How vitamin A and gut microbiota regulate the intestinal immune system

The gut microbiota reduces the production of retinoic acid, a metabolite of vitamin A, to regulate immune activity and prevent pathogens.
Table of Contents
  • What is already known on this topic
    Retinoic acid is a metabolite of vitamin A that drives both protective and pathogenic immune responses in the gut. Little is known whether commensal gut bacteria could regulate the levels of retinoic acid, thus influencing its immunomodulatory functions.

  • What this research adds
    In mice, commensal bacteria curb the synthesis of retinoic acid by the cells lining the gut, which reduces the production of the antimicrobial cytokine IL-22. This in turn protects the gut microbiota from excessive immune activity and from colonization by pathogens.

  • Conclusions
    The study sheds light on how bacteria regulate the gut immune system, which could be important in treating disorders like Crohn’s disease and inflammatory bowel disease.

Gut bacteria curb the production of the vitamin A metabolite retinoic acid to regulate immune activity and prevent pathogen colonization, researchers have found. The study, done in mice, was led by Mayara Grizotte-Lake at Brown University in Providence, Rhode Island, and published in the journal

The cells lining our intestine take up the vitamin A that we ingest with food and transform some of it into retinoic acid, a molecule whose concentration regulates the balance between protective and pathogenic immune responses in the gut.

To address whether commensal bacteria could influence the immunomodulatory functions of retinoic acid by regulating vitamin A metabolism, the researchers quantified the amount of various vitamin A metabolites in the gut of mice grown in the absence or presence of bacteria, referred to as germ-free and conventional mice, respectively.

Gut bacteria regulate vitamin A metabolism

Compared to the gut of conventional mice, the intestine of germ-free mice had a higher concentration of retinoic acid and a lower concentration of its precursor vitamin A. This suggests that gut bacteria curb the conversion of vitamin A into retinoic acid.

The team discovered that gut bacteria modulate the metabolism of vitamin A by reducing the expression of Rdh7 – a gene whose product transforms vitamin A into one of its metabolites –  in the cells lining the gut. Mice treated with antibiotics to deplete their gut bacteria showed higher Rdh7 expression compared to untreated mice.

Because the majority of the gut microbiota is made of anaerobic bacterial species such as Firmicutes and Bacteroidetes, the researchers treated mice with an antibiotic that targets these bacteria. After 4 weeks, treated mice had a significantly increased expression of Rdh7 as well as higher amounts of retinoic acid in the gut.

The team also found that bacteria belonging to the Clostridia family significantly reduced the expression of Rdh7 in the gut.

Retinoic acid influences IL-22 levels and activity in the gut

Next, the researchers tested whether Rdh7 expression in intestinal cells contributes to regulate retinoic acid immunomodulatory functions in the gut. Mice genetically engineered to lack Rdh7 in their intestinal cells have less retinoic acid in the gut as well as fewer immune cells producing IL-22, a cytokine that coordinates the immune response against gut bacteria and is produced in high quantity upon infection with intestinal pathogens.

Depending on the pathogen, IL-22 can either protect the host from colonization or promote pathogen colonization as in the case of Salmonella Typhimurium. Mice that lack Rdh7 were less susceptible to S. Typhimurium colonization and had a lower pathogen load in their stool compared to mice that had Rdh7. The resistance to S. Typhimurium infection was associated with reduced levels of IL-22-induced antimicrobials. Compared to wild-type rodents, mice lacking Rdh7 were also less susceptible to Salmonella-mediated dysbiosis, which leads to the depletion of gut commensal species such as Clostridia.

In conclusion, the researchers propose that gut microbes regulate the expression of Rdh7 and the production of retinoic acid, which in turn modulates IL-22 activity in the gut. Curbing the expression of Rdh7 and retinoic acid protects the gut microbiota and prevents microbial dysbiosis and pathogen colonization by reducing IL-22-mediated responses.

The findings could be important in developing new approaches that exploit gut microbes to modulate the gut immune response in disorders like Crohn’s disease and inflammatory bowel disease, the authors say.