The ability to distinguish between “self” and “non-self” is the hallmark of a healthy immune system. Immune cells must be able to recognize pathogenic “non-self” antigens (i.e. microbial pathogens) and mount an appropriate immune response while remaining quiescent towards “self” agents (i.e. commensal microbes) that are harmless to our health. Nowhere else in the human body is this process more exemplified than the gastrointestinal (GI) tract; an organ that is exposed daily to an overwhelming load of antigens through the foods we eat. When this process goes awry, individuals may begin to experience adverse reactions to normal components of their diet, leading to food sensitivities that span from minor annoyances to life-threatening illnesses. Food sensitivities can have allergic pathophysiology, involving immunoglobulin E (IgE), or they can involve non-IgE-mediated mechanisms. In addition, celiac disease – a digestive condition where the small intestine becomes inflamed and less able to absorb nutrients – involves a well-characterized CD4+ T cell-mediated immune pathway with autoimmune-like features.
It is important to note that not all adverse food reactions are immune-mediated. Instead of involving an immune response, food intolerances, such as lactose maldigestion, involve an abnormal functional response – in this case, a deficiency in the enzyme required to digest lactose. Overall, both food sensitivities and intolerances are on the rise, but scientists are unsure of the cause. Evidence points however, to the role of unknown environmental factors, such as bacterial/viral infections and a dysbiotic gut microbiota. A recent review, published by Dr. Elena Verdú in Nature Reviews, thoroughly explores the available experimental and clinical evidence for the role of these microbial environmental factors in inciting food sensitivities.
Exposure to viral and bacterial infections early in life, especially in the setting of certain genetic predispositions, may increase an individual’s risk for developing food sensitivities. That’s because the neonatal or infant period is especially vulnerable to infections that may disturb the immature immune system. Indeed, epidemiological studies have shown an association between viral and bacterial infections and the onset of celiac disease and food allergies. Rotavirus infection, when encountered by individuals carrying the human leukocyte antigens (HLA) risk alleles for celiac disease and type 1 diabetes mellitus (T1DM), predicts an increased risk of developing celiac disease autoimmunity. Consistent with this hypothesis, the occurrence of Campylobacter jejuni, adenoviral infection, influenza or hepatobiliary virus infections have all also been shown to be additional risk factors of celiac disease.
The role of a dysbiotic gut microbiota is also being investigated as it relates to the development of adverse food reactions. It has been observed that changes in key bacterial groups in infancy are associated with the development of food allergy later in life. One study suggests that infants with IgE-mediated food allergy have increased levels of Clostridium and Anaerobacter and decreased levels of Bacteroides and Clostridium. Celiac disease, in particular, is associated with a dysbiosis in the small intestine that is characterized by increases in Proteobacteria and the presence of opportunistic pathogens. The mechanism by which gut microbiota modulates food sensitivities is still a subject of investigation, though animal studies have provided some insights as outlined in the following paragraphs.
One way that the gut microbiota is able to affect the host immune response is through the metabolism of compounds that would otherwise trigger an immune response if left unmetabolized. For example, when gluten is incompletely digested, it is capable of activating a T-cell immune response. In the presence of gluten-degrading bacteria such as Rothia or Lactobacillus, however, undigested peptides of gluten are metabolized, thereby reducing their immunogenicity. Lactobacillus can also degrade and detoxify gluten peptides produced by human or pathogen proteases. Not all modifications are positive however, as the degradation of gluten peptides by the opportunistic pathogen Pseudomonas aeruginosa leads to shorter peptides that retain immunogenic sequences. These sequences can translocate through the intestinal epithelial barrier better than those produced by human digestive proteases, potentially instigating an immune response rather than reducing it.
Another way the gut microbiota may modulate the immune response is through the production of immunomodulatory metabolites called short-chain fatty acids (SCFAs). SCFAs such as butyrate have been shown to directly regulate mucosal immune function and the intestinal barrier, affecting the predisposition towards food sensitivity. Specifically, butyrate has been shown to regulate forkhead box protein P3 (FOXP3)+ in Treg cells, which are important for tolerance to food antigens or allergens. In further support of this, a previous mouse study showed that a high-fiber diet in mice activates many protective pathways in the GI tract that are necessary for immune non-responsiveness to food antigens.
Normal immune tolerance towards dietary antigens is key to preventing adverse food reactions. While genetic predispositions certainly play a role in the development of food sensitivities and intolerances, evidence also points to the role of unknown environmental factors.
The role that bacterial/viral infections and the gut microbiota play in the development and prevention of adverse food reactions has been an area of intense study over the past two decades. Authors of the review outline how microbial signals may mediate the immune response through the metabolism of antigenic compounds or the production of immune-modulating metabolites. Further studies elucidating these and other mechanisms will hopefully lead to novel therapies to treat and prevent adverse food reactions in the future.
Caminero A, Meisel M, Jabri B, Verdu E. Mechanisms by which gut microorganisms influence food sensitivities. Nature Reviews Gastroenterology & Hepatology. 2018; doi: https://doi.org/10.1038/s41575-018-0064-z.
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