Western medicine appears to be approaching a ‘revolution’ in terms of understanding how the gut functions in health and disease. The rapidly expanding pool of detailed research, mainly in vitro, points to the close association between disorders of gut structure and function and the development of a wide range of acute and chronic diseases. Thus, we now know that, in addition to inflection and trauma, inflammation may be triggered by failure of an essential aspect of gut function, i.e. by breaches of the gut barrier. Traditional Chinese medicine also went through a similar revolution in the Jin-Yuan era, thanks to the work of Li Dong-yuan (a.k.a. Li Gao), who through clinical observation, discovered that in many patients with febrile disorders, the underlying cause was Spleen Qi deficiency, and not invasion by exogenous pathogens. This paper explores the parallels between these two approaches, separated by almost a millennium in time, whose conclusions were reached from opposite ends of the research spectrum (i.e. in vitro vs clinical studies). In addition, several key TCM herbal formulas are discussed from the perspective of gut healing.
New light on gut structure and function
Since the 1980’s there has been a dramatic increase in published research on the gut, relating to intestinal barrier and intestinal permeability, and although the precise mechanisms are at present not fully understood, the link between disruption of the intestinal barrier and diseases has been established. (1) Thus, while empirical research points to various factors such as changes in the gut microbiota, certain nutrients (e.g. gluten), alcohol consumption, viral infections, impairment of local blood supply, etc., that might be the cause of intestinal barrier dysfunction, none of these are established scientific facts. Nor is the role of intestinal barrier function as the cause, effect or contributing factor in the development of various diseases adequately understood. (1, 2, 9) This is important to bear in mind, as most of what is known derives from in vitro research models (i.e. using membranes cultured from intestinal cells), or experiments on rats, mice and zebra fish. (3, 4, 5) Therefore, we should always be a little wary of popular publications which give an oversimplified and overly certain view of these matters, professional qualifications of the authors not-withstanding. (6, 7)
Anatomically, the gut is divided into four layers. These are, from outer to inner: serosa, muscularis externa, submucosa and mucosa. The serosa is a connective tissue covering that is continuous with the peritoneum and mesentery, providing a lubricated surface to allow for small movements of the bowels, as well as helping to hold the bowels in place and prevent tangling as they move. The muscularis externa consists of two smooth muscle layers, an inner circular layer and an outer longitudinal layer, which together are responsible for churning (within the stomach) as well as rhythmic and co-ordinated peristalsis throughout the GIT. The myenteric plexus, which lies between the two layers, coordinates all the various GI movements. (10) The importance of this layer in terms of its contribution to normal permeability and barrier functions is acknowledged (1, 13) but is often discounted or downplayed as research tends to focus on the mucosa and the structures that adhere to it. (e.g. 3, 8)
The submucosa lies between the external muscular layer and the mucosa. It consists of a framework of connective tissue within which are blood vessels, lymphatics and nervous tissue. The submucosal nerve plexus (Meissner’s plexus) controls secretory and absorptive functions of the GI epithelium as well as controlling the submucosal and mucosal smooth muscles. The mucosa consists of three layers; from inner to outer they are the muscularis mucosae, the lamina propria and the epithelial cells. In the intestines this layer is shaped into numerous folds (‘plicae’), which increase the surface area. In addition, the whole surface is formed into multiple densely packed finger-like projections (the villi), and deep crevices between the villi, known as crypts, some of which develop into specialised duodenal glands. (11,12). The muscularis mucosae is a thin layer of smooth muscle cells that overlies the submucosa and extends into the villi. It is responsible for moving the villi in order to facilitate absorption and movement of nutrients.
Figure 1. Histology of the Small Intestine. (a) The absorptive surface of the small intestine is vastly enlarged by the presence of circular folds, villi, and microvilli. (b) Micrograph of the circular folds. (c) Micrograph of the villi. (d) Electron micrograph of the microvilli. From left to right, LM x 56, LM x 508, EM x 196,000. Reproduced from: BC Campus OpenEd Website. Anatomy and Physiology: 158 23.5 The Small and Large Intestines. (11)
The lamina propria is a connective tissue layer containing capillaries and small blood vessels, as well as lymphatics, which together transport the absorbed nutrients away from the intestinal surface. In addition, this layer contains nerve tissue and lymphoid tissue. The immune cells in this layer play a very important role in protecting the body against invasion by pathogenic micro-organisms and foreign material. Immune surveillance is carried out by various migrating cells, such as macrophages and lymphocytes, as well as dendritic cells, which are able to sample the luminal contents by sending an ‘arm’ up between adjacent epithelial cells. In addition, there are small clusters of active lymphoid tissue (nodules) and larger aggregations (e.g. the Peyer’s patches) scattered throughout the lamina propria (see Figure 1).
