Healing The Gut: Restore the Spleen Qi Part 2 – Correlations Between Biomedicine And TCM

The central role of the gut microbiota

‘Amazingly, although the human body is composed of 100 trillion cells, only 10 trillion are human cells, while 90 trillion are microbes’ (1) 

While great strides have been made in recent years, the state of knowledge regarding the composition, function, role in health and disease as well as outcomes of various interventions, the human gut microbiota are still very much an uncharted territory. For instance, we know that there are over 1,000 different bacterial species that may inhabit the GIT, yet a person generally has only around 15% of these as permanent inhabitants; that there is tremendous diversity between individuals, while the composition of the microbiota in any one person tends to remain relatively stable after the second or third year of life and into adulthood. (2, 3, 4) 

As discussed in Part 1, the main functions of the gut microbiota are to help maintain the integrity of the intestinal barrier, provide nutrients, assist digestion, protect against pathogens, help in the maturation and normal function of the immune system, as well as to regulate various aspects of the endocrine and central nervous system function. They play a key role in digestion, drug metabolism, and detoxification. (5, 6, 7) Recently, the microbiota functions were summarised as follows:

• Development of the nervous system
• Maturation and education of the immune system
• Protection against pathogens
• Renewal of the intestinal epithelial layer 
• Regulation of intestinal barrier integrity
• Regulation of appetite and behaviour
• Intestinal angiogenesis
• Recovery of intestinal epithelial injury
• Improved energy harvest through digestion of complex fibers in food
• Production of vitamins
• Metabolism of xenobiotics (6)

Dysbiosis and the maintenance of a healthy microbiota

We can easily see why dysbiosis, even to a mild degree, can lead to serious consequences in terms of overall health. It follows, then, that actual or potential threats to the integrity of the gut microbiota should be taken very seriously. At this point in time we know that it can be adversely affected by dietary factors, certain pharmaceutical drugs (e.g. antibiotics, NSAID’s and PPI’s) (8), some pesticides (e.g. glyphosate) (10) and excessive alcohol consumption. (11, 12) Moreover, there is still insufficient data to ascertain whether or not harmful effects may also be caused by low dose antibiotics from conventionally farmed livestock, pesticide residues on produce, other pharmaceuticals and food chemicals.(9) On the other hand, it has been clearly established that supplementing with prebiotics, probiotics or synbiotics (i.e. prebiotics taken together with probiotics) not only improves the state of the microbiota but also has beneficial effects in the following conditions: diarrhea, constipation, irritable bowel syndrome, inflammatory bowel disorders (e.g. ulcerative colitis, Crohn’s disease), lactose intolerance, allergies, cardiovascular disease, obesity, alcoholic liver disease, and also in the prevention of cancer. (13, 14)

The effects of diet on the composition of the microbiota have been studied extensively. Factors that enhance the microbiota community by promoting diversity and an abundance of probiotic species include adequate intake of the following: plant-based fibre, plant-based protein sources, resistant starches, (9, 15, 16) omega-3 oils (17), fermented foods (18, 19) and a variety of food-based polyphenols (20). 

The importance of dietary components that are not absorbed

Of particular interest are the food components that are not able to be digested by the human host but are required by the microbiota, specifically the probiotic (beneficial) organisms, for sustenance. Previous terms, such as ‘dietary fiber, ‘soluble fiber’, ‘plant polysaccharides’ and ‘prebiotics’, have proven inadequate both in terms of their precise definitions and their application in the assessment of the functional value of foods. The best available term in current use is ‘microbiota accessible carbohydrates’ (MACs). (21) MACs are oligosaccharides or polysaccharides, as opposed to the simple sugars (i.e. monosaccharides and disaccharides), which are all digested and absorbed in the upper GIT. MACs escape digestion by the host and reach the distal small intestines and colon intact, where they provide an energy source for the microbiota, and are converted to short chain fatty acids (SCFA) by the probiotics. MACs are also referred to as ‘glycans’, which is a more inclusive term encompassing glycoproteins and glycolipids derived from animal sources (e.g. glucosamine and chondroitin). MACs include all sources of complex carbohydrates that are available to the gut microbes, and may be derived from the diet, produced by the host (mucous secretions within the GIT), or produced by microbes within the intestines. (21, 22) 

