Focus on Leaky Gut

From ancient Ayurvedic practices to the teachings of Hippocrates, the foundational belief in medicine has always posited that the gut is central to health and disease. It is only in recent times that Western medicine has recognised gut-barrier dysfunction as a pathological phenomenon that is pivotal not just for digestive health but also for chronic allergic, inflammatory, and autoimmune diseases.

Understanding the Gut Barrier’s Role in Health and Disease

The gut barrier, comprising the human body’s largest interface with the external environment, must maintain optimal homeostasis and selective permeability. This ensures the absorption of vital nutrients while blocking harmful microbes, food antigens, pro-inflammatory factors, and toxins. The barrier itself includes the mucus layer, the gut microbiome, epithelial cells, and immune cells within the lamina propria.

Dysfunction and Disease Implications

When disrupted—whether by infection, a low-fibre diet, antibiotics, or alcohol—the gut barrier fails to function properly, leading to the translocation of dangerous substances into the gut wall and systemic circulation. This exposure triggers inappropriate immune activation and dysregulation, subsequently contributing to a spectrum of diseases. These may include gastrointestinal inflammatory disorders like inflammatory bowel disease (IBD) and coeliac disease, systemic autoimmune conditions such as multiple sclerosis and rheumatoid arthritis, and metabolic diseases like obesity and diabetes[1],[2].

Clarifying “Leaky Gut”

The term “leaky gut,” formally known as increased intestinal permeability or intestinal hyperpermeability, is often misunderstood. Dr. Michael Camilleri’s 2019 review in the Journal Gut underscores the necessity for practitioners to recognise the potential of barrier dysfunction in various diseases and to consider it a target for therapeutic intervention[3]. While increased intestinal permeability is implicated in the pathophysiology of chronic diseases, it remains under scientific debate whether it is a standalone disease or a precursor to broader health issues and as such the development and timing of the hyperpermeability is an important mechanism to manage. Increasing interest in the process of development and restoration are attracting attention. The Journal Molecules published a useful review on treatment options in 2023[4]. Research on treating intestinal permeability emphasises reducing high sugar and fat intake while incorporating beneficial strategies such as the FODMAP diet (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols), prebiotics, probiotics, fibres, glutamine, short-chain fatty acids, quercetin, and metformin[5]. Several functional foods and ingredients have demonstrated significant potential in treating leaky gut. Specific herbs, polyphenols, amino acids, minerals, antioxidants, and certain food products can help enhance the body’s ability to address intestinal permeability effectively.

Evolving Research and Clinical Observations

Research continues to reveal the intricacies of gut-barrier dysfunction. For instance, the Crohn’s and Colitis Canada Genetic, Environmental, Microbial Project has identified specific microbial patterns, like increased Ruminococcus torques, that precede Crohn’s disease development in at-risk individuals. R torques are mucin degraders that induce an increase in other mucin-using bacteria, which can contribute to gut-barrier compromise. Similarly, asymptomatic intestinal hyperpermeability has been documented years before clinical diagnosis of Crohn’s, suggesting a potential preventative role if identified early.

Gut-Barrier Disruption: Causes and Clinical Suspicion

Several risk factors have been linked to gut-barrier disruption in human and animal studies. These include dietary components like acrolein (food toxin), aging, alcohol, antacid drugs, antibiotics, burn injury, chemotherapy, circadian rhythm disruption, corticosteroids, emulsifiers (food additives), strenuous exercise (≥ 2 hours) at 60% Vo2 max, starvation, fructose, fructans, gliadin (wheat protein), high-fat diet, high-salt diet, high-sugar diet, hyperglycaemia, low-fibre diet, nonsteroidal anti-inflammatory drugs, pesticide, proinflammatory cytokines, psychological stress, radiation, sleep deprivation, smoking, and sweeteners. Practitioners should consider these factors, particularly when assessing patients with a predisposition to chronic diseases or diagnosed with an aligned condition.

The gut microbiome also plays a crucial role in the intestinal barrier. It not only defends against pathogens by competing for resources and producing antimicrobial compounds, but also directly regulates host functions through the production of metabolites. Various metabolites derived from the microbiome have been found to influence barrier permeability[6].

For instance, butyrate, a short-chain fatty acid (SCFA), enhances barrier function by aiding in the assembly of tight junction proteins and stimulating the expression of claudin-1 in cell line models. Other SCFAs, such as propionate, also promote tight junction protein expression, including ZO-1 and occludin, thereby regulating paracellular transport[7].

ZO-1, or Zonula Occludens-1, is a protein that plays a critical role in the structure and function of tight junctions. Tight junctions are specialised regions where cells in epithelial and endothelial tissues are closely connected to control the passage of substances between cells. ZO-1 is part of a family of proteins known as the zonula occludens, which also includes ZO-2 and ZO-3.

Key functions of ZO-1 include:

• Structural Support: It serves as a scaffold that links the tight junction membrane proteins, such as occludins and claudins, to the actin cytoskeleton inside the cell.
• Regulation: ZO-1 regulates tight junction assembly, barrier integrity, and paracellular permeability, which is the movement of substances across the space between cells.
• Signalling: It also plays a role in cell signalling, interacting with various proteins that regulate gene expression, cytoskeletal dynamics, and other cellular functions.

