A cross talk between microbial metabolites and host immunity: Its relevance for allergic diseases.

BACKGROUND: Allergic diseases, including respiratory and food allergies, as well as allergic skin conditions have surged in prevalence in recent decades. In allergic diseases, the gut microbiome is dysbiotic, with reduced diversity of beneficial bacteria and increased abundance of potential pathogens. Research findings suggest that the microbiome, which is highly influenced by environmental and dietary factors, plays a central role in the development, progression, and severity of allergic diseases. The microbiome generates metabolites, which can regulate many of the host's cellular metabolic processes and host immune responses. AIMS AND METHODS: Our goal is to provide a narrative and comprehensive literature review of the mechanisms through which microbial metabolites regulate host immune function and immune metabolism both in homeostasis and in the context of allergic diseases. RESULTS AND DISCUSSION: We describe key microbial metabolites such as short-chain fatty acids, amino acids, bile acids and polyamines, elucidating their mechanisms of action, cellular targets and their roles in regulating metabolism within innate and adaptive immune cells. Furthermore, we characterize the role of bacterial metabolites in the pathogenesis of allergic diseases including allergic asthma, atopic dermatitis and food allergy. CONCLUSION: Future research efforts should focus on investigating the physiological functions of microbiota-derived metabolites to help develop new diagnostic and therapeutic interventions for allergic diseases.

Bile acids in immunity: Bidirectional mediators between the host and the microbiota.

Host-microbiota interactions are bidirectional. On one hand, ecological pressures exerted by the host shape the composition and function of the microbiota. On the other, resident microbes trigger multiple pathways that influence the immunity of the host. Bile acids participate in both parts of this interplay. As host-derived compounds, they display bacteriostatic properties and affect the survival and growth of the members of the microbial community. As microbiota-modified metabolites, they further influence the microbiota composition and, in parallel, modulate the immunity of the host. Here, we provide a comprehensive overview of the mechanisms behind this unique dialogue and discuss how we can harness bile acids to treat intestinal inflammation.

Bypassing the Gut-Lung Axis via Microbial Metabolites: Implications for Chronic Respiratory Diseases.

The gut microbiome engages in constant interactions with the immune system, laying down the fundamentals of what we perceive as health or disease. The gut microbiota acts locally in the intestines and distally in other organs, such as the lungs. This influence (termed "the gut-lung axis") constitutes the basis for harnessing the microbiome to prevent or treat chronic respiratory diseases. Within this context, two approaches gained the most attention: the diet interventions (which shape the microbiome) and the probiotics (which exert beneficial effects directly on the host). Microbial products, which constitute a means of communication along the gut-lung axis, are only now emerging as a new class of potential therapeutics. Here, we provide a comprehensive overview of microbial products active in the airways, describe the immunological mechanisms they trigger, and discuss their clinical advantages and pitfalls.

FOXC2 controls adult lymphatic endothelial specialization, function, and gut lymphatic barrier preventing multiorgan failure.

The mechanisms maintaining adult lymphatic vascular specialization throughout life and their role in coordinating inter-organ communication to sustain homeostasis remain elusive. We report that inactivation of the mechanosensitive transcription factor Foxc2 in adult lymphatic endothelium leads to a stepwise intestine-to-lung systemic failure. Foxc2 loss compromised the gut epithelial barrier, promoted dysbiosis and bacterial translocation to peripheral lymph nodes, and increased circulating levels of purine metabolites and angiopoietin-2. Commensal microbiota depletion dampened systemic pro-inflammatory cytokine levels, corrected intestinal lymphatic dysfunction, and improved survival. Foxc2 loss skewed the specialization of lymphatic endothelial subsets, leading to populations with mixed, pro-fibrotic identities and to emergence of lymph node-like endothelial cells. Our study uncovers a cross-talk between lymphatic vascular function and commensal microbiota, provides single-cell atlas of lymphatic endothelial subtypes, and reveals organ-specific and systemic effects of dysfunctional lymphatics. These effects potentially contribute to the pathogenesis of diseases, such as inflammatory bowel disease, cancer, or lymphedema.

Cellular and functional heterogeneity of the airway epithelium.

