April 2020 Issue
Eating to Heal a Leaky Gut
By Sarah Thomsen Ferreira, MS, MPH, RD, CDN, IFNCP, CHWC
Vol. 22, No. 4, P. 38
An Exploration of Nutritional Interventions to Maintain Healthy Intestinal Barrier Function
Research over the past 30 years has tied poor intestinal barrier function to digestive and autoimmune disorders. In parallel with increased interest in the microbiome as a modulator of health and disease, the role of intestinal (gut) barrier function in maintaining immune and digestive health has taken center stage.
With a focus on mechanisms by which poor intestinal barrier function could produce clinical and subclinical symptoms, this article reviews the potential role of dietary patterns, specific nutrients, and probiotic supplementation in the maintenance of gut barrier function.
Anatomy of Barrier Function
With a surface area of 200 m2, the intestinal tract acts as a semipermeable physical barrier, enabling absorption of nutrients and fluids while keeping pathogens and food proteins at bay.1 The intestinal wall is composed of columns of epithelial cells held together by highly branched, weblike structures called tight junctions. Tight junctions include the proteins claudin-2, occludin, and cingulin, which form channels for selective diffusion of nutrients and water. In a damaged epithelial cell wall, an unrestricted pathway can develop, enabling compounds, such as proteins and bacteria, of almost any size to pass through.2,3
Above the epithelial cell wall should lie another level of barrier protection: a thick two-part mucus layer comprising antimicrobial molecules (called mucin) secreted by goblet cells.1 When fully functional, the outer layer of this thick mucus coating contains immunoglobulins and other proteins that bind bacteria to prevent contact with the inner layer.
As goblet cells secrete additional mucin to renew both layers, bound bacteria in the outer layer are expelled through peristalsis. If either layer is depleted or defective, bacteria can reach epithelial cells and cause cellular inflammation.4 Humans with inflammatory bowel disease (IBD) have been found to have glycosylation defects and higher levels of sulfide from sulfate-reducing bacteria, which could lessen the disulfide bond between mucins, weakening the barrier function.5
Behind the epithelial cell wall lies a lymphoid-rich network containing up to 70% of the body’s immune cells, otherwise known as gut-associated lymphoid tissue.6 Epithelial cells, then, act as mediators between immune system activity and external exposures (including food antigens), tightly regulating the balance between tolerance and immunity.7
In summary, a fully functional gut barrier requires adequate mucus production, sufficient levels of immunoglobulins within mucus, and properly regulated tight junctions.
Measurement of Intestinal Barrier Function
In clinical research, various methods are used to measure the degree of intestinal permeability. Transepithelial/transendothelial electrical resistance (TEER) is used to measure tight junction dynamics. The lactulose-to-rhamnose (L:R) ratio (or dual-sugar permeability assay) is used widely to assess the degree to which large and small particles pass through the epithelial lining.8,9
Certain dietary sugars, including lactulose and L-rhamnose, pass through the epithelial lining and can be measured in urine. Since lactulose is a large molecule and rhamnose is a small molecule, their ratio and the amount of each measured in urine act as indicators of the degree of permeability. Another marker of permeability are the levels of intestinal fatty-acid binding proteins, which are found in the enterocytes and released into circulation when intestinal damage occurs.9,10
Zonulin, a protein produced in the gut whose circulating levels can be measured in blood, also has been used as an indirect biomarker of intestinal permeability. Release of serum zonulin, which can be triggered by dysbiosis or gliadin in genetically predisposed individuals, independently can weaken tight junction strength.11,12 Disease states under which zonulin has been implicated in humans include autoimmune conditions, such as celiac disease, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, experimental autoimmune encephalomyelitis, and ankylosing spondylitis; metabolic disorders such as obesity, insulin resistance, type 2 diabetes, and polycystic ovary syndrome; and intestinal diseases, including irritable bowel syndrome (IBS) and nonceliac gluten sensitivity.12,13
In a study of 100 patients with IBS—50% with IBS-C (IBS with constipation) and 50% with IBS-D (IBS with diarrhea)—serum zonulin levels were comparable to those found in active celiac disease, with increasing levels of zonulin correlated with increased weekly stool frequency.14
Mechanisms of Dysregulated Barrier Function
Compromised intestinal barrier function can induce or exacerbate dysfunction in both intestinal and extraintestinal diseases through the release of inflammatory molecules and subsequent gastrointestinal (GI) damage.
