Diet,Digestive Health,and Autoimmunity: The Foundations to an Autoimmune Disease Food Pyramid—Part 1

Introduction

Autoimmune disease has been rapidly increasing worldwide over the past 50 years. ^1,2 Autoimmune diseases are a range of diseases in which the immune response to self-antigens results in damage or dysfunction of tissues. It can be described as a failure of the body to tolerate its own cells or tissue. There is a disruption of immune tolerance of self-antigens. Autoimmune diseases can be systemic in nature or can affect specific organs or specific body systems, for example, the gastrointestinal system. ³ There are ∼80–100 known autoimmune diseases. ⁴ The prevalence of autoimmune disease in the United States is estimated to affect 50 million people, ⁴ in comparison with heart disease at 22 million ⁴ and cancer at 14.5 million people. ⁵ The global prevalence of autoimmune disease is estimated to be in the range of 7.6%–9.4% ⁶ and is more common in females. ³ Autoimmune disease is a leading cause of mortality and is the third leading cause of morbidity in Western countries among women. ⁷

Common autoimmune diseases include rheumatoid arthritis (RA) and multiple sclerosis (MS), all of which have debilitating effects on sufferers and their families. RA is characterized by chronic inflammation and destruction of synovial joints, affecting up to 1% of the Western population. ⁸ MS is an incapacitating disease that involves autoimmune-mediated scarring in the central nervous system causing inflammation and progressive muscle weakness with fatigue. ⁹ The worldwide prevalence of MS has increased from 2.1 million in 2008 to 2.3 million in 2013. ¹⁰ Other autoimmune-like conditions include Crohn's disease, which has been suggested to be an autoinflammatory disease. ¹¹ Nevertheless, Crohn's disease results in chronic relapsing intestinal inflammation with life threatening complications ¹² that has an increasing incidence worldwide. ¹³

A common link between these diseases is chronic inflammation. Susceptibility to these autoimmune diseases includes generally unmodifiable risk factors such as genetics, sex, age, and previous infections. However, some risk factors are modifiable. Reducing these modifiable risk factors may not only decrease the susceptibility to an autoimmune disease, but may also reduce the risk of co-occurrence of another autoimmune disease. Once an initial autoimmune disease develops in an individual, there is an increased probability that additional autoimmune diseases will occur. ⁶

Autoimmunity affects various susceptible individuals and involves the loss of normal immune homeostasis, resulting in an abnormal and inappropriate response to the body's own cells and tissue. The hallmark feature of autoimmune disease generally involves the presence of self-reactive T cells, autoantibodies, ¹⁴ inflammation, and cellular damage. ¹⁵ CD4+ T helper (Th) lymphocytes type Th1, Th2, Th17, and Th22 play a role in the pathogenesis of autoimmune disease; however, the etiology of autoimmune disease is not fully understood. ¹⁶ Furthermore, the development of autoimmune disease is suggested to be a combination of genetic (30%) and environmental factors (70%). ¹⁷ Examples of environmental factors include diet, ¹⁸ hormones, ¹⁹ infection/s, ^20,21 toxins, ²² and medications ²² (such as antibiotics). ^{23 –25}

Autoimmune disease has a strong association with the health of the digestive system (Table 1). Digestive health is underpinned by an interplay of factors such as gastric secretions, ²⁶ pH, ²⁷ intestinal barrier integrity, ²⁸ microbiota, ²⁹ inflammatory cytokines, ³⁰ and metabolites (e.g., short-chain fatty acids [SCFAs]). ³¹ The health of the digestive system can be affected by the sympathetic nervous system, ³² diet, ³³ medications including antibiotics, ³⁴ sedentary lifestyle, and strenuous exercise. ^35,36 Moderate exercise, however, can have beneficial effects on the digestive system. ³⁷ Within the gastrointestinal tract, gut-associated lymphoid tissue (the immune system of the gut) and various receptors, including toll-like receptors (TLRs), influence the immune system, immune tolerance, ³⁸ and both intestinal and systemic inflammation. ³⁹ Diet interacts with these immune regulating mechanisms, indirectly influencing gene transcription and autoimmune disease development and progression. ^{39 –41} The classic Western diet is composed of increased animal protein, refined sugar, salt, and long-chain saturated fats derived from animals. ⁴² Epidemiologic data show that Western countries have a greater prevalence of autoimmune disease, such as celiac disease, inflammatory bowel disease, RA, and MS, when compared with developing countries (Asia, Middle East, and South America). ⁶ These data suggest the possible involvement of certain components of the Western diet in the contribution to the development and progression of autoimmune disease.

