Clostridia to the Rescue

Food allergies arise partly because of reduced gut barrier integrity, giving food molecules access to the circulatory system where they contact the immune system. The gut microbiome promotes intestinal health in part by helping to maintain the barrier function of this tissue. Clostridia bacteria promote the gut barrier and reduce food sensitization and allergy.¹ Cathryn Nagler, a mucosal immunologist at University of Chicago, and her team previously found that this class of bacteria were more abundant in nonallergic individuals than those with food allergies.² “We are starting to focus on the host-microbe interactions that mediate this barrier protective response,” Nagler said.

The production of interleukin (IL)-22 from host cells promotes gut barrier integrity, and bacterial products such as metabolites and flagellin induce host IL-22. In an article published in Cell Reports, Nagler’s team demonstrated that Clostridia-produced flagella and indole, a tryptophan metabolite, also promote barrier integrity.³

To determine the role of flagella in preventing gut permeability, the researchers first treated neonatal mice with antibiotics to disrupt their microbiomes. One week after weaning, the team isolated the animals’ intestinal tissues and treated them with flagella from commensal Clostridia or pathogenic Salmonella. “Commensal flagellins and pathogen flagellins are structurally and functionally distinct,” Nagler explained.

Both flagella treatments led to the production of barrier protective IL-22 from intestines. “It's really fascinating that [the] same protein but different amino acids elicit different responses,” said Pamela Chang, an immunologist at Cornell University who was not involved in the study.

Because IL-22 promotes intestinal integrity, the team next determined if these commensal Clostridia molecules reduced gut barrier permeability. They disrupted the intestinal microbiome with neonatal antibiotic treatment. After weaning, the researchers injected mice with flagella from Clostridia or Salmonella on three different days over one week. At the end of these treatments, the team orally administered fluorescein isothiocyanate (FITC)-dextran to the mice. The researchers monitored if FITC-dextran escaped into the blood from the intestines as an indicator of gut-barrier leakage. Mice treated with Clostridia flagella had less FITC-dextran in their serum compared to nontreated animals and those treated with pathogenic Salmonella flagella.

Aryl hydrocarbon receptor (AhR) ligands like indole also promote immune cells to produce IL-22, so the team investigated the effect of this product on IL-22 production. Using a process analogous to their flagella experiments, the researchers disrupted the microbiomes of neonatal mice. They showed that intestinal tissues from weaned mice stimulated with indole induced IL-22, although less than the amount induced by flagella treatments.

To determine the effect of indole on gut barrier integrity, they orally administered indole to mice after weaning for one week before administering FITC-dextran orally to assess gut permeability. Indole treatment decreased the amount of FITC-dextran that entered the blood. However, the researchers demonstrated that this was independent of the actions of IL-22 by neutralizing IL-22 with an antibody in the week after weaning and showing no effect on gut permeability. This suggested that barrier protection through Clostridia products extends beyond IL-22 alone.

According to Nagler, this study reveals how Clostridia bacteria protect the gut barrier and prevent food allergies. “You can imagine that if someone has a dysbiotic microbiome, and they don't have enough or any Clostridia that have these specific molecules, then they might be more likely to develop food allergy,” Chang said.

Nagler believes that these results have broad implications for understanding gut microbe-host health. “Maintaining an effective barrier protective response is fundamental to the whole family of noncommunicable chronic diseases that are rising in parallel with food allergy,” she said.