Disorders that have been associated with increased gut permeability include gastric ulcers, infectious diarrhea, IBS, IBD, celiac disease, food allergies, infections (eg, respiratory), acute inflammation (eg, sepsis, systemic inflammatory response syndrome), autoimmune diseases (eg, multiple sclerosis, systemic lupus erythematosus), and metabolic diseases (eg, nonalcoholic steatohepatitis, CVD).7,15-17
If breached intestinal barrier function enables microbes to interact with the lamina propria, contact can cause the release of excessive proinflammatory cytokines, including interferon gamma, tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 1 beta, and IL-13. As the abundant release of these cytokines causes increased intestinal tissue damage and scarring, a self-perpetuating cycle of poor barrier function, increased proinflammatory cytokines, and intestinal damage can result. For example, cytokine-driven GI damage has been documented in IBD.18
Clinical Relevance in Practice
Markers of elevated permeability have been measured repeatedly in context of GI disease. For example, in a group of 33 children with ulcerative colitis evaluated for rates of relapse over one year, the small intestinal permeability study was abnormal in 77.8% of those who relapsed compared with only 8.3% of those whose disease remained asymptomatic.19
Celiac disease has long been associated with abnormal tight junction structure and increased intestinal permeability. Interestingly, a pharmaceutical peptide and tight junction regulator called larazotide acetate currently is in phase 3 trials as an adjunct treatment for patients with celiac disease who have persistent symptoms on a gluten-free diet.20,21
Persistent GI symptoms triggered by a known or suspected infection also should prompt an assessment of intestinal permeability. In a study of 21 individuals with infectious gastroenteritis from Campylobacter jejuni, intestinal permeability—assessed with an elevated lactulose-to-mannitol excretion ratio—remained elevated for up to 12 weeks. In those whose symptoms persisted 12 months after the initial infection, acute increases in inflammatory cells, particularly T lymphocytes and macrophages, continued, potentially indicating persistent immune dysregulation.22
Dietary Patterns and Nutrients: Key Players in Barrier Function
The following select nutrients are vital for proper barrier function. Since various proinflammatory cytokines and mediators, including NF-kappa-B and lipopolysaccharide, can increase epithelial tight junction permeability, dietary interventions designed to attenuate or resolve a disproportionate inflammatory response also can help maintain healthy levels of permeability.
Dietary Fiber and the Role of Butyrate
Fermentable dietary fibers are preferred fuel for microbiota in the large intestine. In the absence of adequate fermentable carbohydrate sources, gut microbiota will break down mucus glycoproteins as a secondary fuel source, degrading the protective mucus barrier. A deteriorated colonic mucus layer, in turn, is a risk factor for colitis and pathogenic infection.23
In response to adequate amounts of select forms of fermentable fiber, certain bacteria in the microbiome (eg, Fecalibacterium prausnitzii, Roseburia intestinalis) can produce short-chain fatty acids, including butyrate.24 Butyrate maintains tight barrier function through an influence on tight junction proteins and has been shown to inhibit activation of the NLRP3 inflammasome induced by lipopolysaccharide.24,25
Arabarabinoxylan-rich whole grains and brans from wheat, rye, and oats have been shown to stimulate butyrate production, while cellulose, xylan, and pectin induce low levels of butyrate.26
In a study of 18 older adults with diarrhea or constipation, beta-glucan from oats significantly attenuated intestinal hyperpermeability in subjects with GI symptoms.24 Together, a high-fiber diet and sodium butyrate supplementation increased tight junctional proteins in an experimental model of autoimmune hepatitis.27
In a small group of 10 patients with Crohn’s disease, treatment with F prausnitzii and a mix of six butyrate-producing bacteria significantly increased butyrate synthesis and improved epithelial barrier integrity in vitro.28 Increased butyrate production via fiber-rich dietary patterns also may explain the positive impact of the Mediterranean diet on symptoms of rheumatoid arthritis, the autoimmune pathology of which may be exacerbated by increased intestinal permeability.29
Vitamin D deficiency is associated with barrier dysfunction, while sufficient levels of vitamin D can help restore function of the tight junction proteins zonula occludens-1 (ZO-1) and claudin-2.30 Adequate vitamin D status has been tied to lower disease activity and prolonged remission in Crohn’s disease, which could be due to lower circulating inflammatory markers and increased maintenance of excessive intestinal permeability.31
Vitamin A has been shown to enhance tight junction protein markers, including ZO-1, occludin, and claudin-1, and protect against lipopolysaccharide-induced intestinal epithelium permeability.32
Zinc deprivation may cause epithelial barrier disruption through the disassembling of tight junction proteins in caco-2 monolayer cells.33 Furthermore, even minor zinc deficiency may exaggerate the detrimental effect of alcohol on the epithelial barrier.34
In a study with eight healthy athletes, supplementation with zinc carnosine at 37.5 mg twice daily was associated with a 70% decrease in exercise-induced permeability values after 14 days of treatment.35
Curcumin, an anti-inflammatory, bioactive compound found in turmeric, may be especially relevant as a barrier modulator during acute infectious or exercise-induced barrier stress. Athletes exposed to heat-stress–induced GI barrier damage from working out in the heat received 500 mg per day of dietary curcumin supplementation for three days. Levels of intestinal fatty acid–binding protein were measured pre and post exercise.