Diet and the Gut Barrier

The consumption of a Western diet, characterised by low fibre intake, and processed foods is a significant driver of gut-barrier disruption[8]. A Western diet typically contains less than 15 grams of fibre per day, which is significantly lower than the intake observed in many other cultures. For example, the hunter-gatherer Hadza community of Tanzania consumes over 100 grams of fibre daily through their traditional diet. This stark difference arises from the heavy reliance on processed and refined foods in Western diets, which strips away the natural fibre content. In contrast, traditional diets, like that of the Hadza, are rich in fruits, vegetables, tubers, and other whole foods, providing a wide array of fibres.

The fibre-rich diet of the Hadza not only promotes healthier digestion but also helps maintain a diverse gut microbiome, which has been linked to various health benefits, including improved immune function and reduced inflammation[9].

Emerging Tools and Practical Approaches

Emerging diagnostic tools, such as confocal laser endomicroscopy, have begun to shed light on gut-barrier abnormalities in conditions like functional dyspepsia and irritable bowel syndrome (IBS). This evolving understanding expands the knowledge required to mediate the barrier and provides a foundation for targeted therapeutic interventions, aiming to reinforce barrier integrity and prevent the progression of related diseases. Probiotics also remain a useful part of interventional care. Han et al., 2023 presented research demonstrating that a multi-species probiotic mixture can preserve the integrity of the epithelial barrier function by enhancing tight junctions and reducing inflammatory responses in human intestinal cells. They observed that this mixture prevents leaky gut conditions by increasing the occludin protein level and activating the AMPK signalling pathway[10]. When the AMP-activated protein kinase (AMPK) pathway is activated, it influences various cellular processes that can help improve gut health and repair intestinal barrier function.

Advice for Healthcare Professionals

Educating patients about the importance of a high-fibre diet, the benefits of fermented foods, and lifestyle adjustments that support gut health is crucial. Numerous interventions have demonstrated effectiveness in improving intestinal permeability. These include berberine, butyrate, caloric restriction and fasting, curcumin, dietary fibre (prebiotics), moderate exercise, fermented foods, fish oil, glutamine, quercetin, probiotics, vagus nerve stimulation, vitamin D, and zinc[11]. Treatment protocols should be customised to each patient based on their unique risk factors, diet, and lifestyle.

This short exploration of the gut barrier not only underscores its significance in maintaining health but also highlights the evolving strategies that healthcare professionals can adopt to manage and prevent diseases associated with its dysfunction.

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References

[1] Martel J, Chang SH, Ko YF, Hwang TL, Young JD, Ojcius DM. Gut barrier disruption and chronic disease. Trends Endocrinol Metab. 2022 Apr;33(4):247-265.

[2] Kinashi Y, Hase K. Partners in Leaky Gut Syndrome: Intestinal Dysbiosis and Autoimmunity. Front Immunol. 2021 Apr 22;12:673708.

[3] Camilleri M Leaky gut: mechanisms, measurement and clinical implications in humans Gut 2019;68:1516-1526.

[4] Aleman RS, Moncada M, Aryana KJ. Leaky Gut and the Ingredients That Help Treat It: A Review. Molecules. 2023 Jan 7;28(2):619.

[5] Bischoff S.C., Barbara G., Buurman W., Ockhuizen T., Schulzke J.D., Serino M., Tilg H., Watson A., Wells J.M. Intestinal permeability—A new target for disease prevention and therapy. BMC Gastroenterol. 2014;14:189.

[6] Ghosh S., Whitley C.S., Haribabu B., Jala V.R. Regulation of Intestinal Barrier Function by Microbial Metabolites. Cell Mol. Gastroenterol. Hepatol. 2021;11:1463–1482.

[7] Ma J., Piao X., Mahfuz S., Long S., Wang J. The interaction among gut microbes, the intestinal barrier and short chain fatty acids. Anim. Nutr. 2022;9:159–174.

[8] Jaquez-Durán G, Arellano-Ortiz AL. Western diet components that increase intestinal permeability with implications on health. Int J Vitam Nutr Res. 2023 Nov 27.

[9] Carter MM, Olm MR, Merrill BD, Dahan D, Tripathi S, Spencer SP, Yu FB, Jain S, Neff N, Jha AR, Sonnenburg ED, Sonnenburg JL. Ultra-deep sequencing of Hadza hunter-gatherers recovers vanishing gut microbes. Cell. 2023 Jul 6;186(14):3111-3124.e13

[10] Han H, You Y, Cha S, Kim T-R, Sohn M, Park J. Multi-Species Probiotic Strain Mixture Enhances Intestinal Barrier Function by Regulating Inflammation and Tight Junctions in Lipopolysaccharides Stimulated Caco-2 Cells. Microorganisms. 2023; 11(3):656.

[11] Martel J, Chang SH, Ko YF, Hwang TL, Young JD, Ojcius DM. Gut barrier disruption and chronic disease. Trends Endocrinol Metab. 2022 Apr;33(4):247-265.