As one would expect, different microbial species feed on different types of MACs, and this is the reason why diets with a wider variety of MACs correlate with increased microbial diversity. (9, 21, 22)  However, while a diet rich in MACs tends to promote diversity and increased SCFA production (indicating an increase in number and/or activity of probiotic species), it is important to note that, unless the critical species of microbe are already present, dietary MACs will not be able to induce them; in such cases dysbiosis may worsen, with diversity becoming reduced as specific (and possibly non-probiotic) species gain dominance. (9, 21) Hence the importance of the traditional naturopathic ‘weed, seed and feed’ approach to correcting intestinal dysbiosis. (83, 84) 

 An important and readily accessible type of MAC is referred to as ‘resistant starch’. There are various types of resistant starch (RS), all of which resist the effect of our digestive enzymes and are therefore available as food for the microbiota. While abundant in raw potato and raw rice, it is unlikely that these items will become staple food items anytime soon. However, once cooked and allowed to cool the starches in these and other similar items become ‘retrograded’, i.e. the amylose and amylopectin recrystallise to form a structure similar to raw starch and thus become resistant to digestion. (22) These foods may be reheated without loss of their resistant properties. (23) Many studies suggest that diet supplementation with RS improves colonic health and stimulates SCFA production, particularly butyrate. (24). (Foods rich in RS include lentils, peas, beans, cooked and cooled potato, cooked and cooled pasta, cooked and cooled rice, firm bananas, and certain wholegrain products 24, 25)

The other important class of nutrients that provides its main benefits through not being absorbed are the plant derived flavan-3-ols, which include phenols, polyphenols and tannins (PPT). Although earlier research focused on the antioxidant effect of these compounds, they are very poorly absorbed within the small intestines (only 5 – 10%), where they are immediately conjugated before reaching the blood stream. In other words, they are treated like potential toxins and undergo phase two detoxification so that they may be rapidly removed from the body. Moreover, in this process, the antioxidant effects of the native molecules are mostly attenuated. (37) Therefore, it is unlikely that the health benefits of this class of compounds are due to their antioxidant actions in the body tissues. In view of the fact that over 90% of these compounds find their way to the large intestines, it is far more likely that their beneficial effects are derived from three different mechanisms: direct action on the microbiota, promoting beneficial species and suppressing pathogens; direct action on the intestinal epithelial cells enhancing barrier function (33); and thirdly via PPT metabolites, derived from the microbiota, which, in turn, may act locally or after absorption into the blood stream, act on distant organs and tissues. (16, 37) 

Dietary factors that damage the microbiota

While dietary factors that are beneficial to the microbiota are quite complex, the dietary factors that promote dysbiosis, can be summed up in two words: ‘Western diet’. (9, 16, 21) Subjects consuming a standard Western type diet, (high animal protein, low fibre, high refined carbohydrates and processed foods, etc.) for one month showed ‘a 71% increase in plasma levels of endotoxin activity (endotoxemia) … The Western-style diet might, therefore, contribute to endotoxemia by causing changes in gastrointestinal barrier function or the composition of the microbiota’. (26) As one might expect, the addition of chlorine to the drinking water is another factor that can damage the microbiota. (27)

Certain types of dietary restriction (apart from the standard Western diet) have also been shown to reduce microbiota diversity with a critical reduction in probiotic species. One example that has been studied extensively is a gluten free diet, which has been shown to cause a reduction in beneficial species and an increase in potentially harmful bacteria. (9, 28) This may be due to a reduced amount of plant polysaccharides in a diet that avoids gluten (29). In addition, a large observational study showed an increased risk of heart disease in non-celiac adults who avoid gluten. (9) A recent study on the effects of a gluten free diet on healthy human subjects over a four weeks period found that the blood and stool biomarkers for inflammation remained unchanged. (30) This is at odds with what would be expected in light of findings from studies on cultured membranes, which have consistently found that gliadin (a component of gluten) strongly and consistently increases intestinal permeability through disruption of the tight junctions (TJ) between the intestinal epithelial cells, leading to a leaky gut, and local inflammation (31, 32, 33, 34). The fact that there was no dramatic reduction in the markers of inflammation speaks to the need to view such experimental findings in context: looking at one component of the intestinal barrier in isolation may not necessarily be relevant to a complex living system. Moreover, in populations that traditionally consume wheat products as a dietary staple, such as those in Northern India, we do not find a high incidence of inflammatory bowel diseases until only very recently correlating with the increasing adoption of Western lifestyle factors. (35, 36)

