Understanding the gut’s role in disease: Why this is one of the most exciting times in medicine
The Centre for Gastrointestinal Health comprises of a number of Australia’s leading Gastroenterologists. Here, the team explain why a clear understanding of the gut as well as diet and lifestyle plays such as critical role in preventing disease.
The internet is awash with anecdotes of the dilemma that is commonly referred to as “leaky gut”. With the proposed solutions to this problem ranging from simple dietary manipulations and supplementation to strict elimination protocols, this has largely been the territory of alternative or complementary health professionals. However, given the sheer wealth of scientific literature that is currently available on the role of the gut in health and disease, it is imperative that all medical professionals consider the possibility of “leaky gut” in their patient assessments.
Intestinal Permeability (a.k.a “Leaky Gut”)
The mammalian and in particular the human gastrointestinal tract is a marvel of evolution. We have developed a very complicated and highly specialized gastrointestinal system maintained by the mucosal barrier (1). The gut is a “gateway” to innumerable bacteria toxins (both pathogenic & commensal) and environmental antigens. Thus, a specialised system is needed to block the variety of these antigens whilst still maintain the ability to absorb digested nutrients –the primary function of the small intestine. Astoundingly, in the intestine, the first line of defence is maintained by only a single layer of epithelial cells that are linked together by tight junction (TJ) proteins. The other factors that make up this barrier including mucins, antimicrobial molecules, immunoglobulins, and cytokines. If any abnormalities occur among these factors, the intestinal permeability may increase. Increased intestinal permeability allows the entry of exterior antigens/toxins from the gut lumen into the host, which may promote both local and systemic immune responses. Multiple diseases may arise or be exacerbated by this phenomenon, including autoimmune diseases such as Inflammatory Bowel Disease (IBD), Celiac disease, Autoimmune Hepatitis (AIH), Type 1 Diabetes (T1D), Multiple Sclerosis (MS), and Systemic Lupus Erythematosus (SLE) (2-6).
There is an efficient multifaceted intestinal barrier system with physical, biochemical, and immunological components that prevents the entry of most pathogens or toxins. These components coordinate with each other to prevent uncontrolled translocation (leak) of microscopic luminal contents into the body. Below is a diagram demonstrating of the main components comprising the intestinal barrier.
A large variety of gut barrier disruptors and/or gut microbiota disturbers may potentially result in microbial translocation and subsequent inflammation locally and systemically. These include diet, infections, alcohol consumption, and burn injury (7). Of interest is the role nutrients and food ingredients that contribute to the maintenance or alterations of gut microbiota and the intestinal barrier function. Considering the contributions of leaky gut and bacterial translocation to inflammation and multiple diseases, reversing gut leakiness appears to be an attractive therapeutic strategy. At the Centre for Gastrointestinal Health we prioritise the role that diet and nutrition may play on an individual’s illness. Early dietary intervention in those patients keen to use this this modality in conjunction with standard medical therapy in done in our centre. Pragmatically, minimising or reversing the leaky gut may act to attenuate disease and thus may serve to benefit the patient. These sorts of interventions maybe a cost-neutral treatment option for people with autoimmune diseases in the foreseeable future.
Evidence-Based Dietary Strategies
These is early evidence for dietary approaches aimed at reducing intestinal permeability to help complement medical therapy in combating autoimmune illness.
The structured removal of “trigger” foods is a common and viable approach. In 2017, Konijeti and colleagues published the results of a clinical trial investigating the efficacy of an autoimmune diet protocol for inflammatory bowel disease (8). Fifteen patients underwent an 11-week diet intervention which involved a 6-week step-down elimination of grains, legumes, nightshades, dairy, eggs, coffee, alcohol, nuts and seeds, refined/ processed sugars, oils, and food additives. This was followed by a 5-week maintenance phase where no further foods were eliminated and none were introduced. Additionally, some patients received targeted nutrient repletion of essential vitamins and minerals using supplementation, if it was indicated. From week 0 to weeks 6 and 11, mean partial Mayo score significantly improved from 5.8 (SD 1.2) to 1.2 (SD 2.0) and 1.0 (SD 2.0) for ulcerative colitis, and mean Harvey–Bradshaw index significantly improved from 7 (SD 1.5) to 3.6 (SD 2.1) and 3.4 (SD 2.6) for Crohn’s disease (8). Mean fecal calprotectin improved from 471 (SD 562) to 112 (SD 104) at week 11 (P ¼ 0.12) (8). Among those with follow-up endoscopy at week 11 (n ¼ 7), improvements were noted in simple endoscopic score for Crohn’s disease (n ¼ 1), Rutgeerts score (n ¼ 1), and Mayo endoscopy subscore (n ¼ 4) (8).
