Facultad de Medicina

Background: The pathological mechanism of the gastrointestinal forms of food aller-gies is less understood in comparison to other clinical phenotypes, such as asthmaand anaphylaxis Importantly, high-IgE levels are a poor prognostic factor in gastroin-testinal allergies.Methods: This study investigated how high-IgE levels influence the development ofintestinal inflammation and the metabolome in allergic enteritis (AE), using IgE knock-in (IgEki) mice expressing high levels of IgE. In addition, correlation of the altered me-tabolome with gut microbiome was analysed.Results: Ovalbumin-sensitized and egg-white diet-fed (OVA/EW) BALB/c WT micedeveloped moderate AE, whereas OVA/EW IgEki mice induced more aggravated in-testinal inflammation with enhanced eosinophil accumulation. Untargeted metabo-lomics detected the increased levels of N-tau-methylhistamine and 2,3-butanediol,and reduced levels of butyric acid in faeces and/or sera of OVA/EW IgEki mice, whichwas accompanied with reduced Clostridium and increased Lactobacillus at the genus level. Non-sensitized and egg-white diet-fed (NC/EW) WT mice did not exhibit anysigns of AE, whereas NC/EW IgEki mice developed marginal degrees of AE. Comparedto NC/EW WT mice, enhanced levels of lysophospholipids, sphinganine and sphin-gosine were detected in serum and faecal samples of NC/EW IgEki mice. In addi-tion, several associations of altered metabolome with gut microbiome—for exampleAkkermansia with lysophosphatidylserine—were detected.Conclusions: Our results suggest that high-IgE levels alter intestinal and systemic levelsof endogenous and microbiota-associated metabolites in experimental AE. This studycontributes to deepening the knowledge of molecular mechanisms for the developmentof AE and provides clues to advance diagnostic and therapeutic strategies of allergicdiseases

The human gut microbiome establishes and matures during infancy, and dysregulation at this stage may lead to pathologies later in life. We conducted a multi-omics study comprising three generations of family members to investigate the early development of the gut microbiota. Fecal samples from 200 individuals, including infants (0-12 months old; 55% females, 45% males) and their respective mothers and grandmothers, were analyzed using two independent metabolomics platforms and metagenomics. For metabolomics, gas chromatography and capillary electrophoresis coupled to mass spectrometry were applied. For metagenomics, both 16S rRNA gene and shotgun sequencing were performed. Here we show that infants greatly vary from their elders in fecal microbiota populations, function, and metabolome. Infants have a less diverse microbiota than adults and present differences in several metabolite classes, such as short- and branched-chain fatty acids, which are associated with shifts in bacterial populations. These findings provide innovative biochemical insights into the shaping of the gut microbiome within the same generational line that could be beneficial in improving childhood health outcomes.

Purpose of Review Allergic diseases have become a burden in industrialized societies. Among children, food allergy (FA) constitutes a major impairment of quality of life. FA is partly due to a lack or loss of tolerance to food antigens at the level of the intestinal mucosa, where the microbiota plays a crucial role. Early changes in the composition of the gut microbiota may influence the development of the immune system and can be related to the risk of allergic diseases, including FA. This review will focus on the role of sphingolipids and the major bacteria involved in their metabolism, in the development of food antigen sensitization and FA. Recent Findings Numerous studies have identified different patterns of microbial composition between individuals with and without FA, pointing to an interaction between gut microbiota, enterocytes, and immune cells. When this interaction is lost and an imbalance in the composition of the intestinal microbiota occurs, the integrity of the epithelial barrier may be altered, leading to intestinal permeability and sensitization to food antigens and the development of FA. Gram- negative bacteria, especially those of the Proteobacteria phylum, have been associated with the development of FA. Investigating the interactions between the intestinal microbiota and the immune system, their influence on intestinal barrier function, and their production of metabolites and signaling molecules may contribute to understanding the pathogenesis of FA. Summary Sphingolipids, a class of bioactive amphipathic lipids found in cell membranes, have emerged as critical regulators of inflammation. In this review, we will attempt to summarize the existing knowledge on the role of these molecules and the major bacteria involved in their metabolism in the mechanisms underlying sensitization to food antigens and the development of FA.

The prevalence and severity of allergic diseases have increased over the last 30 years. Understanding the mechanisms responsible for these diseases is a major challenge in current allergology, as it is crucial for the transition towards precision medicine, which encompasses predictive, preventive, and personalized strategies. The urge to identify predictive biomarkers of allergy at early stages of life is crucial, especially in the context of major allergic diseases such as food allergy and atopic dermatitis. Identifying these biomarkers could enhance our understanding of the immature immune responses, improve allergy handling at early ages and pave the way for preventive and therapeutic approaches. This minireview aims to explore the relevance of three biomarker categories (proteome, microbiome, and metabolome) in early life. First, levels of some proteins emerge as potential indicators of mucosal health and metabolic status in certain allergic diseases. Second, bacterial taxonomy provides insight into the composition of the microbiota through high-throughput sequencing methods. Finally, metabolites, representing the end products of bacterial and host metabolic activity, serve as early indicators of changes in microbiota and host metabolism. This information could help to develop an extensive identification of biomarkers in AD and FA and their potential in translational personalized medicine in early life.