Food triggers for increased gut permeability

There is an inherent weakness in studies on cell cultures that investigate the effects of various food components and other commonly ingested molecules on intestinal barrier function: they examine the intestinal epithelium (or rather a cultured membrane of intestinal epithelial cells) in isolation from the other components, i.e. the protective layer of mucous, the various barrier enhancing chemicals, the intestinal microbiota and the gut associated immune tissue. In healthy human subjects all of these contribute to intestinal barrier function; and they all interact in complex ways that are only just beginning to be unravelled. Therefore, any information gained from these studies can only be provisional, as the effects on the intestinal barrier may be profoundly modified by the other components. However, there is some value in this type of research. Their inherent strength, and hence clinical usefulness, lies in the fact that under pathological conditions (e.g. in patients with inflammatory bowel disease, obesity or an autoimmune disease – as well as in subjects on a Western diet and following a Western lifestyle) the intestinal barrier components are severely compromised and may thus begin to approximate the experimental conditions. In such patients, then, we would expect there to be a heightened sensitivity to certain ingested substances with an exacerbation of gut leakiness. Therefore, it is reasonable to advise a period of avoidance of the following common triggers: gliadin and gluten (components of wheat), capsianoside (from sweet peppers and chilli), and ethanol (in alcoholic beverages). (33) Support is given to this argument by studies showing that in patients with active inflammation in the gut, gliadin and moderate amounts of alcohol cause increased gut permeability, whereas in healthy controls and patients in remission they do not. (39, 40) In addition, commonly used industrial food additives, found in processed ‘foods’, have been shown to cause leakage at the TJ between intestinal epithelial cells, (38) and these should likewise be avoided. On the other hand, intestinal barrier function is enhanced and maintained by sufficient dietary supply of vitamin D, vitamin A, glutamine and zinc. (33) 

The alcohol question

As discussed above, because of its deleterious effect on the microbiota and the potential to cause leaky gut, alcohol consumption needs to be intelligently restricted. 

Studies on heavy drinkers have shown that every aspect of the intestinal barrier is compromised. (41) These effects are seen even after a single episode of binge drinking, with a rapid increase in serum endotoxin and bacterial translocation from the gut, along with markers of local and systemic inflammation. (42) However, there is good news for healthy people who enjoy ‘a drink or two’; and it is precisely that: one can safely, and healthfully, enjoy a drink or two. Moderate consumption of red wine (and de-alcoholised red wine) at 272 ml (= just under 2 standard glasses) per day resulted in beneficial effects on the microbiota (as well as blood pressure, triglyceride, total cholesterol, HDL cholesterol, and C-reactive protein), whereas spirits at 100ml per day had deleterious effects on the microbiota. (43, 44) Thus, we have a real-life demonstration where a substance (ethanol) that causes significant disruption to the TJ in experimental models, as well as deleterious effects on the microbiota when ingested on its own, is modified by dosage and accompanying substances (i.e. the phenols, polyphenols and tannins), not only neutralising harmful effects, but also providing net health benefits. Although it has not been studied as extensively, it is likely that moderate consumption of beer may also have similar health benefits to those of red wine. The antioxidant content of beer is equivalent to that of red wine, but the specific antioxidants are different because the barley and hops used in the production of beer contain flavonoids different from those in the grapes used in the production of wine. In addition, beer contains more proteins and B vitamins than wine. (45)

One important caveat: it is best to drink wine (or beer, if you prefer) with or after food. When taken on an empty stomach, around 80% of the alcoholic beverage passes into the upper small intestine for absorption. (46) You will remember that ethanol’s potential to damage the gut barrier is counteracted by the accompanying polyphenols, and that these substances exert their health benefits via the microbiota. You will also remember that the gut barrier is at its weakest in the upper small intestine: the mucous layer is relatively thin and the microbiota quite sparse. This is the most vulnerable part of the GIT and it would be wise to avoid unnecessary exposure to any kind of alcohol. In patients with abnormal levels of inflammation in the gut or any of the diseases associated with leaky gut and gut inflammation, the use of alcohol should be strictly avoided. 

