Thursday 27 September 2018

Taming bacteria with food

A recent study has revealed that nutritional interventions aimed at the metabolism of pathogenic bacteria can be incredibly effective in the fight against infectious diseases. The study was published in the authoritative professional journal Cell.  


The study was prompted by the worldwide rapid development of resistance by bacteria to antibiotics. That rapid development of resistance of (intestinal) bacteria has various causes, including significant evolutionary pressure to acquire resistance mechanisms. Furthermore, densely-packed bacteria in the intestine create an environment in which resistance genes can be relatively easily passed on from one bacterium to another. 


Longer life expectancy through iron

The researchers, affiliated with the Salk Institute in the United States, discovered that iron supplementation vastly increased the survival rate of mice after a lethal injection of pathogenic bacteria had been administered to these animals. Over time, the remaining bacteria were also found to be less virulent (pathogenic). For the avoidance of doubt: an infection only occurs when a micro-organism has entered a host, multiplies there and causes damage. The study suggests that the host’s health can improve by manipulating the pathogenic bacteria with a nutrient. This has a positive effect on both the bacteria population and the host and the interaction between the bacteria and the host. 

The researchers, who specialise in the interaction between micro-organisms and the host, say that the immune system doesn’t only focus on killing and eliminating pathogens. The immune system also has a component that focuses on cooperation between micro-organisms and the host. Back in 2017, the study team discovered that a Salmonella contamination and/or infection does not always give rise to food aversion and malaise. In the laboratory in 2015, an E.coli strain was also discovered in mice that improved tolerance to disease. This was partly explained by the fact that it was demonstrated that the loss of muscle strength was lower. 


Cooperative defence mechanisms

The current study used a Citrobacter rodentium (C. rodentium) mouse model. Injection of these pathogens in mice resulted in various bowel diseases, such as infectious diarrhoea, hyperplasia, colitis and, in extreme cases, death. To detect new cooperative defence systems, mice were also injected with pathogenic bacteria, at a lethal dose of 50 (LD50). This means that, theoretically, half of the animals die and the other half survive. Then the gene expression of three sub-groups of mice populations was studied: infected healthy, infected ill and non-infected mice. This system analysis revealed that the iron metabolism of the infected healthy mice had increased. 

It was then investigated how the iron metabolism boosts the cooperative immune system during an infection. This time, the dose of C. rodentium was increased to LD100. One half of the group of animals ate a normal diet, whilst the other half consumed a diet supplemented with iron for 14 days. After those 14 days, the animals ate a normal diet. 

After 20 days, all infected mice that ate a normal diet died. The mice that had received iron supplementation for 14 days all survived the infection. Even after increasing LD100, the animals that consumed iron (temporarily) were found to have a much better survival rate. 


Pathogenic genes switched off

Why is it that mice who received short-term iron supplementation pulled through when they had a life-threatening infection? It appears that temporary iron supplementation caused an acute state of insulin resistance in the mice. As a result of that, a higher concentration of glucose remained in the gastrointestinal tract of the animals. The bacteria then set to work on this. In other words, the bacteria convert the available glucose and process this into other intermediate substances, but switch off pathogenic genes that, for example, produce toxins. Interestingly, the researchers observed similar effects following the administration of glucose instead of iron. 

Interestingly, the animals infected with C. rodentium that, at that time, had increased iron absorption for a short time, were still alive after one year. These animals were also found to still have ‘pathogenic’ pathogens in their gastrointestinal tracts. Very surprisingly it was found that the evolution of weakened bacteria strains was boosted.  In other words, that the population of pathogens in the gastrointestinal tract of the mice had weakened instead of strengthened, which is as a result of the use of antibiotics, where a small number of bacteria survive and can successfully reproduce. 


Evolution in depth

To verify the evolutionary changes, the DNA sequencing of the C. rodentium that remained was determined. This showed that the bacterial changes in the DNA had increased (mutations) because of which pathogenic genes were switched off. Increasing the amount of glucose available for the bacteria ensured that the pathogens concentrated on this. Genes to convert glucose will be produced first, because of which there is insufficient space to also activate pathogenic genes. Furthermore, after a good meal in the form of glucose, the bacteria were much more focussed on cooperating rather than on defiant behaviour. 


Iron: not in all infections!

In summary, it appears that iron in the food is effective in infectious diarrhoea. At the same time, it is not the solution for all infectious diseases. There are infections, such as malaria, where, to the contrary, the parasites thrive on iron and can multiply in the body. What is certain, however, is that the metabolism of pathogens can be effectively manipulated. An indirect sweetener, in the form of iron supplementation or more direct administration of glucose, increases the survival rate in the event of serious infections with C. rodentium in mice. Clinical and larger scale follow-up research is needed to be able to extrapolate this splendid result successfully to people and possibly other infections and combinations of nutrients. 



Karina K. Sanchez, Grischa Y. Chen, Alexandria M. Palaferri Schieber, Samuel E. Redford, Maxim N. Shokhirev, Mathias Leblanc, Yujung M. Lee, Janelle S. Ayres. Cooperative Metabolic Adaptations in the Host Can Favor Asymptomatic Infection and Select for Attenuated Virulence in an Enteric Pathogen. Cell, 2018; DOI: 10.1016/j.cell.2018.07.016