The epithelial cell layer is a single layer of cells, containing various types of cells, predominantly the absorptive epithelial cells (a.k.a. ‘enterocytes’), between which are scattered the mucous secreting goblet cells, Paneth cells, enteroendocrine cells (hormone secreting) and, concentrated in base of the crypts, the stem cells. From their apical surfaces the enterocytes project microvilli in to the layer of mucous above. This is known as the brush border, which dramatically increases the apical surface area of each cell and is the site for exchange of nutrients, water and electrolytes as well as the release of cellular secretions (e.g. digestive enzymes in the stomach and small intestines, bicarbonate in the duodenum). The epithelial layer consists of rapidly dividing cells, migrating up to the top of the villi to be sloughed off within around 72 hours. (10,11,13)
Structures within the gut lumen
Although not strictly speaking a part of GIT structure, the mucous layer adhering to the mucosal surface and the microbiota within and above the intestinal mucous are never-the-less vitally important in terms of GIT function. The mucous layer is formed mainly from the secretions of the goblet cells and is stratified into an inner dense layer and an outer more diffuse layer. The intestinal mucous allows for the easy passage of the intestinal contents, protects the epithelium from the corrosive effect of digestive enzymes, and prevents adhesion and entry of micro-organisms into the cellular layer. Colonisation by micro-organisms is mainly confined to the outer loose mucous layer, while the inner layer that adheres to the intestinal cells is mostly free of bacteria due to the presence of antimicrobial proteins (AMP’s) secreted mainly by the Paneth cells, secretory immunoglobulin A (sIgA) secreted by plasma cells, and other protective proteins such as lactoferrin, secreted within the intestinal glands. In addition, there are specialised mucins attached to the apical cellular membranes, forming a protective coating. As soon as a microorganism tries to bind onto one of the epithelial cells, these mucins are released and ‘fly off’, carrying with them the potential invader. Thus, any microorganisms that manage to reach the cell border are prevented from forming colonies and invading into the lamina propria. (1, 3, 5)
The layer of microorganisms, the gut microbiota (a.k.a. intestinal flora) varies in its density and composition throughout the GIT. From being only very sparsely populated in the stomach and duodenum, it steadily becomes more concentrated and diversified throughout the length of the small and large intestines. Because it is quicker and easier to study their DNA, much of what we know about the various microbial species and what they are capable of doing is derived from studying their DNA which gives information about genetic material; hence, the use of the term ‘microbiome’ in reference to the collective genomes of the micro-organisms in a particular environment. In terms of numbers, there are approximately 100 trillion microbes in the human GIT, mostly bacteria, but also archea, viruses, fungi and protozoa. They outnumber their human host cells by a factor of 10 and contain around 100 times more genetic material than their host. Mostly composed of strict anaerobes, the human microbiota carry out several essential metabolic, nutritional, physiological and immunological functions that we humans are unable or only partially able to perform. Moreover, the gut microbiota influence brain function and exert a profound influence on the host’s reactions to stress. (21, 22) A humbling thought, that our health and well-being is dependent on the activities of the earliest known life form on this planet.
Amongst other things, the intestinal microbiota are responsible for the normal development of the immune system in early life, various aspects of carbohydrate metabolism, production of essential vitamins (e.g. folate), production of several short chain fatty acids (e.g. butyrate, which is the sole source of energy for enterocytes in the colon), some of the essential pathways in bile acid metabolism, production of antioxidants and maintenance of normal insulin sensitivity. In addition, they are indispensable for the maintenance of normal intestinal barrier function. (2,14,15) Without our gut microbiota we would be unable to digest and absorb nutrients nor resist infections. (16) Diseases closely linked to abnormal changes in the microbiota include allergies, obesity and inflammatory bowel disease. (15) Other diseases that are associated with altered intestinal barrier function due to abnormal microbiota include the auto-immune diseases and various types of cancer. (3, 9,17,18,19, 20)
Normal and abnormal microbiota communities
The composition of the gut microbiota varies widely between individuals and is profoundly influenced by diet, ingestion of pharmaceutical drugs, stage of life, age and body mass index, amongst other things. The microbiota of healthy adults contains over 100 trillion bacteria, comprising over 1,000 species and 7,000 strains, with the majority belonging to only two phyla: Bacteroidetes and Firmicutes. Marked differences at the level of bacterial species are observed between healthy individuals, without any compromise in the essential functional processes that they provide. Thus, there appears to be a high degree of functional redundancy built into the system, whereby one group of microbes is able to carry out the same functions at the same rate and under the same conditions as another. This diversity serves as a backup option to ensure that the needs of the host are met, despite various environmental onslaughts (e.g. dietary restrictions, antibiotic treatment, invasive pathogens) that may decimate various segments of the microbial population. (2,14,15)
Dysbiosis, defined as any significant change to the composition of the gut microbiota relative to that which is found in healthy individuals, has three aspects: loss of beneficial microbial organisms, overgrowth of potentially harmful microorganisms, and reduced microbial diversity. Thus, in relation to patients with the various diseases mentioned above, one or more of these mechanisms is consistently found.