Microbiota, intestinal barrier function and TCM

The symbiotic relationship between the gut microbiota and our good selves is so close that many researchers regard the microbiota as an additional bodily organ in its own right; a ‘metabolic organ’ with a metabolic potential equivalent to the liver. (2, 6). This organ carries out many essential functions in relation to both the structure and the function of the digestive system, with additional immune, endocrine and nervous functions. Importantly, it is a critical component of the intestinal barrier, ensuring that potential antigens, such as large food-derived molecules, various toxins and bacteria are prevented from entering the blood stream.

A common analogy that recurs amongst researchers and authors is one that has been part of TCM since the beginning: that of the Earth; specifically, the lush vegetation growing on the Earth’s surface, together with the relatively thin layer of soil that supports and nourishes it. The microbiota serves a similar function to the grasses and plants that bind the topsoil, enabling other life forms to grow and thrive. The intestinal mucosa, consisting of epithelial cells, immune cells and smooth muscle is like the topsoil, which, without the protection of the layer of vegetation would become subject to erosion, allowing various toxic chemicals from the environment to leach into the groundwater (i.e. our blood stream). (47, 48) A healthy state of the microbiota may be compared to a well trended garden with a beautiful display of many different leafy and flowering plants. Loss of some species and overgrowth by weeds is comparable to a state of dysbiosis. 

Without taking this analogy too far, suffice to say that this image fits perfectly with the TCM conception of the Earth element and the macrocosmic-microcosmic correlation with the digestive system, emblematically represented by the Spleen. For the purposes of the following discussion, instead of regarding the microbiota as an organ in its own right, I propose that we regard the microbiota as an essential component of the Spleen Qi; treatment strategies that target the microbiota may be useful in the treatment of Spleen disorders and vice versa. Additionally, things that harm the microbiota or disrupt intestinal barrier function are harming the Spleen, leading to various patterns of imbalance, e.g. Spleen Qi deficiency, Spleen Yang deficiency, Cold-Damp disturbance of the Spleen. It is clear from the above discussion that although it is possible to study each of the components of the gut in isolation, clinical realities are generally quite different from the findings of such studies. Thus, from a TCM perspective, the integrated functions of the gut, as revealed by Western analytical research, can augment our knowledge of the various aspects of the Spleen Qi and the various Spleen disorders. 

TCM theories are mainly concerned with functional activities and relationships (49), and as such may be regarded as a highly elaborate compass. On the other hand, knowledge derived from Western scientific research provides us with a detailed map (generally without much of a compass). Just as TCM doctors and scholars have integrated new clinical findings with traditional theory, modifying the latter in light of the former, (51, 52) we should continue this process by integrating and adopting any relevant scientific research. In this way we can continue to deepen our understanding of the human body-mind complex in health and disease. Importantly, we are then able to expand our therapeutic horizons. Thus, for example the Spleen’s transformation functions, not only include the activities of the digestive enzymes, but also those of the microbiota, which not only produce essential nutrients but also enhance the therapeutic and protective actions of dietary components that are poorly absorbed (e.g. plant derived flavon-3-ols and polysaccharides). The critical function of ‘separating the clear from the turbid’ gains deeper meaning when we can relate it to intestinal barrier function and understand all of the factors that may impact upon it, not least of which are compounds manufactured by our probiotic commensal micro-organisms.

Functions of the Spleen in TCM

As noted above, the Spleen is emblematic for the Earth element in the human body, and the functional activities of the Spleen, i.e. the ‘Spleen Qi’, include some of the functions of several anatomical organs, specifically the stomach, the small intestine and the large intestine. Now, this is not a new interpretation of TCM theory; it was elaborated in Ch.9 of the Yellow Emperor’s Classic of Medicine (huang di nei jing), over two millennia ago. (50) The important point is that depending on the context and the viewpoint, Spleen Qi may be considered in a narrow or in a broad sense; in other words, we are dealing with an elaborate compass here, not a precise map. 

