How our immune system works to not attack harmless dietary nutrients and microbes

In the gastrointestinal tract, the immune system is tasked with constantly patrolling the gut content to discriminate friend from foe. We consume a myriad of food components and over a billion microbes per day (1). Although the majority are harmless, certain food components and microbes can cause disease.

In the small intestine, the mesenteric lymph nodes (mLN) are inductive sites where an immune function called “oral tolerance” is generated. Oral tolerance is an active process where the immune system is intentionally unresponsive to orally ingested antigens such as food components (2). In brief, when antigens in the gut lumen are sampled by dendritic cells (DC) and presented to naïve T cells in homeostatic conditions, regulatory T cells (Treg) are induced, which are critical to oral tolerance. However, when DCs have an inflammatory phenotype, they promote the shift towards inflammatory T helper 1 (TH1) cells, which elicit immune responses against food antigens referred to as the loss of oral tolerance.

Celiac disease is a food sensitivity where oral tolerance towards cereal proteins collectively called “gluten” is broken. Dr. Reinhard Hinterleitner and colleagues, from the University of Chicago, had previously uncovered a potential mechanism leading to oral tolerance disruption to food antigens. They identified an inflammatory enterovirus that activated transcription factors such as regulatory factor 1 (IRF1) and NF-κB, which in turn resulted in proinflammatory DCs, rather than the tolerogenic type, which lead to the loss of tolerance to gluten (3).

 

A gut-colonizing protist confers protection against virus-mediated loss of oral tolerance

Supported by a study indicating that active inflammation in celiac disease is associated with niches of proinflammatory bacteria unique to the different portions of the duodenum (4), Dr. Hinterleitner recently uncovered a mechanism by which commensal microbes could favor oral tolerance.

They discovered this when mice that were maintained “in-house” did not develop viral-mediated inflammatory responses to dietary antigens such as ovalbumin, but newly obtained mice from Jackson laboratories did. Further investigation revealed that the in-housed mice were colonized with a new species of Tritrichomonas from the Parabasalia class, which promoted the expansion of tuft and goblet cells in the small intestines, features that are associated with a shift towards T helper 2 (TH2) humoral immunity. However, the colonization with T. arnold did not affect viral replication or host type 1 IFN responses. T. arnold also did not affect the existing microbiota composition, or metabolism, and was even able to confer protection in germ-free mice, suggesting the microbiota was not required.

The authors found that T. arnold specifically suppressed induction of inflammatory DCs in the mLN. The presence and antigen-presenting ability of mLN DCs were not affected, but rather their transcriptional profiles. Unidentified metabolites from T. arnold cultures restricted viral induction of genes regulated by IRF1 and NF-κB transcription factors and mitigated inflammatory responses in DCs, and in the absence of viral infection, facilitated Treg generation to promote tolerance. In summary, the authors discovered a new species of protist, T. arnold, that produces undefined metabolites that protect against viral-induced loss of oral tolerance by inhibiting inflammatory transcription factors in antigen-presenting DCs and promoting Treg responses.

Using transgenic mice expressing the human risk gene for celiac disease, HLA-DQ8, the authors showed that colonization with T. arnold protects mice against virus-induced loss of oral tolerance to gluten. T. arnold did not modify gluten digestion, but it prevented viral induced activation of tissue transglutaminase 2, which modifies gluten peptides increasing their affinity for antigen-presenting cells. These findings have clinical implications for CeD management and preventing the loss of gluten tolerance in patients.

 

The protist T. arnold is underrepresented in patients with celiac disease and needs fibre to protect against food tolerance

The class Parabasalia was identified in ~7% of celiac disease patients compared with ~35% of healthy volunteers. This could be explained by the use of antibiotic treatments, as a recent meta analysis concluded that both early infection and treatment with antibiotics can increase the risk of developing celiac disease later in life (6). Therefore, these results provide a possible mechanistic link to the associations between antibiotic use and celiac disease risk.

The results raise the possibility that in the future, strategies to promote colonization of beneficial protists could be considered in the prevention of celiac disease. The authors also observed that a diet containing soluble fibre was required to sustain the colonization of T. arnold in mice. Interestingly, there is a clinical fibre gap in celiac disease patients consuming a gluten-free diet (7). This warrants further investigation to address the clinical managements gap in optimal recommendation on type, and dose of fibre for celiac patients on a gluten-free diet.

 

References:

  1. Lang JM, Eisen JA, Zivkovic AM. The microbes we eat: abundance and taxonomy of microbes consumed in a day’s worth of meals for three diet types. PeerJ. 2014;2:e659.
  2. Commins SP. Mechanisms of Oral Tolerance. Pediatr Clin North Am. 2015 Dec;62(6):1523–9.
  3. Bouziat R, Hinterleitner R, Brown JJ, Stencel-Baerenwald JE, Ikizler M, Mayassi T, et al. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science (80- ) [Internet]. 2017 Apr 7;356(6333):44–50. Available from: https://doi.org/10.1126/science.aah5298
  4. Constante M, Libertucci J, Galipeau HJ, Szamosi JC, Rueda G, Miranda PM, et al. Biogeographic Variation and Functional Pathways of the Gut Microbiota in Celiac Disease. Gastroenterology. 2022 Nov;163(5):1351-1363.e15.
  5. Medina Sanchez L, Siller M, Zeng Y, Brigleb PH, Sangani KA, Soto AS, et al. The gut protist Tritrichomonas arnold restrains virus-mediated loss of oral tolerance by modulating dietary antigen-presenting dendritic cells. Immunity [Internet]. 2023;56(8):1862-1875.e9. Available from: https://www.sciencedirect.com/science/article/pii/S1074761323002790
  6. Jiang H, Zhang X, Zhou Y, Jiang C, Shi Y. Infection, antibiotic exposure, and risk of celiac disease: A systematic review and meta-analysis. J Gastroenterol Hepatol [Internet]. 2020 Apr 1;35(4):557–66. Available from: https://doi.org/10.1111/jgh.14928
  7. Cardo A, Churruca I, Lasa A, Navarro V, Vázquez-Polo M, Perez-Junkera G, et al. Nutritional Imbalances in Adult Celiac Patients Following a Gluten-Free Diet. Vol. 13, Nutrients . 2021.