The aim of Part 1 of this article is to lay the foundations and core concepts surrounding the link between diet, digestive health, and autoimmune disease. In particular, dysbiosis, inflammation, and increased intestinal permeability are explained in relation to their effect on autoimmune disease.

Dysbiosis: A Contributing Factor of Autoimmune Disease

The human body contains ∼37.2 trillion somatic cells. ⁶⁰ The human intestinal system, in addition to its functional role, is inhabited by ∼40 trillion bacteria, belonging to >500 different species. ^61,62 Furthermore, the microbiota contains 150-fold more genetic material than human genes. ⁶³ A lower genetic material (decreased gene richness in the gut) is associated with a number of health implications including low-grade systemic inflammation and obesity. ⁶⁴ The microbiota plays a protective and therapeutic role in the human body, by modulating metabolic, neurologic, hormonal, and immune pathways. ⁶⁵ The diversity of microbiota forms a symbiotic ecosystem that can determine and modulate the immune system and influence health and disease. ⁶⁶

Dysbiosis is a term used to describe any change to the composition of the intestinal microbiota relative to healthy individuals. ² Dysbiosis falls into three main categories: (1) loss of beneficial microbial organisms, (2) expansion of potentially harmful microbial organisms, and (3) reduced biodiversity. ² The microbiota diversity includes both quantity and balance of bacteria, and changes in either quantity or balance may contribute to the progression of inflammatory diseases. ⁶⁷ Dysbiosis can alter SCFA production, ³⁰ intestinal permeability, ^35,68 tolerance to self, ⁶⁹ and inflammatory gene transcription. ^39,70 Disruption to the microbiota has been associated with long-term health complications, including obesity, ⁷¹ type 1 diabetes, ⁵⁶ irritable bowel syndrome, ⁷² Crohn's disease, ⁴⁶ and MS. ⁵¹

The microbiota can be influenced by diet, ^69,73 herbicide use (glyphosate), ⁷⁴ long-chain saturated fats, ⁷⁰ ω-6 polyunsaturated fatty acids, ^75,76 inflammation, ⁷⁷ antibiotics, ²³ sex hormones (particularly testosterone), ⁷⁸ age, ³⁰ location (community living versus retirement living), ⁷³ and strenuous exercise. ³⁵ The complexity of the influence of the microbiota on the development and progression of autoimmune disease is still not clearly understood. However, supporting the microbiota with fiber, ⁷⁹ fermented foods (kefir, yogurt, kimchi, and fermented soy milk), ^{80 –82} and probiotics ^35,83 have all been shown to positively influence autoimmune disease management.

Dysbiosis may influence the T effector/T regulatory (Treg) cell balance, Th1/Th2 and Th17 cell proliferation, and molecular mimicry. In addition, dysbiosis plays a critical role in innate and adaptive immune development. ^{2,51,66,69,70,84 –89} As a result, dysbiosis plays a causative and consequential role in autoimmune disease development and progression. ⁶⁵ Therefore, correcting dysbiosis may serve as a management strategy for autoimmune disease. Furthermore, it has been suggested that the immune system and the interaction with the microbiota are a critical target in overcoming diseases in the 21st century. ⁹⁰