In addition to digestion, absorption and distribution of nutrients, the Spleen Qi contributes to the production of the defensive Qi, which repels exogenous pathogens (i.e. maintains immune functions); promotes mental equilibrium and sound judgment; keeps toxic materials from being absorbed (i.e. separates the clear from the turbid); helps to maintain muscle tone and strength; and holds the blood within the vessels.  (i.e. promotes platelets and the integrity of the capillaries). These seemingly disparate functions appear to be quite separate from the ability to break down and absorb nutrients. However, we now know that all these functions are strongly affected by and are, most likely, highly dependent upon the condition of the gut microbiota.

Li Dong-yuan’s Contribution to TCM: The ‘Nourishing Earth’ School

At this point one may ask whether or not these correlations remain relevant when we look at diseases that are closely linked to the gut microbiota and intestinal barrier function. To answer this, we need to go back to the great TCM reformer, Li Gao (a.k.a. Li Dong-yuan, 1180 – 1251), whom we will hereafter mostly refer to as Dr Li. Placing Dr Li in his historical context is no easy task: the situation is quite complex, and misinformation abounds. I will therefore provide a brief historical overview of the life and times of Dr Li before discussing his novel theories and their application then and now. 

Historical context

The Song dynasty ruled most of China from 976 – 1127, after a 16 years struggle to seize and consolidate power, ending more than 50 years of political upheaval, known as the Five Dynasties and Ten Kingdoms period. The Song capital was located in what is now the city of Kaifeng in Henan province in north-east China. Hence the ruling dynasty during this period is referred to as the Northern Song. The country flourished under Song rule, with improvements in agriculture that provided more food for a burgeoning population, and cultural advances such as paper currency, woodblock printing and movable-type printing. This was a period of rapid development and widespread dissemination of science, technology, mathematics, engineering, the arts, philosophy, psychology and ethics.  This was also a particularly good time for medicine, as the government set up medical schools and imperial pharmacies, which involved the creation of a specialized department, the Pharmacy Bureau (he ji ju), to oversee the collection, manufacture, dispensing and selling of herbal formulas. Public dispensaries were established, in which ready prepared formulas were applied in the treatment of specific symptoms or groups of symptoms, generally with little or no modification, and without the elaborate diagnostic protocols that are the hallmark of contemporary Chinese medicine. The largest and most renowned compilation of medicinal formulations from this period is the ‘The Formularies of the Tai Ping People’s Welfare Bureau of Pharmacy’ (tai ping hui min he ji ju fang). Originally called the Pharmacy Bureau Formularies (he ji ju fang), it was revised and considerably expanded over the years, with the final compilation by Chen Shi-wen et al., which was published in 1151, incorporating the new name of the Bureau. The Pharmacy Bureau had been renamed during the Southern Song and given a splendid title, in honor of the first era of the Song’s second emperor (Song Taizhong), the ‘Tai Ping’ or ‘Era of Great Peace’ (tai ping xing guo, 976-984 CE), thus also honoring Song Taizhong. For it was emperor Taizhong who had initiated the above-mentioned medical and compilation projects, in a bid to consolidate the newly reunified empire through medicine and scholarship. (53, 57) The Song dynasty was also a period when the study and practice of medicine first started to become an acceptable vocation for the educated elite class, who generally strove to enter the civil service by way of proficiency in the Confucian classics. (54, 57) The increasing involvement of the educated elite is arguably the principal factor underlying the momentous advances in theory and practice that occurred in the following Jin and Yuan eras, now known as the Jin-Yuan medical reforms. (57)

Unfortunately, the Song dynasty and its flourishing culture began to experience serious disruptions when, in 1115, the Jurchen people, a former ally from the north-east became unified and, gaining power, took over the region north of the Qinling mountains and the Huai river. The Song retreated south, to relocate their capital in what is now the city of Hangzhou, thus beginning the Southern Song dynasty. The leader of the Jurchen gave the name ‘Jin’ (gold) to his state and dynasty, ruling northern-eastern China from 1126 – 1234, after 11 years of conflict with the Song. The Southern Song managed to hold on to their territory in southern China from 1127 – 1279, and China was thus divided into two hostile empires for a period of around 150 years, each claiming to hold the ‘mandate of heaven’ to rule ‘the empire’. Although they were able to hold off any further incursions by the Jin, due to the superior strength of their navy and the skillful use of gunpowder, the Southern Song was eventually overthrown by the Mongols (who took the Chinese name ‘Yuan’ for their dynasty) under Kublai Kahn in 1279, after two decades of conflict.

