The human gut is the habitat to trillions of microbial cells with over 1,000 diverse microbial species that contribute to the primary functions of the gastrointestinal tract, including nutrition and defense. On the other hand, the gastrointestinal tract mucosa constitutes the major interface that separates the luminal environment from the internal milieu and it is also the body’s primary site for interaction with the microbial world living within the gut lumen. The surface of the gastrointestinal mucosa is estimated at up to 4,000 square feed when laid out flat and, most importantly, contains adapted structures allowing bi-directional host- microbe communication (Lozupone et al., 2012).
The gut barrier has to guarantee nutrient and metabolite exchange with the microbiota but at the same time also protection against the microbial world. The gut barrier consists of three major components including a mucus layer, an intact epithelial monolayer and a lamina propria with mucosal immune cells. All three layers contribute to well-functioning of the gut barrier (Spadoni et al., 2017). The epithelial monolayer is not a static structure and the tight junctions that seal spaces between epithelial cells are regulated by the gut microbiota and dietary components (Shen, 2008; Zhou & Zhong, 2017; Ulluwishewa et al., 2011).
Regarding intestinal barrier functions, it can be considered a functional unit involved in supporting water, nutrient and ion transport, and limiting pathogens and harmful substances’ penetration from the luminal content to the underlying immune system and the rest of the body (Zhou & Zhong, 2017). Translocation of nutrients to systemic tissues occurs via the portal vein, through the gut vascular barrier that impedes bacterial translocation to the liver (Spadoni et al., 2015).
Western diets high in fats and sugars, modern lifestyles with stress and sedentarism and the indiscriminate use of antibiotics together with other frequently prescribed drugs −such as non-steroidal anti-inflammatory drugs and proton pump inhibitors− are major drivers of changes in microbiota composition and gut barrier disruption (Odenwald & Turner, 2017).
Disruption of this barrier may result in an increased intestinal permeability, which in turn facilitates translocation of water, ions, macromolecules, microbial molecules (like lipopolisaccharide) and pathogens to the bloodstream and the underlying tissues. It leads to the popularization of the leaky gut syndrome, which is a term restricted to those situations where epithelial tight junctional function is impaired. That’s why intestinal barrier function is nowadays emerging as a hallmark of intestinal homeostasis and host health (Odenwald & Turner, 2017).
A dysfunctional intestinal barrier has been related with many gastrointestinal diseases, but also with systemic conditions, including autoimmune diseases (such as inflammatory bowel disease, celiac disease, autoimmune hepatitis, type 1 diabetes, multiple sclerosis, and systemic lupus erythematosus), allergic diseases or some neurological disorders (Mu et al., 2017). Although the majority of associations between intestinal barrier function and disease are merely correlative, experimental research has demonstrated the role of barrier dysfunction in inflammatory bowel disease and coeliac disease pathogenesis (Quigley, 2016).
Many promising approaches to target and restore the epithelial barrier from both an anatomic and a functional point of view, especially in the preclinical setting, have been proposed. Among them, dietary fiber and probiotics have been shown to protect the gut barrier and counteract many of the deleterious effects triggered by Western dietary patterns and stress (Bron et al., 2017; De Santis et al., 2015).
The maintenance of a healthy intestinal barrier is therefore a prerequisite for homeostasis of gastrointestinal mucosal function, which is crucial for allowing the mucosal barrier absorptive capacity while maintaining effective defensive reactions against harmful substances and pathogens.
Targeting the epithelial barrier as a potential therapeutic goal
Research has shown the relevance of environmental triggers such as stress in driving intestinal barrier dysfunction. Besides this, dietetic strategies aimed at maintaining an adequate intestinal barrier function homeostasis has been involved as a potential avenue for preventing gut-related and systemic diseases.
- Physiologic stress impacts intestinal permeability and both gut microbiota composition and function in adults.
