Food and gut microbes for thoughts

The ambulance returns to the hospital with a young motor cyclist who had lost the control of his vehicle on an icy patch on the road. The surgeon observes heavy injuries on one leg, the bones are shattered, severe torsions were exerted on the knee and ankle and a deep open wound goes down into the bone. A lengthy operation will be needed and he knows that an infection with pathogenic staphylococci and streptococci can annihilate his efforts. The surgeon hates amputation and prosthetics in such a young man as a personal defeat. The surgeon will try his best. Surprisingly, he does not disinfect the wound nor does he apply antibiotics into the operation wound. After a first cleaning of the wound, he sprays a mixture of commensal skin bacteria and starter bacteria used in meat fermentation (Staphylococcus carnosus and Lactobacillus plantarum) on the wound. It turned out that these bacteria work quite well: they digest the dead tissue, the production of metabolites like lactic acid and hydrogen peroxide fights off Staphylococcus aureus from the wound and assists in the build‐up of granulation tissue.

This scenario is of course science fiction but not so much as you might think. US military surgeons observed in the 19th century that wounded soldiers left for one or two days on the battle field fared better than rapidly rescued soldiers. Flies had the time to lay their eggs into the wounds. The maggots, i.e. the fly larvae that hatched from the eggs, make their living from living flesh. They digest the wound tissue by proteolytic enzymes. Notably, the saliva of the maggots also contains substances that have a strong anti‐bacterial activity including one against S. aureus. Small wonder that maggot therapy – despite its emotional disgust reaction – recently got FDA approval and starts to become popular with wound surgeons.

Antibiotics, the big success story of mid‐20th century medicine, were not mentioned in our fiction. The magic bullets, how Paul Ehrlich called the agents of early chemotherapy, are loosing their spell. We urgently need alternatives. In addition to antibiotics, which are the brain child of the chemical industry, commensal bacteria might become the future tools of a biological industry that uses whole organisms as ecological competitors not only against pathogens. Prominent scientists explore the impact of commensal bacteria on host physiology (obesity and related diseases, Turnbaugh et al., 2006). Others investigate the effects of commensals on the metabolism of food (soy isoflavons in the context of postmenopausal disturbances, Bolca and colleagues 2007) or drugs (to explain distinct pharmacokinetics, Sousa et al., 2008). There are already bacteria on the market with documented clinical studies showing activity against diarrhoea or inflammatory gut diseases or with generalized immunostimulatory activity. On the analytical side, it is much more difficult to define the mode of action of these biologicals than for antibiotics, which target a specific biochemical reaction. However, the pathogen will also be confronted with the same dilemma when competing with the commensal and there is some theoretical hope that the pathogen might less easily escape from control by commensals than from antibiotics.

The Iron Curtain crossing Europe during the Cold War period has also prevented the flow of ideas across this ideological frontier. Biological research was not an exception. The former Soviet Union relied more on biological approaches against infectious diseases than on antibiotics. Antibiotic‐resistant bifidobacteria and lactobacilli were sold in Russian pharmacies before probiotics became popular in the Western world. Even the above science fiction scenario was to a certain extent realized in the Soviet Union with a wound spray and wound dressing containing a cocktail of phages. The phages are directed against six major wound pathogens including S. aureus, Streptococcus pyogenes and Pseudomonas aeruginosa. We cannot, however, claim that the future is already now. The phage approach – despite its application to ten thousands of soldiers of the Red Army over half a century – has never been tested in controlled clinical trials fulfilling current criteria of clinical science. The jury is thus still out with respect to their efficacy.

If you object that our crystal ball gazing goes into the past, you can easily modernize the commensal and phage approach biotechnologically. Lactobacilli have been constructed that express single chain antibodies with anti‐rotavirus activity. Lactococci were modified for intestinal delivery of human interleukin 10 providing a therapeutical approach for inflammatory bowel disease (Steidler et al., 2000). The bacterial carrier offers not only a safe passage through hostile environments like the stomach; commensals derived from defined body sites might re‐home to their natural site. Proteins of medical interest could thus be targeted to particular anatomical sites and expressed in situ (for ex. Bifidobacterium breve expressing cytosine deaminase for tumour‐targeting enzyme/prodrug therapy, Hidaka et al., 2007). Phages are particularly attractive for biotechnologists as they are not only genetically more tractable than bacteria but also known to reach practically all body sites, including those which you cannot easily target with conventional drugs. Filamentous phages were extensively studied for foreign gene expression and phage display technology was developed with them. Now take the following scenario: modify such a phage such that it expresses a cocaine‐binding single chain antibody. Apply the recombinant phage to the nose of a drug‐addict. Taking the privileged neuronal pathway of the first cranial nerve, the recombinant phage travels directly into the brain of the subject. Here the phage binds the cocaine, which reaches the brain of the drug addict and prevents the psychoactive processes including the self‐administration drive for cocaine. This story sounds even more science fiction than the opening story. However, it is the content of a 2004 PNAS paper demonstrating these effects in mice (Carrera et al., 2004).

Looking beyond the time horizon of grant applications is a daring exercise. Microbiology, which currently enjoys and suffers a data flood derived from genomics, transcriptomics, proteomics, metabolomics and metagenomic analyses, needs long‐term visions based on a sound theoretical reasoning. Microbiologists cannot leave the field to computational scientists expecting them to sort out new ideas from the data accumulated by the various ‘‐omics’ approaches. A relationship as between theoretical and experimental physicists must be developed in microbiology where new theoretical concepts are tested with available data sets leading to new experiments testing refined theories. The challenge of the antibiotic crisis might therefore also be a healthy push for biological approaches not only against infectious diseases.