The airway epithelium protects us from environmental insults, which we encounter with every breath. Not only does it passively filter large particles, it also senses potential danger and alerts other cells, including immune and nervous cells. Together, these tissues orchestrate the most appropriate response, balancing the need to eliminate the danger with the risk of damage to the host. Each cell subset within the airway epithelium plays its part, and when impaired, may contribute to the development of respiratory disease. Here we highlight recent advances regarding the cellular and functional heterogeneity along the airway epithelium and discuss how we can use this knowledge to design more effective, targeted therapeutics.

Microbial metabolism of L-tyrosine protects against allergic airway inflammation.

The constituents of the gut microbiome are determined by the local habitat, which itself is shaped by immunological pressures, such as mucosal IgA. Using a mouse model of restricted antibody repertoire, we identified a role for antibody-microbe interactions in shaping a community of bacteria with an enhanced capacity to metabolize L-tyrosine. This model led to increased concentrations of p-cresol sulfate (PCS), which protected the host against allergic airway inflammation. PCS selectively reduced CCL20 production by airway epithelial cells due to an uncoupling of epidermal growth factor receptor (EGFR) and Toll-like receptor 4 (TLR4) signaling. Together, these data reveal a gut microbe-derived metabolite pathway that acts distally on the airway epithelium to reduce allergic airway responses, such as those underpinning asthma.

The influence of the microbiome on respiratory health.

The revolution in microbiota research over the past decade has provided invaluable knowledge about the function of the microbial species that inhabit the human body. It has become widely accepted that these microorganisms, collectively called 'the microbiota', engage in networks of interactions with each other and with the host that aim to benefit both the microbial members and the mammalian members of this unique ecosystem. The lungs, previously thought to be sterile, are now known to harbor a unique microbiota and, additionally, to be influenced by microbial signals from distal body sites, such as the intestine. Here we review the role of the lung and gut microbiotas in respiratory health and disease and highlight the main pathways of communication that underlie the gut-lung axis.

Antibiotics as Instigators of Microbial Dysbiosis: Implications for Asthma and Allergy.

The human body and its resident microbiota form a complex ecosystem, shaped by both inherited and environmental factors. The use of antibiotics represents an extreme example of environmental pressure and can broadly disrupt the microbial landscape. The benefits that antibiotics have brought to modern medicine are unquestionable; however, their overuse comes with consequences, including the potential for secondary infections by opportunistic pathogens and the spread of antibiotic resistance. Here, we discuss the implications of microbial dysbiosis driven by antibiotics, with a focus on potential links with allergy and asthma. We review epidemiological data on humans, as well as mechanistic studies performed in animal models, and highlight gaps in current knowledge, which if addressed, could drive the design of novel therapeutic strategies and improved clinical care.

The Impact of Diet on Immunity and Respiratory Diseases.

The Western world has witnessed a tremendous increase in the occurrence of allergy and autoimmunity in the second half of the 20th century. Extensive efforts have been made to explain this phenomenon and various hypotheses have been formulated. Among them, two concepts have attracted the most attention: the "hygiene hypothesis," identifying the reduced exposure to environmental microorganisms as a driving force behind the observed epidemiological trends; and the "diet hypotheses," pointing to the importance of changes in our dietary habits. In this review, we discuss the interplay between the Western diet, microbiota, and inflammatory conditions, with particular emphasis on respiratory diseases. This is followed by an in-depth overview of the immunomodulatory potential of different dietary fatty acids. We conclude by identifying the outstanding questions, which, if answered, could shed further light on the impact of dietary habits on immunity and interconnect it with postulates proposed by the hygiene hypothesis. Linking these two concepts will be an important step towards understanding how Western lifestyle shapes disease susceptibility.

Diet Hypotheses in Light of the Microbiota Revolution: New Perspectives.

From an evolutionary standpoint, allergy has only recently emerged as a significant health problem. Various hypotheses were proposed to explain this, but they all indicated the importance of rapid lifestyle changes, which occurred in industrialized countries in the last few decades. In this review, we discuss evidence from epidemiological and experimental studies that indicate changes in dietary habits may have played an important role in this phenomenon. Based on the example of dietary fiber, we discuss molecular mechanisms behind this and point towards the importance of diet-induced changes in the microbiota. Finally, we reason that future studies unraveling mechanisms governing these changes, along with the development of better tools to manipulate microbiota composition in individuals will be crucial for the design of novel strategies to combat numerous inflammatory disorders, including atopic diseases.