Short-chain fatty acids (SCFAs) (such as acetate, propionate, butyrate) are byproducts of bacterial fermentation in the gut and are frequently reduced in people with diabetes, obesity, autoimmune disorders, and cancer. A growing body of research points to the role of SCFAs in governing the mechanism by which the gut microbiome affects host physiology – an exciting prospect considering the current demand for probiotics with well-characterized modes of action. Specifically, SCFAs can activate G-coupled protein receptors (GPCRs) such as free fatty-acid receptor 2 and 3 (FFAR2/3), inhibit histone deacetylases, and be used as energy substrates. Scientists with the ultimate goal of benefiting human health, often screen for probiotic candidates that may enhance the SCFA-producing capacity of the gut microbiota.
Researchers at the Wake Forest School of Medicine in North Carolina have developed a new probiotic-cocktail of infant-gut origin that modulates the gut microbiota of mice (in-vivo) and human feces (ex-vivo) by increasing native production of SCFAs. This probiotic-cocktail contains 10 carefully selected strains of Lactobacillus and Enterococcus and can also inhibit the growth of uropathogenic E. coli in vivo.
Interest in probiotics as a natural therapeutic option remains considerable in the scientific and medical community, however, barriers to development are substantial as the list of FAO/WHO criteria for a successful probiotic grows ever longer. A probiotic for use in humans must first lack any potential virulence genes, be sensitive to common antibiotics, and be able to adhere to the intestinal and epithelial membrane. Furthermore, it must be tolerant to gastric and intestinal physico-chemical conditions, be able to compete with other microbes in the gut and be catalase-negative. Scientists at the Wake Forest School of Medicine took these WHO criteria into account during their screening for bacterial strains, ultimately choosing 10 out of 321 isolates with high probiotic potential with which to conduct their study.
The consortium of 5 lactobacillus and 5 enterococcus strains inhibited the growth of uropathogenic E. coli CFT073 and K. pneumoniae KPPR1 in mice, with lactobacilli exhibiting a stronger antagonistic effect. The team observed profoundly higher levels of organic acids in the probiotic culture supernatants, supporting their hypothesis that the antimicrobial activity they observed was mediated by SCFAs. Neutralizing the pH of the supernatant to 6.5 diminished this antimicrobial effect, offering further support to their assertion.
To test the ability of the probiotic-cocktail to modulate the SCFA-producing potential of the gut microbiome in vivo, the team designed a single (one dose) and multi-dose (once daily for 5 days) regimen to be administered orally to mice. The probiotics (either alone or in combination), significantly increased the levels of lactate, propionate, and butyrate in mouse feces. Furthermore, after just one day the team observed an increase in the abundance of Bacteroidetes and a decrease in abundance of Firmicutes, a result that was not observed when mice were treated with Lactobacillus or Enterococcus alone. The team sees this result as a positive indication that their probiotic may modulate the types and quantities of bacteria in the gut while also increasing the population of SCFA-producers.
In order to understand the potential human applications of their newly developed probiotic, scientists inoculated a human fecal suspension designed to mimic the conditions of the human gut. After 24 hours, probiotic-treated samples showed lower abundance of Firmicutes, and greater abundance of Bacteroidetes, paralleling results of the in-vivo mouse study. In groups treated with lactobacilli or enterococci alone, the team saw increases in propionate, whereas butyrate was elevated in the probiotic-cocktail group. Further studies exploring the functional diversity of the gut microbiome are needed in order to fully understand the significance of this shift in gut microbiota composition.
“This human-origin probiotic of lactobacilli and enterococci could prove to be a potential therapy for diseases involving reduced SCFAs production in the gut,” scientists say. Next steps would be to evaluate the influence of the probiotic cocktail on the disease phenotypes they wish to treat. Although positive effects were observed after short-term treatment, it would be interesting to observe effects after a more prolonged treatment regimen in the context of a well-designed follow-up human intervention study. Scientists will also need to further optimize the most effective treatment dose and regimen, as promising results were not observed in all experimental cases. Overall the study contributes valuable data to a community that is still investigating the influence of probiotics on the human microbiota, metabolism and associated diseases.
Nagpal R, Wang S, Ahmadi S, et al. Human-origin probiotic cocktail increases short-chain fatty acid production via modulation of mice and human gut microbiome. Sci Rep. 2018; 8(1):12649. doi: 10.1038/s41598-018-30114-4.