In those not given curcumin, intestinal fatty acid–binding protein rose 87% pre to post exercise, while levels in the curcumin group increased only 58%.36 Curcumin treatment also has been shown to protect against C jejuni–triggered barrier deficits.37
Green Tea or EGCG
In a mouse model of IBD, treatment with EGCG (epigallocatechin gallate), a polyphenol found in plants, improved intestinal permeability while also suppressing proinflammatory cytokines, including IL-6, monocyte chemoattractant protein-1, and TNF-alpha.38
Omega-3 Polyunsaturated Fatty Acids
When intake of omega-3s is adequate and in proportion to consumption of omega-6s, omega-3s generate specialized proinflammatory mediators known as resolvins, protectins, and maresins. When acute inflammation occurs in response to injury, it’s now known that active resolution and cleanup of cellular debris must occur to prevent chronic inflammation. Specialized proinflammatory mediators are central to resolving acute inflammation, including attenuating mucosal cytokine responses.39 Specialized proinflammatory mediators also may dampen endotoxin (eg, lipopolysaccharide) signaling.40
Glutamine is a conditionally essential amino acid that potentially can be depleted under conditions of metabolic stress, such as exhaustive exercise, trauma, sepsis, and IBD.41-43
In one in vitro model of experimental hyperpermeability, glutamine application reduced hyperpermeability by 19% and 39% in the respective cell lines.44 In another study, after active males completed a 60-minute run, there was a large increase in the L:R ratio in all trials compared with measurements while they were at rest before the run. When glutamine was consumed at 0.9 g/kg of body weight preexercise under the same conditions, a moderate decrease was observed in the postexercise L:R ratio.45 A decrease in the L:R ratio also was seen in Crohn’s disease patients with abnormal permeability values who were given 0.5 g/kg of ideal body weight of oral glutamine for two months.46
High-fat diets have been shown repeatedly to be risk factors for intestinal permeability, partially because they influence the development of a proinflammatory gut microbiota. However, this often-cited connection likely is associated with types of fat and mitigating dietary factors.
Meals high in saturated fat could provoke lipopolysaccharide release47; however, in one study, after 20 individuals followed a Mediterranean diet (40% fat with emphasis on monounsaturated fats and <10% saturated fat) for 16 weeks, no increase in intestinal permeability was observed.48
Polyphenols may play a role in protecting against higher-fat diets. In an animal model, researchers fed mice a high-fat (lard) diet for 15 weeks. The diet caused insulin resistance and was associated with increased intestinal permeability, decreased expression of ileal tight junction proteins, and endotoxemia. However, supplementation with dietary (-)-epicatechin at a dose of 2 to 20 mg/kg of body weight mitigated all of these adverse effects.49
Other compounds or polyphenols worth consideration are quercetin, myricetin, and kaempferol, which have been shown to participate in intestinal barrier regulation by promoting a higher expression of tight junction proteins, including claudin-1.29
Glucose and fructose are transported against the gut epithelium via facilitated diffusion, where these sugars are absorbed through membranes, using SGLT1 and GLUT2 transporters. In order for increased levels of facilitated diffusion to occur, the shape of tight junctions can change to accommodate increased passage of absorbed sugars. These changes may contribute to decreased intestinal defenses.
