What is already known on this topic
The increasing prevalence of food allergies and intolerances is likely due to environmental factors. Alterations in the gut microbiota could promote adverse reactions to food, but the specific mechanisms remain unclear.
What this research adds
This review summarizes and discusses the evidence that supports a link between changes in the gut microbiota and the appearance of adverse food reactions.
Understanding the mechanisms underlying these processes could help to develop therapeutic and prevention strategies.
The recent increase in the prevalence of food allergies and intolerances is likely due not only to genetic predispositions but also to environmental factors. Studies have linked adverse food reactions to alterations in the gut microbiota, but the exact mechanisms are unknown.
A review by Alberto Caminero and his colleagues, published in Nature Reviews Gastroenterology & Hepatology, summarizes the clinical and experimental evidence to support a link between changes in the gut microbiota and the appearance of adverse reactions to specific dietary components, especially gluten. The authors focus on the mechanisms through which diet-microbe and host-microbe interactions can trigger specific adverse food reactions. The review also discusses treatment strategies that could be developed to prevent or treat food allergies.
Adverse food reactions: introduction
About 20% of the world’s population experiences adverse food reactions, with different manifestations depending on the causes and pathophysiological processes involved. Adverse food reactions can be divided into food allergies and food intolerances, according to their underlying pathophysiology.
In case of food allergies, the exposure to the allergen produces an abnormally vigorous immune response, normally mediated by immunoglobulin E. In case of food intolerances, the immune system is not involved, but the organism lacks an enzyme required to digest the food component – for example, the enzyme β-galactosidase in lactose intolerance – which leads to gas production and bloating.
Microbial environmental factors
Several studies have reported a link between adverse food reactions and practices, such as early eating behaviors, antibiotics, or Caesarean section, that can alter the gut microbiota composition. In the case of coeliac disease, one of the most common food allergies, an increasingly accepted hypothesis is that a combination of factors, from genetic predisposition to viral and bacterial infections to an alteration of the gut microbiota, could play a role.
Clinical and preclinical studies have shown that:
- In mice, the severity of gluten immunopathology depends on the gut microbiota background
- In vitro and in mice, the gut microbiota is involved in gluten metabolism and gluten-peptide immunogenic modification
- People with coeliac disease show an intestinal dysbiosis, which seems to be characterized by Proteobacteria expansion
- People with coeliac disease who do not respond to a gluten-free diet have altered duodenal microbiota
- Coeliac disease as well as other food allergies and intolerances have been associated with practices, including Caesarean section and antibiotic intake, that affect the gut microbiota
Diet and microbiota
Our dietary habits are key in determining the gut microbiota diversity, as they affect microbial community structure and metabolite production.
The gut microbiota is considered a metabolic organ that uses dietary food components that are not metabolized by the host. Gut microbes can also metabolize food protein antigens, altering their immunogenicity. Changes in the gut microbiota make-up or its metabolic capabilities could promote immune system-mediated food sensitivities in genetically predisposed people.
For example, lactobacilli, which are able to metabolize non-digested gluten peptides,
have been reported to be less abundant in people with coeliac disease compared to healthy subjects. Further studies are needed to test if this reduced lactobacilli abundance is a cause or an effect of the disease.
Gut microbes are implicated not only in gluten degradation, but also in its deamidation and, in turn, in its immunogenicity. This aspect could apply to other food allergies, including those to peanut or egg proteins.
Metabolites with immunomodulatory function
Under healthy conditions, the gut microbiota plays a pivotal role in maintaining a “tolerant” gut environment, which prevents an inflammatory response against foreign antigens by promoting epithelial integrity and the function of regulatory T cells (Treg).
Bacterial metabolites resulting from the metabolism of dietary substrates mediate many of these effects.
Short-chain fatty acids
Among the bacterial metabolic products, some of the most relevant for food allergies are short-chain fatty acids (SCFAs). Alterations of these metabolites have been reported in people with food allergies. Studies have found that:
- The SCFA butyrate regulates both the proportion and the function of FOXP3+Treg (pTreg) cells, which contribute to maintain tolerance to food antigens or allergens
- In mice, a high-fiber diet increased the release of SCFAs, improving oral tolerance to food allergens by activating a specific enzymatic activity in CD103+ dendritic cells
- The SCFA acetate promotes epithelial integrity during enteropathogenic infections in mouse models
Other microbial determinants
Gut bacteria prevent the development of adverse food reactions. For example, Bacteroides fragilis was shown to promote the production of IL-10 and the differentiation of pTreg cells. What’s more, studies in mice reported that germ-free animals developed more severe allergies and more severe immunopathology.
Probiotic treatments with either mouse- or human-derived strains of live bacteria reduced or even prevented food allergies, as in the case of Bifidobacterium breve M-16V and Bifidobacterium longum BB536 supplementation.
However, probiotic bacteria aren’t yet recommended in the clinic, and further evidence of their efficacy is needed.
Allergies and other non-bacterial factors
Additional factors that contribute to the development of food allergies are mainly inflammatory events, such as:
- Dysfunction of the gut epithelial barrier and innate immunity
- Altered immune response mediated by T helper 1 and 2 cells and IL-15
- Reovirus-mediated inflammatory responses
- The mechanisms involved in the development of food allergies and intolerances remain unclear, although several studies have shown that gut bacteria, among other factors, play an important role in adverse food reactions.
- The gut microbiota can degrade and transform food antigens and allergens, altering their immunogenicity.
- In addition to bacterial dysbiosis, which is found in some people with food allergies, the integrity of the gut epithelial barrier as well as the activity of Treg immune cells are key factors for the development of adverse food reactions.
Further studies to unravel specific diet-microbes interactions and their underlying mechanisms are needed to develop new prevention and treatment approaches to food allergies.