Omics strategies have triggered a revolution in the understanding of the microorganisms that reside in our body, and their implications in health and disease. For diagnosis and therapeutics, metabolomic fingerprinting is the most powerful approach, since the metabolites represent the actual interplay between humans and microbes. Studying the metabolome requires several new high-throughput analytical techniques and innovative computational methodologies. Herein, we will focus on the metabolomics workflow for gut microbiota analysis, including sampling, laboratory procedures, and available analytical techniques, paying special attention to microbiota isolation and multiplatform complementarity. Finally, we will summarize some applications and implications of gut microbiota metabolites in biomarkers discovery and several therapeutic strategies, such as fecal microbiota transplantation and the usage of prebiotics and probiotics.

Non-IgE-mediated gastrointestinal food allergy (non-IgE-GI-FA) is the name given to a series of pathologies whose main entities are food protein-induced allergic proctocolitis (FPIAP), food protein-induced enteropathy (FPE), and food protein-induced enterocolitis syndrome (FPIES). These are more uncommon than IgE-mediated food allergies, their mechanisms remain largely unknown, and their diagnosis is mainly done by clinical history, due to the lack of specific biomarkers. In this review, we present the latest advances found in the literature about clinical aspects, the current diagnosis, and treatment options of non-IgE-GI-FAs. We discuss the use of animal models, the analysis of gut microbiota, omics techniques, and fecal proteins with a focus on understanding the pathophysiological mechanisms of these pathologies and obtaining possible diagnostic and/or prognostic biomarkers. Finally, we discuss the unmet needs that researchers should tackle to advance in the knowledge of these barely explored pathologies.

Composition of the gut microbiota changes during ageing, but questions remain about whether age is also associated with deficits in microbiome function and whether these changes occur sharply or progressively. The ability to define these deficits in populations of different ages may help determine a chronological age threshold at which deficits occur and subsequently identify innovative dietary strategies for active and healthy ageing. Here, active gut microbiota and associated metabolic functions were evaluated using shotgun proteomics in three well‐defined age groups consisting of 30 healthy volunteers, namely, ten infants, ten adults and ten elderly individuals. Samples from each volunteer at intervals of up to 6 months (n = 83 samples) were used for validation. Ageing gradually increases the diversity of gut bacteria that actively synthesize proteins, that is by 1.4‐fold from infants to elderly individuals. An analysis of functional deficits consistently identifies a relationship between tryptophan and indole metabolism and ageing (p < 2.8e−8). Indeed, the synthesis of proteins involved in tryptophan and indole production and the faecal concentrations of these metabolites are directly correlated (r2 > .987) and progressively decrease with age (r2 > .948). An age threshold for a 50% decrease is observed ca. 11–31 years old, and a greater than 90% reduction is observed from the ages of 34–54 years. Based on recent investigations linking tryptophan with abundance of indole and other “healthy” longevity molecules and on the results from this small cohort study, dietary interventions aimed at manipulating tryptophan deficits since a relatively “young” age of 34 and, particularly, in the elderly are recommended.

The role of the microbiome in the molecular mechanisms underlying allergy has become highly relevant in recent years. Studies are increasingly suggesting that altered composition of the microbiota, or dysbiosis, may result in local and systemic alteration of the immune response to specific allergens. In this regard, a link has been established between lung microbiota and respiratory allergy, between skin microbiota and atopic dermatitis, and between gut microbiota and food allergy. The composition of the human microbiota is dynamic and depends on host-associated factors such as diet, diseases, and lifestyle. Omics are the techniques of choice for the analysis and understanding of the microbiota. Microbiota analysis techniques have advanced considerably in recent decades, and the need for multiple approaches to explore and comprehend multifactorial diseases, including allergy, has increased. Thus, more and more studies are proposing mechanisms for intervention in the microbiota. In this review, we present the latest advances with respect to the human microbiota in the literature, focusing on the intestinal, cutaneous, and respiratory microbiota. We discuss the relationship between the microbiome and the immune system, with emphasis on allergic diseases. Finally, we discuss the main technologies for the study of the microbiome and interventions targeting the microbiota for prevention of allergy.

Cow’s milk allergy (CMA) is one of the most prevalent food allergies in children. Several studies have demonstrated that gut microbiota influences the acquisition of oral tolerance to food antigens at initial stages of life. Changes in the gut microbiota composition and/or functionality (i.e., dysbiosis) have been linked to inadequate immune system regulation and the emergence of pathologies. Moreover, omic sciences have become an essential tool for the analysis of the gut microbiota. On the other hand, the use of fecal biomarkers for the diagnosis of CMA has recently been reviewed, with fecal calprotectin, -1 antitrypsin, and lactoferrin being the most relevant. This study aimed at evaluating functional changes in the gut microbiota in the feces of cow’s milk allergic infants (AI) compared to control infants (CI) by metagenomic shotgun sequencing and at correlating these findings with the levels of fecal biomarkers ( -1 antitrypsin, lactoferrin, and calprotectin) by an integrative approach. We have observed differences between AI and CI groups in terms of fecal protein levels and metagenomic analysis. Our findings suggest that AI have altered glycerophospholipid metabolism as well as higher levels of lactoferrin and calprotectin that could be explained by their allergic status.