In 1211, the Mongols, under Genghis Kahn, began to invade the Jurchen, who were finally defeated in 1234, after 23 years of conflict. The Mongols successively took over the western, eastern and central capital cities of the Jin Empire, and in 2014 the Jin emperor gave up his central capital and relocated his government to Kaifeng (previously the capital of the Northern Song), which became known as the ‘southern capital’ of the Jin. This situation only lasted about 18 years, and in 1232 the city of Kaifeng was besieged by the Mongol army, the siege lasting a total duration of 10 months. Not long after the Mongols had surrounded the city, the siege was lifted for a short period while the Jin emperor sent out envoys to negotiate a settlement with the Mongols. Around this time a severe epidemic broke out, affecting almost the entire population inside the walled city, killing around 1,000,000 people within less than three months. This number represented more than 40% of the city’s population, based on records of the numbers of people who died during the epidemic compared with the number of inhabitants at the end of the siege, some 6 months later; however, the death rate may actually have been closer to 60% as the population was considerably increased, after the epidemic had burned itself out, by large numbers of refugees fleeing the Mongol’s second wave of attacks. (55, 56) These early negotiations failed, and food supplies began to run out soon after. 

Li Gao’s early life and teacher

Li Gao (1180 – 1251) was born into a wealthy family that owned several thousand acres of land in and around Zhending (modern day Baoding) in Hebei province. He was brought up within an essentially Song dynasty elite culture in north-east China under Jin rule. His family was well connected and had close ties to high ranking local officials and scholars. This was a period of vigorous cultural development under the foreign Jurchen rule; most of the Jurchen emperors and most of their aristocracy had adopted Chinese culture to such an extent that the Jin emperor claimed the ‘mandate of heaven’ as the legitimate successor to the Northern Song, and Chinese culture flowered during the last half of the 12^th up to the first decade of the 13^th centuries. This period has been referred to as the ‘High Jin’, characterized by creative advances in literature, religious thought and institutional restructuring. (80) 

Young Li Gao received an elite education in the Confucian classics. He was taught by the renowned Fan Zun, a descendant of the iconic Fan Zhong-yan (989 – 1052). One of his study mates under Fan was Yuan Hao-wen, who went on to become a leading figure in Jin dynasty culture of the time, and he remained a close friend during the turbulent years ahead. (56) Li Gao did not strive for a position in the civil service; as the oldest son of the family, he was closely involved in the management of the family estate. 

When he was still a young man, his mother became ill and died after being treated by several ‘common’ physicians, who appeared not to be able to make an accurate diagnosis. (51, 54, 59) It should be noted that up to this time medicine was practiced by people of various levels of education, generally far below the standard of the educated elite. The practice of medicine was more like a trade that was often passed down from father to son, with closely guarded family secrets and very little sharing of knowledge and clinical experience that comes with an academic based medical tradition. Thus, at this time there were various sectors of medical practice: the ritual healers (using spells, charms and incantations to drive out evil spirits), common physicians (medical technicians, who were literate but not well educated) and the nascent literati physicians. The latter group deplored the rudimentary or misguided knowledge of the other groups and believed that because of the extreme complexity of illness and healing, in addition to adequate training in the essential practical skills, only a well-rounded academic approach, together with the highest moral standards was equal to the task. (57) Young Li Gao was himself affected by this social dilemma in possibly the deepest and most painful way, as he was compelled to stand by, in grief and frustration, unable to help his ailing mother as her health declined and she eventually died. 

