The gut microbiota and immune‐regulation: the fate of health and disease

Abstract

T he gut microbiota is relevant to many diseases due to its direct impact on the development and maintenance of the immune system. Moreover, both the gut microbiota and the immune system are intimately related to many other physiological processes such as metabolism and behavior, as well as the digestive, respiratory and nervous systems. The amount of information gained in the last 5 years signifies the gut microbiota now as another important organ in our body. With diseases such as obesity, stroke, cancer, depression and autism increasing in prevalence, the debate centres upon whether many diseases have a gut origin. The interplay between the intestinal immune system, the epithelial barrier and the bacteria that resides within, is fundamental to maintaining a healthy gut homeostasis and determining the fate of health and disease. The host genetics and many environmental factors such as diet, early exposition to antibiotics, stress, drugs and many pollutants contribute to altering the balance of good and bad bacteria (dysbiosis) in the gut, subsequently compromising the gut permeability, often called 'Leaky gut'. Many inflammatory diseases are collectively being pinned on having a gut wall that allows toxins and autoimmune triggers to escape from the intestinal lumen leading to health problems. In this Special Feature of Clinical & Translational Immunology, we share our insights into the interplay between environmental factors, gut microbiota and metabolites, and their effects on human development, inflammation, infection, obesity, diabetes and chronic kidney disease. Likewise, we briefly discuss the challenges and opportunities in gut microbiota research and how novel therapeutic strategies targeting the gut microbiota will be beneficial for humans. The trillions of microbes that reside in our body and particularly in our gastrointestinal tract, together with our genome, constitute a complex dialogue. Vieira et al. 1 explain how the gut microbiota develops from birth and their interactions with the host become critical for the formation of a healthy or a disease-promoting microbiota. This review exposes the relevance of maternal diet and breastfeeding on gut microbiota modulation from early to late stages of life and the use of prebiotic, probiotic and postbiotic treatment, and fecal microbiota transplantation. The intense enthusiasm for research into the gut microbiota over the past decade has resulted in a deeper understanding into how the bacterial alteration of dietary components may have critical roles in host health and disease. Our diet is one of the main environmental factors that can dramatically affect the gut microbiota ecology. Richards et al. 2 illustrate that changes in lifestyle are more pronounced in Western societies where the consumption of processed foods high in fat and carbohydrates are important contributors to the worldwide rates of obesity, autoimmune and inflammatory diseases such as type 1 and type 2 diabetes. In this review, Richards et al. 2 explain that, from fiber fermentation, gut microbiota produce high concentrations of dietary metabolites or short-chain fatty acids (SCFAs) such as acetate, propionate and butyrate that keep the gut healthy, but also have beneficial anti-inflammatory effects. The reviews by Richards et al. 2 and Correa et al. 3 describe a whole mechanistic process by which the microbial SCFAs modulate the innate and adaptive immune system. These articles describe how SCFAs are known to modify several cellular processes including gene expression, chemotaxis, differentiation, proliferation and apoptosis, and discuss the signaling pathways such as activation through G-protein coupled receptors (GPCRs) or inhibition of histone deacetylases (HDACs) as the possible mechanisms of action. Studies in both mice and humans are showing the impact of dietary or host-derived metabolites on host metabolic processes such as insulin resistance and diabetes as the leading causes for the development of cardiovascular and chronic kidney disease (CKD). Felizardo et al. 4 discuss that the progression of CKD is strictly related to changes in the composition of the gut microbiota and poorly ingested fibre-enriched foods. More importantly, they explain how microbial metabolites have an impact on advanced renal failure and secretion of nitrogen compounds (urea, uric acid), which leads to the influx and overgrowth of bacteria in the gastrointestinal tract that correlates with the generation of uremic toxins. This Brazilian team discusses whether CKD development is a consequence or cause of an unhealthy gut microbiota—many lines of evidence supporting how dysbiosis could be linked to the progression of kidney diseases. The advances in understanding of diet–microbiota–host interactions proposes significant possibilities to create new therapeutic strategies, including re-engineering gut bacteria species to selectively alter the microbial production of molecules to promote human health and prevent disease. Lobo et al. 5 reveal several studies on Bacteroides fragilis and Polysaccharide A (PSA) as the first evidence of a symbiotic bacterial molecule that coordinates anti-inflammatory responses essential for the host's health. More importantly, this review reminds us that, although gut microbiota may have beneficial effects in health, in cases where the epithelial barrier of the gut is breached, commensal bacteria can escape the gut lumen, translocate to other organs and may be involved in pathogenic processes. Lobo et al. 5 describe this process in inflammatory peritonitis and systemic sepsis. Interestingly, this article reflects on the use of antibiotics that affect the gut microbiota