Inflammatory diseases of the gut are on the rise. In North America and Europe, more than 0.3% of the population suffers from inflammatory bowel diseases (IBD), characterized by abdominal pain, diarrhea, and weight loss. Higher urbanization in newly-industrialized countries such as India or China is steadily increasing the number of people with IBD, making it a truly global disease of the 21st century.1 Another troubling trend is the rapid increase in early-childhood-onset IBD, sometimes with complications such as growth failure and malnutrition.
What can we do about it? Genetic risk factors for the disease are inherited and out of our control, and environmental risk factors are either not known or difficult to change. New anti-inflammatory treatments, typically aimed at specific immune targets, have reached the market in recent years and many more are under development. However, not all patients respond to these treatments and many more lose response after repeated use. Some drugs have severe side effects or carry associated risks that make them unattractive for use in young children. Long-term complications of the disease lead to repeated surgeries with an impact on quality of life. Alternatives and new approaches for treatment are needed.
For patients, prevention of acute disease, accelerated healing responses, and measures to extend the disease-free phase are desirable. Promising new strategies are aimed at improving the gut bacteria (microbiota), making them more diverse and boosting beneficial bacteria. Reinforcing the gut barrier is a complementary approach that helps to maintain the physical separation of microbiota and epithelium and promotes healing when injuries occur. The ability to enhance the intestinal barrier has been proposed for a variety of probiotic bacteria, but how these bacteria improve gut health is often not clear.
In our recent study, Hydrogen peroxide production by lactobacilli promotes epithelial restitution during colitis by Ashish Singh, Rosanne Hertzberger and Ulla G. Knaus, which was published in the journal Redox Biology,2 we set out to identify one of the mechanisms lactobacilli, the leading probiotic bacteria on the market, use to exert their beneficial effects.
Lactobacilli produce many substances ranging from lactic acid and other organic compounds, proteins, or antimicrobial and neuromodulatory peptides to the chemical hydrogen peroxide (H2O2). The release of nanomolar concentrations of H2O2 is a defining feature of lactobacilli, which sets them apart from most other bacteria. H2O2 is a diffusible, relatively stable and mild oxidant that is used in higher concentrations as disinfectant and bleaching agent.
Commonly, oxidation has been associated with enhanced inflammation and with tissue injury, and while not effective in clinical trials, antioxidants are still propagated as a remedy for IBD. The use and health-promoting effects of oxidant-generating lactobacilli and the discovery of pediatric IBD patients with specific genetic changes that lead to decreased oxidant production in the gut challenge the notion of oxidation being always the culprit. In fact, antimicrobial or antivirulence activity, depending on the concentration, is a hallmark of H2O2, and lactobacilli can use this chemical to downregulate the virulence of intestinal pathogens.3
But which protective effects could be attributed to H2O2 in gut inflammation? We used models of gut barrier disruption together with a human Lactobacillus strain which was modified by deleting the enzymes required for H2O2 production. In contrast to the original Lactobacillus, this modified strain lacked the ability to enhance wound healing and to accelerate re-establishment of the epithelial integrity. The healing responses promoted by low levels of H2O2, as provided by lactobacilli, include the movement of epithelial cells to close a wound and the restoration of the impenetrable mucus layer. Other studies indicated that H2O2 is important for a balanced microbiota and its resilience to disruption. Thus, H2O2 production is a major part of the beneficial repertoire of lactobacilli.
To date, probiotic therapy trials in IBD have been largely disappointing.4 Some factors underlying this underperformance could be overcome. For example, standardization and appropriate delivery of these bacteria can and should be addressed. However, other issues and concerns may not be easily amenable to modification. For instance, in inflammatory conditions such as ulcerative colitis, the mucus layer is reduced or even absent, thereby preventing efficient colonization with lactobacilli, which is a prerequisite for their activity. Furthermore, caution is needed when supplementing patients having a compromised immune system using live bacteria, even if these are probiotics.
An alternative approach might be to deliver the beneficial products or effects of bacteria directly to the intestine. In the case of H2O2, one could harness the body’s own oxidant-producing enzymes or devise preparations capable of local release. Considering the potential of H2O2 as positive gut barrier and microbiota modifier, new tactics for efficient delivery of the proper dosage of this active ingredient are needed.
These findings are described in the article entitled Hydrogen peroxide production by lactobacilli promotes epithelial restitution during colitis, recently published in the journal Redox Biology. This work was conducted by Ashish Singh and Ulla G. Knaus from the University College Dublin, and Rosanne Hertzberger from the University of Amsterdam.
References:
- Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 2018;390:2769-2778.
- Singh AK, Hertzberger RY, Knaus UG. Hydrogen peroxide production by lactobacilli promotes epithelial restitution during colitis. Redox Biol 2018;16:11-20.
- Alvarez LA, Kovacic L, Rodriguez J, et al. NADPH oxidase-derived H2O2 subverts pathogen signaling by oxidative phosphotyrosine conversion to PB-DOPA. Proc Natl Acad Sci U S A 2016;113:10406-11.
- Vitetta L, Coulson S, Thomsen M, et al. Probiotics, D-Lactic acidosis, oxidative stress and strain specificity. Gut Microbes 2017;8:311-322.