In addition, there is some evidence that suggests the type of dairy consumed is important in relation to its potential inflammatory effects on the gastrointestinal system. A 2017 systematic review reported that A1-type bovine B-casein (A1) consumption is associated with delayed intestinal transit and looser stool consistency compared to A2-type bovine B-casein (A2) (9). Furthermore, digestive discomfort was correlated with inflammatory markers in humans for A1 protein, but not A2 (9).
The role of diet in gut function, autoimmunity and inflammation goes far beyond the identification and removal of individual “trigger foods”. Individual nutrients themselves have essential roles in maintaining healthy gut barrier function, and targeted repletion of vitamin and mineral deficiencies should always be considered. A prime example is vitamin D, an essential fat-soluble vitamin commonly known for its role in bone and heart function. However, vitamin D is also responsible for the barrier function of the intestinal epithelium and for the modulation of the bowel immune system (10-13). In particular, vitamin D receptor signalling controls mucosal inflammation by suppressing epithelial cell apoptosis (11). Ultimately, low levels of vitamin D is likely a major contributing factor to gut permeability and low-grade inflammation.
Finally, there is evidence for the anti-inflammatory benefits of dietary patterns involving carbohydrate restriction (all starches and sugars). This approach may be particularly useful for patients with metabolic dysregulation, such as hyperinsulinemia or hyperglycaemia, where the positive effects of low-carbohydrate diets are established (14). Jonasson et al. 2014 compared the effects of diet on inflammation in type 2 diabetes by comparing a traditional low-fat diet (LFD) with a low-carbohydrate diet (LCD) containing 20% energy from carbohydrate (15). After 6 months, the levels of IL-1Ra and IL-6 were significantly lower in the LCD group than in the LFD group, 978 (664–1385) versus 1216 (974–1822) pg/mL and 2.15 (1.65–4.27) versus 3.39 (2.25–4.79) pg/mL, both P < 0.05 (15). The authors concluded that only the LCD was found significantly to improve the subclinical inflammatory state in type 2 diabetes (15).
There is certainly need for more high-quality randomised clinical trials investigating various diet, lifestyle and medical interventions targeting improved intestinal permeability for the prevention and management of chronic disease. However, with consideration of the current available data, this is an exciting time in medicine where we have the opportunity to increase our understanding of the role that our gut integrity and microbiome plays in causing disease or even indeed how its restoration may coincide with improvement in disease.
The experienced team at the Centre for Gastrointestinal Health hosts a list of impressive qualifications and accolades, so you can be assured you are in the very best of care. For more information about our specialists visit: www.centreforgastrointestinalhealth.com.au
Dr Pran Yoganathan
Gastroenterology & Hepatology
MBChB. (Otago), FRACP
Dr Pran Yoganathan is the Director of The Centre for Gastrointestinal Health. He is an accomplished and highly experienced endoscopist with expertise in quality colonoscopy. Read more >>>
Dietitian, Founder of Ellipse Health
Jessica Turton Founder of Ellipse Health, Dietitian & Nutritionist Masters Nutrition & Dietetics Bachelor of Applied Science (Exercise and Sports Science) Jessica is an Accredited Practising Dietitian (APD) with postgraduate qualifications in Nutrition & Dietetics and full membership with the Dietitians Association of Australia. Visit: www.ellipsehealth.com.au
Dr Ramesh Paramsothy
Gastroenterology & Hepatology
BSc (Med Hons 1)
MBBS, MMed (Clin Epi), FRACP
Dr Ramesh Paramsothy is an enthusiastic consultant gastroenterologist, with an interest in inflammatory bowel disease and hepatology. Read more >>>
Dr Praka Sundaralingam
MBBS, MMed (Clin Epi), FRACP
Dr Praka Sundaralingam is a consultant gastroenterologist and Interventional Endoscopist. He is experienced in the endoscopic diagnosis and management of diseases of the gastrointestinal tract. Dr Sundaralingam has a special interest in pancreatic and biliary disease including therapeutic EUS and ERCP, as well as endoscopy.
- Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol (2014) 14(3):141–53.10.1038/nri3608
- 2. Lin R, Zhou L, Zhang J, Wang B. Abnormal intestinal permeability and microbiota in patients with autoimmune hepatitis. Int J Clin Exp Pathol (2015) 8(5):5153–60.
- 3. Khaleghi S, Ju JM, Lamba A, Murray JA. The potential utility of tight junction regulation in celiac disease: focus on larazotide acetate. Therap Adv Gastroenterol (2016) 9(1):37–49.10.1177/1756283X15616576
- 4. Fasano A, Shea-Donohue T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol (2005) 2(9):416–22.10.1038/ncpgasthep0259
- 5. Tlaskalova-Hogenova H, Stepankova R, Kozakova H, Hudcovic T, Vannucci L, Tuckova L, et al. The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases. Cell Mol Immunol (2011) 8(2):110–20.10.1038/cmi.2010.67
- 6. Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci (2012) 1258:25–33.10.1111/j.1749-6632.2012.06538.x
- Mu Q, Kirby J, Reilly CM, Luo XM. Leaky Gut As a Danger Signal for Autoimmune Diseases. Front Immunol. 2017;8:598. Published 2017 May 23. doi:10.3389/fimmu.2017.00598
- Konijeti GG, Kim N, Lewis JD, Groven S, Chandrasekaran A, Grandhe S, et al. Efficacy of the Autoimmune Protocol Diet for Inflammatory Bowel Disease. Inflamm Bowel Dis. 2017;23:2054-60.
- Brooke-Taylor S, Dwyer K, Woodford K, Kost N. Systematic Review of the Gastrointestinal Effects of A1 Compared with A2 beta-Casein. Advances in nutrition (Bethesda, Md). 2017;8:739-48.
- Du J, Chen Y, Shi Y, Liu T, Cao Y, Tang Y, et al. 1,25-Dihydroxyvitamin D Protects Intestinal Epithelial Barrier by Regulating the Myosin Light Chain Kinase Signaling Pathway. Inflamm Bowel Dis. 2015;21:2495-506.
- He L, Liu T, Shi Y, Tian F, Hu H, Deb DK, et al. Gut Epithelial Vitamin D Receptor Regulates Microbiota-Dependent Mucosal Inflammation by Suppressing Intestinal Epithelial Cell Apoptosis. Endocrinology. 2018;159:967-79.
- Flanagan PK, Chiewchengchol D, Wright HL, Edwards SW, Alswied A, Satsangi J, et al. Killing of Escherichia coli by Crohn’s Disease Monocyte-derived Macrophages and Its Enhancement by Hydroxychloroquine and Vitamin D. Inflamm Bowel Dis. 2015;21:1499-510.
- Sassi F, Tamone C, D’Amelio P. Vitamin D: Nutrient, Hormone, and Immunomodulator. Nutrients. 2018;10:1656.
- Turton J, Brinkworth GD, Field R, Parker H, Rooney K. An evidence-based approach to developing low-carbohydrate diets for type 2 diabetes management: A systematic review of interventions and methods. Diabetes, Obesity and Metabolism. 2019;21:2513-25.
- Jonasson L, Guldbrand H, Lundberg AK, Nystrom FH. Advice to follow a low-carbohydrate diet has a favourable impact on low-grade inflammation in type 2 diabetes compared with advice to follow a low-fat diet. Ann Med. 2014;46(3):182–187. doi:10.3109/07853890.2014.894286