Pereira and colleagues studied the impact of sugar absorption in an in vitro human coculture model, in which certain epithelial cells were studied outside of the human body. When cells were exposed to high concentrations of sugar, decreased levels of the mucosal defense factor (intestinal alkaline phosphatase) were seen in exposed cells.50 In a mouse model, hyperglycemia lead to intestinal barrier dysfunction, but only in mice who had the GLUT2 transporter.51
Dose-dependent alcohol intake can influence gut lining health in a couple of ways: by depleting occludin levels in the colon and through a dysbiotic microbiota induced by alcohol, which correlates with a high level of endotoxin.52
In a time-course study in rats, researchers found that increased gut permeability, intestinal oxidative injury, and endotoxemia occurred two weeks into daily alcohol consumption.53 Just one week of moderate consumption of red wine among 21 individuals with inactive IBD was associated with a significant decrease in stool calprotectin and a significant increase in intestinal permeability.54
Gliadin, a class of proteins found in wheat, barley, and rye, can trigger the release of zonulin by binding to the CXCR3 receptor, which is overexpressed on the apical surface of enterocytes in patients with celiac disease.12 Zonulin release also has been observed in nonceliac gluten sensitivity.55
Using TEER, Hollon and colleagues analyzed intestinal permeability of duodenal biopsy explants in celiac disease (both active and in remission). They also analyzed permeability in nonceliac gluten sensitivity and nonceliac controls. After exposure to gliadin, an increase in permeability was present in all groups, with the greatest increase in those with active celiac disease and nonceliac gluten sensitivity.56,57
Can Probiotics Help?
Just as some nutrients and dietary patterns can promote proper barrier wall function, so too can select probiotic species by decreasing inflammatory mediators or enhancing the protective mucus layer.
In a randomized, double-blinded, placebo-controlled trial in obese humans, sucralose excretion was reduced with both Bifidobacterium lactis BB-12 and prebiotic supplementation with galactooligosaccharides, indicating improvements in colonic permeability.58 Among 11 physically active men receiving multispecies probiotics (Ecologic Performance or OMNi-BiOTiC POWER) for 14 weeks, zonulin levels after intense cycling decreased.59 However, in another study using Ecologic Barrier, which contains eight different probiotic strains, researchers observed no difference in gut permeability.60
A recent review by Wan and colleagues discussed the following supplemental bacterial species as potentially supportive to barrier function: Lactobacillus plantarum, Lactobacillus casei, Lactobacillus brevis, Bifidobacterium infantis, Lactobacillus rhamnosus GG, and Lactobacillus plantarum MB452.61 In a group of 30 patients with IBS-D given fermented milk (Streptococcus thermophilus, Lactobacillus bulgaricus, Lactobacillus acidophilus, and Bifidobacterium longum) for four weeks, small bowl permeability, but not colonic permeability, decreased significantly from baseline.62
As with any other concern or condition, probiotic strains should be chosen for their specific benefits, as not all probiotic strains will be efficacious for improving barrier function.
Dietitians who counsel clients and patients who may have a variety of digestive disorders associated with poor intestinal gut barrier function can help them integrate dietary and lifestyle factors that can support a healthy microbiome. Recommend clients do the following:
• Consider a Mediterranean-style, polyphenol-rich, gluten-free diet.
• Minimize alcohol intake.
• Ensure frequent intake of varied fermentable carbohydrate sources.
• Assess for butyrate-producing bacteria; consider supplemental butyrate as appropriate.
• Measure EPA and DHA status; consider supplementation with fish oil or specialized proinflammatory mediators.
• Measure and correct vitamin D status.
• Ensure adequate intake of retinol or beta-carotene; if relying heavily on beta-carotene, consider assessing genetic capacity to convert beta-carotene to retinol.
• Consider supplementation with zinc carnosine and/or glutamine.
• Consider using turmeric in foods, beverages, and snacks, or supplementing with curcuminoids in phospholipid delivery systems for enhanced bioavailability.
— Sarah Thomsen Ferreira, MS, MPH, RD, CDN, IFNCP, CHWC, is manager of clinical nutrition at the Cleveland Clinic Center for Functional Medicine in Ohio. She also hosts the Nourished Brain podcast, which features conversations about food, mood, brain health, nutritional psychology, and the art of intentional eating. More information is available at sarahferreirard.com.
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