal pain, though some infections are more severe and can be life threatening.

When it comes to treatments, each strain reacts differently to the range of antibiotics available for prescription by doctors. So getting it right the first time is crucial.

Specifically in Michigan, doctors are seeing more strains that are resistant to ampicillin, a common antibiotic prescribed to treat salmonella. Multidrug resistance, or resistance to more than three classes of antibiotics, has also increased in Michigan and could further complicate patient treatment plans.

"We're still uncertain as to why this is happening; it could be that these antibiotics have been overprescribed in human and veterinary medicine and that possessing genes for resistance has allowed these bacteria to grow and thrive in the presence of antibiotics," Manning said. "Each state has its own antibiotic-resistance issues. It's important that the medical profession remains vigilant to ever-changing patterns of resistance in salmonella and other foodborne pathogens, rather than look for a blanket national solution."

Historically, salmonella has affected young children and the elderly, but now there's been a rise in adult cases, suggesting that the epidemiology of the infections has changed in Michigan.

Diving into individual strains of salmonella, the team of scientists found that patients with Typhimurium were more likely to have resistant infections as were patients infected during the fall, winter or spring months.

Another distinction was revealed between the strains affecting people living in rural and urban areas. Enteritis infections tend to be higher in rural areas. This may be attributed to rural residents' exposure to farm animals or untreated sources of water.

Each state's salmonella population has its own personality; so every state's approach to identifying disease drivers and effective treatments should be modified to reflect these traits.

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