In relation to the immune mediated diseases, ‘emerging evidence supports that rather than one or two dominant organisms inducing host health, the composition of the entire community of microbial residents influences a balanced immune response.’ (23) In the modern world, threats to the integrity of the gut microbiota are ubiquitous; in addition to those mentioned above in the previous paragraph, these include antibiotics fed to livestock, pesticide residues on produce, artificial sweeteners and emulsifiers in processed foods. However, even if we are following a completely organic diet, we may still compromise our microbiota by eating strictly vegan, gluten fee or following a low FODMAP diet. (2) It is worth repeating, however, that it is still unclear whether dysbiosis is a cause or effect of the diseases with which it is associated. As discussed below, there are several possible pathways that may provide causal connections, all of which are plausible. However, there are often findings that conflict with the theory, so a certain degree of caution is warranted, in order to avoid prematurely jumping to conclusions.
Intestinal barrier function
The mucosal lining of the intestines has a surface area of 300 – 400 m2 in adults and is the largest bodily surface in contact with the external environment. Along with its essential function of absorbing nutrients, equally important is its barrier function – keeping out incompletely broken-down food molecules (i.e. food antigens) and toxins, as well as ensuring that the seething mass of variegated microbes, whose main concern is their own survival and propagation, remain safely confined within the intestinal lumen as they pass through the GIT. Structurally, this barrier comprises only a single layer of cells. However, there are additional components, which together comprise the intestinal barrier: these include biochemical, immunological and microbiological aspects. (3, 25) As mentioned above, normal intestinal motility also contributes to the barrier function. However, the following discussion is mostly concerned with mucosal barrier function.
The structural, or ‘physical’ barrier of specialized epithelial cells is maintained and supported by tight junctions (TJ), which seal the paracellular space (i.e. the space between neighboring cells). Located around the apical surface of the epithelial cells, the TJ regulate the flow of water, ions and small molecules through the paracellular pathway and bar entry to microorganisms and other antigenic substances. The TJ control the opening and closing of the paracellular space in response to various chemical stimuli, which, under normal conditions, are derived from the microbiota and food components. Pathological increases in permeability due to ‘loosening’ of the TJ may be caused by bacterial and viral toxins, pharmaceutical drugs (e.g. NSAID’s) and various food components (e.g. gliadin). (9, 26) An important source of disruption to the epithelial barrier may occur at sites of cell shedding. Intestinal epithelial cells have a very rapid turnover and under normal conditions the TJ around a shedding cell secure the potential breach. However, if there is inflammation in the mucosa, the rate of cell shedding is increased, exceeding and the capacity of the TJ to seal the gap, particularly when adjacent cells are shed at the same time. (1) On the other hand, TJ barrier function is enhanced by chemical signals from probiotic (i.e. ‘friendly’) bacteria and various food components, including components uniquely derived from microbial fermentation within the gut. Moreover, some of these friendly commensals are capable of preventing or reversing the effects of pathogens on the gut barrier. (26)
The mucous layer performs both physical as well as biochemical barrier functions; it keeps the luminal contents away from the epithelium by forming a protective layer and it is also the medium within which a variety of chemical signals are conveyed. The composition and amount of mucous secreted by the goblet cells is profoundly influenced by the composition of the gut microbiota as well as by inflammatory mediators, such as cytokines and nitric oxide. Physically, the mucous layer provides a diffusion barrier against unwanted substances, while specialized mucins that adhere to the apical surface of the epithelium prevent bacteria from binding onto it. The outer diffuse layer of mucous is colonized by bacteria and it serves as an anchor and source of nutrients for the beneficial types (which thrive and exclude pathogens), while the inner compact layer prevents the penetration of pathogens due to its of dense structure as well as the relatively high concentration of antimicrobial substances secreted by the epithelium. These substances include various types of antimicrobial proteins (AMP’s) and secretory IgA (sIgA). (3, 25)