Inflammation and Autoimmune Disease

Autoimmune disease is characterized by elevated inflammatory cytokine activity that can consequently exacerbate autoimmune disease progression. Intestinal inflammation may impair the balance of commensal and pathogenic bacteria, resulting in dysbiosis. ^91,92 Recent research has illustrated that reducing inflammation in the intestinal system may have a beneficial effect on reducing dysbiosis and normalizing the microbiota. ⁷⁷ There are a number of dietary metabolites capable of reducing intestinal inflammation including SCFAs ⁹³ and ω-3 fatty acids. ⁹⁴ SCFAs, such as acetic, propionic, and butyric acid, are the major metabolites bacteria produce from fermentation of indigestible polysaccharides. ⁶⁷ Consequently, these SCFAs can positively modulate intestinal and systemic inflammation by inhibiting activation of nuclear factor-κ B (NF-κB) and regulating tumor necrosis factor (TNF)-α, interleukin-2 (IL-2), IL-6, and IL-10. ⁹³ NF-κB, TNF-α, and IL-6 facilitate inflammation through a number of mechanisms. Systemic inflammatory cytokines, namely IL-6 and IL-8, may also alter the gut microbiota profile to a dysbiotic state; this includes the reduction of butyrate producing bacteria. ³⁰ Therefore, intestinal and systemic inflammation can affect the microbiota's ability to modulate inflammation through butyrate's effect on NF-κB, resulting in further inflammation and dysbiosis.

TLRs are a group of receptor proteins located within cell membranes. TLRs are found particularly on macrophages and dendritic cells and act like sensors, forming a bridge between innate immunity and autoimmune disease. ³⁹ TLRs mediate the activation of the innate immune system, as a defense mechanism against pathogens and immune disorders, through recognition of surface proteins unique to microorganisms. ⁴¹ TLRs recognize invading organisms by specific ligands, such as lipopolysaccharide (LPS), and modulate gene transcription as a defense mechanism. ³⁹ TLRs mediate the activation of NF-κB gene transcription that can consequently activate proinflammatory cytokines, including TNF-α and IL-6. Furthermore, dysregulation of NF-κB activation promotes autoimmunity by mediating the stimulation and differentiation of T cells, such as Th17. ⁴⁰ Depending on environmental factors, a healthy immune system has CD4+ T cells that differentiate into distinct lineages, including Th1, Th2, Th3, Th9, Th17, and Th22 cells. ⁹⁵ Treg cells are an important member of the T cell family that is essential in controlling the autoimmunity, inflammation, allergic, and infection response. ⁹⁶ Treg cells regulate the function of other T lymphocytes and prevent excessive immune activation. ⁹⁷ An increase in Th17 cells can promote production of proinflammatory cytokines IL-17, IL-22, and TNF-α. Th17 cells and IL-17 are considered major drivers of autoimmune disease and autoantibody production. ^66,95,98 Therefore, dietary components that support Treg cells and regulate Th17 may be considered potentially beneficial in autoimmune disease management. Butyrate, the by-product of dietary fiber fermentation, can positively impact the immune system by influencing the function and number of Treg cells and indirectly Th17 cell regulation.

Both intestinal and systemic inflammation have a direct effect on immune dysfunction and the microbiota. Activation of intestinal inflammation through dietary compounds such as long-chain saturated fats and dysbiosis can directly establish low-grade systemic inflammation and exacerbate autoimmune disease through a number of mechanisms including increasing intestinal permeability. ⁷⁰

Intestinal Permeability: Causative Factor of Autoimmune Disease

There is only a single layer of epithelium cells in the small intestine, of which enterocytes are a major component that contribute to the barrier of the small intestine. Between the enterocytes are tight junctions, formed by an array of proteins that are highly regulated. The dysregulation of the tight junctions and loss of integrity between the cells of the small intestine lead to increased intestinal permeability, also known as “leaky gut.” This further leads to the loss of intestinal homeostasis, functional impairments, and disease, and has been suggested to contribute to the pathogenesis and exacerbation of many chronic diseases, such as autoimmune diseases. ⁹⁹ Increased intestinal permeability may cause low-grade endotoxemia, as LPS from the intestine is able to translocate into the blood stream, causing an immune reaction and inflammation. ¹⁰⁰