A multiple-stressor military training environment −considered as a model of physiologic stress− may lead to an increased intestinal permeability that has been correlated with increased plasma lipopolysaccharide and interleukin-6 inflammatory markers. Collection of fecal samples before and after the stress intervention also showed that less dominant bacteria taxa have increased and there was reported an alteration in 23% of bacterial metabolites.
- A diet lack in fiber leads to gut microbiota disturbance and reduction in colonic mucus layer thickness.
In mice, a diet lack in fiber may drive a degradation of the colonic mucus layer and results in more severe colitis by the enteric pathogen Citrobacter rodentium. Specific changes secondary to fiber deprivation include an increase in the proliferation of bacteria that degrade mucus as alternative nutrient (including Akkermansia muciniphila) and a decrease in fiber-degrading bacteria such as Eubacterium rectale. Besides this, the lack of fiber also leads to physiological changes in mucus layer thickness and altered inflammatory markers. Although these preliminary findings allow us understanding why fiber is so important for health, researchers have used a simple model that does not necessarily reflects the complexity of the real gut ecosystem, which implies that more research is needed for a better characterization of host-microbiota interactions in the context of a diet lack in fiber.
- The probiotic Lactobacillus fermentumCECT 5716 prevents stress-induced intestinal barrier dysfunction in rats.
The probiotic Lactobacillus fermentum prevents intestinal epithelium dysfunction induced by both maternal separation and water avoidance stress in newborn rats. Mechanisms involved include a switch from the T helper 1 immune response phenotype to T helper 2-driven immune responses, together with an increase in exploratory behaviours.
- Probiotics might have a role in restoring the weakened intestinal barrier in non-steroidal anti -inflammatory drugs-induced small intestinal damage.
Among current treatments for preventing or reducing non-steroidal anti-inflammatory drugs (NSAID) -induced intestinal damage, a narrative review suggests the potential of probiotics. Based on experimental and clinical data, probiotics have been reported as a potential effective therapeutic option for preventing NSAID -induced gastrointestinal side effects.
- The probiotic Lactobacillus rhamnosusCNCM I-3690 counteracts high-fat diet induced metabolic impairments and gut barrier dysfunction in mice.
The pathobiont Bilophila wadsworthia aggravates high fat diet-induced deleterious metabolic effects in mice, which can be partly reversed by a probiotic strain L. rhamnosus CNCM I-3690. This is a probiotic with documented anti-inflammatory properties, protective effects against intestinal barrier dysfunction and high-fat diet-induced metabolic alterations in mice.
- Probiotics may modulate human disease through impacting intestinal barrier function.
Data from in vitro cell lines, animal models and small clinical trials supports the protective role of probiotics in intestinal epithelial integrity, with the most solid evidence demonstrating their beneficial effects for the reduction of gastrointestinal disease symptoms rather than systemic disorders.
Looking toward the future
The involvement of a compromised intestinal barrier function in gastrointestinal and systemic disorders underpins the need to take it into account as a new player for preventing or reverting the diseased state back to homeostasis and health.
The majority of research exploring the composition and function of the gut barrier comes mainly from preclinical models. Further research in the clinical setting is therefore needed before making conclusions about the relevance of targeting it on human health and disease.
The fact that current nutrition studies not always include the systematic use of markers aimed to evaluate intestinal barrier function make it difficult inferring clear conclusions. Besides this, factors that influence barrier integrity should also be taken into account as confounders. The challenge moving forward will be to provide evidencefor dietary and microbiota influences on the gut barrier that have meaningful effects not only for an overall wellbeing, but also for preventing digestive and extra -intestinal conditions. Intervention based on prebiotics, probiotics or postbiotics (microbial metabolites) may help restore the gut barrier function, but additional studies in the human setting with clear clinical outcome are required.
Text adapted from: GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM GUT MICROBIOTA & GUT BARRIER; a selection of content from the Gut Microbiota for Health 2017 & 2018, November 2018.