Gut Microbiota Species May Protect against Typhoid

Scientists at the University of Maryland, School of Medicine (UMSOM) have for the first time found evidence that the presence of a key species in the human gut microbiome is associated with protection from infection with typhoid fever. If the research is borne out, it could offer an exciting new way to reduce intestinal infections from microbes.

The study establishes for the first time that certain gut microbes may keep infection at bay, according to the scientists, who published their work (“Compositional and Functional Differences in the Human Gut Microbiome Correlate with Clinical Outcome following Infection with Wild-Type Salmonella enterica Serovar Typhi”) in mBio.

“Insights into disease susceptibility as well as the efficacy of vaccines against typhoid and other enteric pathogens may be informed by better understanding the relationship between the effector immune response and the gut microbiota. In the present study, we characterized the composition (16S rRNA gene profiling) and function (RNA sequencing [RNA-seq]) of the gut microbiota following immunization and subsequent exposure to wild-type Salmonella enterica serovar Typhi in a human challenge model to further investigate the central hypothesis that clinical outcomes may be linked to the gut microbiota. Metatranscriptome analysis of longitudinal stool samples collected from study subjects revealed two stable patterns of gene expression for the human gut microbiota, dominated by transcripts from either Methanobrevibacter or a diverse representation of genera in the Firmicutes phylum,” write the investigators.

“Immunization with one of two live oral attenuated vaccines against S. Typhi had minimal effects on the composition or function of the gut microbiota. It was observed that subjects harboring the methanogen-dominated transcriptome community at baseline displayed a lower risk of developing symptoms of typhoid following challenge with wild-type S. Typhi. Furthermore, genes encoding antioxidant proteins, metal homeostasis and transport proteins, and heat shock proteins were expressed at a higher level at baseline or after challenge with S. Typhi in subjects who did not develop symptoms of typhoid. These data suggest that functional differences relating to redox potential and ion homeostasis in the gut microbiota may impact clinical outcomes following exposure to wild-type S. Typhi.”

The study’s lead author, Claire M. Fraser, Ph.D., a professor of medicine at UMSOM as well as director of the school’s Institute for Genome Sciences, said the researchers sought to examine how differences in the gut microbiome might affect infection with typhoid bacteria. “From our previous work we suspected that the microbiome might have an effect on how these illnesses developed in the gut,” noted Dr. Fraser. “We wanted to better understand the molecular basis these interactions in the intestinal environment.”

Other researchers on the paper include Marcelo B. Sztein, M.D., a professor of pediatrics at UMSOM and associate director for basic and translational research at the school’s Center for Vaccine Development and Global Health.

The study was carried out using samples obtained from subjects who had been vaccinated against typhoid and were subsequently exposed to virulent typhoid bacteria. The vaccine is helpful, but sometimes is not that effective, especially in the developing world. Dr. Fraser and her colleagues found that those who had higher levels of the microbes, which are known as methanogens, were significantly less likely to become sick following exposure, even if they had not been vaccinated.

“We found a strong correlation between the composition and function of the gut microbiome and the clinical outcome following exposure to S. Typhi,” said Dr. Fraser. “One interpretation of these findings is that in some individuals the gut microbiome may offer some protection against infection.” She says that it may also be that people with different microbiomes may respond differently to the vaccine.

Typhoid fever is caused by the bacterium S. Typhi. An estimated 5700 cases occur each year in the United States. Most infections occur in international travelers. Typhoid fever is common in the developing world, where it affects about 21.5 million people annually and kills 200,000.

It is not clear exactly how methanogens might help ward off typhoid. They thrive in an environment that has very little oxygen; generally, the gut has very little oxygen, but this can vary. Scientists have found that typhoid can gain a foothold in the gut by producing reactive oxygen molecules.

The researchers theorize that methanogens may help reduce the risk of typhoid by reducing the amount of oxygen in the gut. This could potentially reduce the ability of typhoid to thrive. “There are so many questions that this initial set of findings raises. This is step one in a 100-step journey,” continued Dr. Fraser. Another question is whether methanogens, which have been received little research, may also protect from other intestinal infections.

The research has broad implications. In the future, it may be possible to reduce the risk of infection by creating a certain environment that is populated with particular gut microbes, according to Dr. Fraser.