researchers have known that normal bacteria in the gut can induce intestinal immune cells to extend tentacle-like structures, known as dendrites, to “capture” antigens; triggering both immediate and long-term immune responses. What was less clear was how the bacteria activate this process. Now, a research team led by Osaka University has found that the molecules responsible have been hiding in plain sight.
Metabolites are small molecules produced during metabolism, the chemical processes that occur inside all living cells to keep them ticking over. Metabolic pathways have been intensively studied in many organisms, with most common metabolites having very few secrets. Yet; in a recent paper published in the journal Nature; the team describes how they made an important discovery—two well-known metabolites; pyruvate, and lactate, are in fact the instigators of dendrite protrusion by CX3CR1+ macrophages in the small intestine.
“After studying the available research, we hypothesized that bacterial metabolites present in the small intestine could possibly mediate dendrite protrusion,” explains lead author Naoki Morita. “After purifying different fractions from the contents of the small intestines of mice; we discovered that lactic acid and pyruvic acid, produced by lactic acid bacteria in the normal gut flora; act directly on intestinal macrophages.”
Next, the researchers identified GPR31, a protein residing on the surface of small intestinal macrophages, as the specific receptor for the two metabolites. Mice lacking GPR31 show reducing dendrite protrusion by CX3CR1+ cells after being administering pyruvate or lactate and, as a result; decreased antibody production following infection with a non-pathogenic strain of Salmonella. However; the most significant revelation was yet to
They then examined whether pre-treatment of normal mice with pyruvate or lactate as well as non-pathogenic Salmonella could protect against infection with a virulent strain of the bacterium,” says co-lead author Eiji Umemoto. “As we predicted; normal pre-treated mice; but not pre-treated GPR31-defective mice; showed increased survival and an enhanced immune response following infection with the virulent Salmonella strain.”
Corresponding author Kiyoshi Takeda explains that the research has multiple clinical applications. “Because these metabolites enhance the immune response; they are using to improve the effectiveness of oral vaccines; while GPR31 is a promising target for therapies aim at eliminating intestinal pathogens. Because of this; we expect that lactic acid; pyruvic acid, and GPR31 will all be exploring in the near future as new targets for activating immunity.”
n humans; the gut microbiota has the largest numbers of bacteria and the greatest number of species comparing to other areas of the body. In humans; the gut flora is establishing at one to two years after birth; by which time the intestinal epithelium and the intestinal mucosal barrier that it secretes have co-developed in a way that is tolerant to; and even supportive of; the gut flora and that also provides a barrier to pathogenic organisms.
The relationship between some gut flora and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship.:700 Some human gut microorganisms benefit the host by fermenting dietary fiber into short-chain fatty acids (SCFAs), such as acetic acid and butyric acid, which are then absorbed by the host.
Intestinal bacteria also play a role in synthesizing vitamin B and vitamin K as well as metabolizing bile acids, sterols, and xenobiotics. The systemic importance of the SCFAs and other compounds they produce are like hormones and the gut flora itself appears to function as an endocrine organ, and dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.
The composition of human gut microbiota changes over time, when the diet changes; and as overall health changes. A systematic review from 2016 examined the preclinical and small human trials that have been conducted with certain commercially available strains of probiotic bacteria and identified those that had the most potential to be useful for certain central nervous system disorders.