The biochemical aspect of the intestinal barrier comprises the AMP’s secreted by specialized epithelial cells, the bile salts and stomach acid (mainly in the luminal contents of the upper small intestine), as well as sIgA. The latter is produced by plasma cells in the lamina propria and passes into and through the epithelial cells to be secreted into the lumen. Secretory IgA is an immunoglobulin (i.e. antibody) that is able to resist the effects of proteolytic enzymes in the gut and carry out its protective functions in that environment; namely to resist pathogens (both enteric toxins and microorganisms) by disabling their activity, as well as assisting other aspects of immune functions in the bowel wall. (1, 3, 24, 25)
The immunological component comprises both innate and adaptive immune cells, collectively referred to as the gut associated lymphoid tissue (GALT). In the lamina propria there are organized lymphoid follicles, including the Peyer’s patches and isolated lymphoid nodules, as well as mobile cells, such as macrophages, lymphocytes and dendritic cells. In addition, scattered throughout the mesentery are the mesenteric lymph nodes. Specialised epithelial cells, the microfold cells (M cells), goblet cells, as well as enterocytes that are directly above lymphoid follicles, play an important role by transferring antigens (including intact microorganisms in the case of the M cells) from the lumen into the lamina propria for presentation to the immune cells. Amongst the lymphoid cells, only the dendritic cells are able to transfer selected components from within the gut lumen into the lamina propria, while the mobile lymphocytes may translocate from within the lamina propria to the epithelium, where they are dispersed between adjacent epithelial cells throughout the GIT (see Figure 2). These intraepithelial lymphocytes are able to sample antigenic material within the mucous layer while also maintaining direct contact with epithelial cells. With all of these surveillance and monitoring activities, it is important that the intestinal immune system exhibits tolerance to dietary antigens as well as the microbiota, otherwise it would be in a constant state of inflammation. Exposure to a diverse population of commensals in early childhood appears to be an essential requirement for normal development of the intestinal immune system, so that it maintains only a low level of inflammation as part of its ongoing surveillance, while being ready to mount a rapid response to invading pathogens and toxins. (24, 27)
The gut microbial community represents a specialised barrier, which also provides crucial support for all the other intestinal barrier components. The gut microbiota can prevent colonisation by pathogens in several ways: by producing antimicrobial compounds, competing for nutrients and attachment sites, as well as stimulating the proliferation of other beneficial microbes (which also compete with the pathogens for nutrients and space). Moreover, our friendly commensals promote the production of mucous by goblet cells, stimulate the production and secretion of various types of antimicrobial proteins by epithelial cells, enhance TJ barrier function and provide the epithelium with essential nutrients. In other words, the viability and function of the intestinal epithelial cell layer depends upon a healthy microbiota.
The microbiota also play an important role in regulation of the gut immune system. Not only is a diverse population of commensals crucial for normal development of the GALT in early life, a stable and diverse microbiota also has a major influence on its day to day functioning. A healthy microbiota ensures that the intestinal immune system remains actively alert but relatively quiescent, and in the event of an inflammatory response to a pathogenic invasion, that the response remains confined to the gut wall without the potentially dangerous involvement of systemic immunity.