A number of theories have speculated how increased intestinal permeability results in autoimmune disease. One of these theories is molecular mimicry, which involves foreign antigens that share a similar structural sequence as self-tissue, inducing the production of autoantibodies against self-tissue. Certain foreign antigens are capable of inducing autoantibodies, including dietary proteins and microorganisms; however, this depends on the degree of increased intestinal permeability. ¹⁰¹ Consequently, genetically susceptible individuals are unable to sufficiently suppress production of these autoantibodies, resulting in damage of target cell or tissue. ^102,103 The pathogenesis of a number of autoimmune diseases, for example, MS, Grave's disease, RA, and type 1 diabetes, can be attributed to molecular mimicry of tissue targets that mimic particular viral and bacterial antigens. ^101,104 In addition, a number of dietary proteins are thought to trigger a variety of other autoimmune diseases through molecular mimicry. These may include the protein components found in gluten, cow's milk, soybean, corn, tomato, and spinach. ¹⁰⁵ However, if the intestinal permeability is stable, these proteins pose little harm, as they are confined in the lumen and are unable to cross and interact with the immune system.

A prominent mechanism in which intestinal permeability can be increased is through the activation or upregulation of the zonulin pathway. ⁴³ Zonulin is released from enterocytes to regulate the permeability of the tight junctions. ⁴³ Gliadin, a protein found in gluten, has the ability to increase intestinal permeability through upregulation of the zonulin pathway. Consequently, gliadin can stimulate enterocytes to release zonulin upon contact. ¹⁰⁶ In addition, a number of pathogenic and nonpathogenic bacteria found within a dysbiotic state are able to alter the tight junctions through the activation of the zonulin pathway. ^68,99 In contrast, a randomized double-blinded placebo-controlled trial demonstrated a reduction of fecal zonulin levels with the use of a multistrain probiotic. ³⁵

Dysbiosis can also alter intestinal integrity by reducing butyrate-producing bacteria. ³⁰ Butyrate strengthens intestinal integrity by promoting the assembly of tight junctions within the intestinal tract. ¹⁰⁷ There are also a number of dietary components known to increase intestinal permeability, such as long-chain saturated fats, ¹⁰⁸ sugar, ¹⁰⁹ energy intake, ¹¹⁰ animal-derived protein intake, ¹¹¹ and alcohol. ¹¹² External factors, such as strenuous exercise, can increase core temperature leading to disruption of tight junctions and increased intestinal permeability. ³⁶ Inflammatory cytokines, such as TNF-α, have the ability to increase intestinal permeability. ¹¹³ Transforming growth factor β, a protein secreted from a number of cells, can enhance and protect epithelial barrier function by promoting tight junction assembly. ^114,115

Increased intestinal permeability has been observed to precede the clinical onset of autoimmune disease. ¹¹⁶ Therefore, it can be suggested that increased intestinal permeability can be an underlying factor in the pathogenesis of autoimmunity. ¹¹⁶ This fundamental aspect of autoimmune disease requires particular attention. Reducing intestinal permeability, and, therefore, entry of foreign antigens, may prevent the interaction with the immune system that leads to the production of autoantibodies and autoimmune disease.

Although a number of risk factors (genetics, sex, and age) are unmodifiable, there are a number of modifiable risk factors associated with autoimmune disease. These include dysbiosis, intestinal and systemic inflammation, increased intestinal permeability, and exposure to dietary or microorganism-derived antigens. Diet and dietary components play a major role in the management of chronic disease ¹¹⁷ and are known to have modulatory effects on the known modifiable risk factors, and, therefore, can influence the development and progression of autoimmune disease in genetically susceptible individuals through a number of interconnected mechanisms. Having a greater understanding of the causes and effects of intestinal permeability and autoimmune disease can pave the way to an Autoimmune Disease Food Pyramid.

Conclusion

Autoimmune disease is a complex disorder and the global prevalence is increasing. Environmental factors contribute to 70% of autoimmune disease development, of which diet accounts for a large proportion. Dysbiosis, intestinal permeability, and inflammation are key digestive health issues that are involved in the development and exacerbation of autoimmune diseases. In Part 2 of this article, a review of the complexity that diet and digestive health have on autoimmune disease is explored and dietary strategies for the prevention and management of autoimmune disease are discussed. In particular, diets including the Mediterranean diet, vegetarian/vegan diet, Paleolithic (paleo) diet, gluten-free diet, and a low arachidonic acid diet are reviewed for their effectiveness in supporting digestive health and autoimmune disease. Finally, the concept of an “Autoimmune Disease Food Pyramid” is introduced.