(1, 3, 24, 25)
Finally, gut motility pays an important role in maintaining normal intestinal barrier functions. Intestinal motility has a marked influence on microbiota growth; a high turnover is maintained as bacteria and their toxins are propelled through the lumen by peristaltic movement of the external muscular layer. In areas of higher motility, i.e. the proximal small intestines, microorganism populations are relatively sparse. Moving distally, as motility becomes reduced, the microbiota become more prolific. In addition to the control exerted by the nervous system and gastro-intestinal secretions, intestinal motility may also be affected by strenuous exercise and emotional stimulation. Normal motility may be disrupted by the effects of certain foods, pharmaceutical drugs and mood disorders, e.g. depression. (29) Motility may be influenced in either direction by components of the microbiota, which are able to secrete substances, or stimulate other cells to release substances that influence intestinal motility. (25) Reduced intestinal motility, associated with ageing, may be the underlying cause of systemic inflammation and reduced barrier function seen in the elderly. (28)
Figure 2. Schematic figure of the intestinal barrier and affecting factors. The intestinal barrier is composed of several layers providing protection against microbial invasion. The intestinal lumen contains anti-microbial peptides (AMPs), secreted immunoglobulin A (IgA), and commensal bacteria, which inhibit the colonization of pathogens by competitive inhibition and by production of, e.g., butyrate, which has barrier-protective properties. A mucus layer covers the intestinal surface providing a physical barrier. The epithelial layer consists of a single layer of epithelial cells that are sealed by tight junction proteins such as occludin, claudin, and zonulin-1 preventing paracellular passage. This layer also harbors intraepithelial lymphocytes, M cells (overlying Peyer’s patches and lymphoid follicles), mucus-producing Goblet cells and bacteriocin-producing Paneth cells (not shown). The lamina propria contains a large amount of immune cells, both of the innate immune system (e.g., macrophages, dendritic cells, mast cells) and the adaptive immune system (e.g., T cells, IgA producing plasma cells). In addition, cells of the central and enteric nervous system innervate in the lamina propria (not shown). Factors affecting the intestinal barrier function include pathogenic bacteria such as enteropathogenic E. coli, high-fat diet, lipopolysaccharides (LPS), drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), and proton pump inhibitors (PPIs), as well as various food allergens and the gluten component gliadin. Reproduced from: https://www.nature.com/articles/ctg201654/figures/1 (9)
Breaches to the gut barrier: the ‘leaky gut’
From the above discussion, it will be apparent that gut barrier function is not absolute; it is never able to completely block the entry of unwanted material. Under normal conditions gut permeability is variable, being influenced by food components, the presence or scarcity of certain nutrients, the presence or absence of certain probiotic bacteria, alcohol consumption and various stresses. Moreover, components of the gut immune system actively transport materials (including microorganisms) from the intestinal lumen into the lamina propria. Under normal conditions, there are mechanisms in place to preserve health and deal appropriately with minor amounts of toxic materials and pathogenic micro-organisms that may ‘slip through the net’, and these are dealt with locally, inflammation being confined within the gut wall. (3, 5, 26)
However, depending on individual factors, disruption to the gut barrier may be sufficiently severe to allow significant quantities of toxins, antigens and bacteria to enter the blood stream and cause inflammation at various bodily sites, both local and distant. Common examples of stresses that push the barrier functions beyond their limits include: dietary factors, infections, antibiotic use, excessive alcohol consumption and burn injuries. Important dietary factors include vitamin D deficiency, zinc deficiency, low fiber intake, a diet high in saturated fat and refined carbohydrates, and some of the additives used in processed foods (i.e. a diet that is high in processed ’foods’). These factors may directly affect the epithelial barrier by acting on the TJ (18, 19) or may cause increased epithelial cell shedding (due to localised inflammation); they may also act indirectly via deleterious changes to the composition of the gut microbiota. Indeed, in most of the conditions thought to be due to leaky gut (e.g. auto-immune diseases, atopic diseases, inflammatory bowel disease), patients exhibit marked dysbiosis. (1, 3, 26)
Although this issue was mentioned above, it bears repeating. You will recall the comments about ‘cultured membranes … and zebra fish’ in the second paragraph: most of the information discussed in this article has been derived from in vitro models and experiments on non-human subjects. Moreover, this kind of research involves experimentation on isolated components of the GIT and the results may not hold up under real life conditions where the microbiota, the gut immune system, and all the other components of the GIT – let alone the rest of the person and their environment – are continually interacting.
Unfortunately, the mass of data generated in this way may prevent us from ‘seeing the forest for the trees’. In the interests of brevity, the succinct presentation of research findings may give the impression of certainty and established fact. However, this is not the case; and the important things to understand from the above discussion centre upon the different ways in which the various components of the GIT interact, along with the influences of lifestyle factors. Hopefully, this will lead us to discover appropriate ways in which this information may be applied in the clinic; by using this broad understanding as a guide to point us in the general direction of possible underlying causes and to help us find suitable treatment approaches for each individual patient.
In Part 2 we will explore how contemporary scientific research on the gut correlates with TCM theory, specifically examining the work of Li Dong-yuan (1180 – 1251), founder of the ‘Tonifying Earth’ school, which is a major current of thought within TCM.
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