This experience, to be repeated later under different circumstances, sowed within him the seeds of an intense interest in, and desire to learn medicine. Consequently, he sought a suitable eminent scholar-physician to teach him and found this in Zhang Yuan-su, the leading physician in the region, and founder of the Yi Shui school (named after his home province). Li Gao’s father fronted up ‘1,000 ounces of gold’, which represented either a gift or payment for three years’ study and apprenticeship with Zhang. (56) 

Little is known about Zhang, apart from the fact that he had received an elite education, passed the necessary imperial examinations and after a period of government service was stripped of his degree due to violating the taboo on the use of characters from the personal name of a deceased emperor. He then turned to the study of medicine and, with his elite literati background, devoted his efforts to improving all aspects of Chinese medical tradition. Subsequently, his teachings and innovations became seminal to the medical reforms of the Jin-Yuan era. (57, 59)

Although teaching and practicing outside the imperial arena, Zhang sought to bring to Chinese medicine the elements for which the literati elite had been calling: a unified and detailed theoretical framework encompassing physiology, pathology, pathogenesis, diagnosis, treatment principles and prescribing of herbal medicines. In addition to his teaching, Zhang was a renowned physician and a prolific medical author, who was able to bring together the great ideas from the ancient classics and the recorded experiences of past generations of physicians with the aid of his own clinical observations, critical judgement and unique insights. In this way, Zhang bequeathed to future generations the following theoretical innovations: further refinements to internal organ (zang-fu) pattern differentiation, a more detailed elaboration of the qualities of the materia medica (closely integrating the five elements paradigm with herbal medicine to clearly define the association between the flavor of each herb and its effects on the different internal organs, as well as the specific Channel tropism for each medicinal substance). His work also expanded and consolidated the relationship between theories of disease causation and treatment methodology. (54 56, 59) 

Zhang has often been misquoted with the assertion attributed to him that ‘the prescriptions (i.e. formulas) of the past are not appropriate for the illnesses of today’. However, Zhang himself never said this in any of his extant works; the words quoted above come from a preface to one of Zhang’s books, written after his death. In fact, Zhang had a very high regard for the ancient formulas in the classic texts, such as the ‘Treatise on Cold-Induced and Miscellaneous Diseases’ (shang han za bing lun), and ‘Prescriptions Worth a Thousand Gold Pieces’ (qian jin yao fang). Moreover, like the physicians of succeeding generations, he sought to expand the scope of their clinical use. His main contention, however, was that the common physicians did not understand how to apply them correctly, nor modify them appropriately. (57) 

It was Zhang who started Li Gao on his journey to develop the theories and clinical practices that would later become known as the ‘Nourishing Earth (i.e. Spleen-Stomach) School’, through the former’s emphasis on the importance of the Spleen and Stomach as the basis for vigorous health and in the full recovery from illness. As a student, Li Gao observed Zhang’s routine use of medicinals to strengthen the Spleen in his prescriptions, and his use of pills made from bitter orange and Atractylodes rhizome to treat what is now known as functional dyspepsia, due to stagnation and deficiency. (59, 60, 61, 62) There is now evidence that part of the therapeutic actions of this simple two herb formula are mediated through favourable changes to the gut microbiota. (63, 64)

The move to Kaifeng and the siege by the Mongols

Dr Li continued to manage the family estate after serving his apprenticeship with Zhang. However, he had already distinguished himself as a brilliant student and was regarded by fellow colleagues as a promising literati physician. (51, 57) It therefore seems reasonable to presume that Dr Li had his own herb dispensary on the estate in Zhending and that he found time to practice medicine as an act of benevolence/ compassion (ren), treating family, friends, acquaintances and the local peasantry. Moreover, he would also have gained the attention of the educated elite in the civil service, several of whom were close friends, for he represented a rare and precious commodity – a literati physician. Thus, when the Jin emperor relocated the capital to Kaifeng in 2014, in the wake of the Mongol invasion, Dr Li would have been urged to join them, not only for the sake of his own safety, but also for the contribution that he could make to the emperor and his government in this time of crisis. He did, in fact, move to the new capital in that same year, and was given a position in the civil service, while he also continued to practice medicine, to the growing acclaim of his literati peers. (80, 81) Reports of the devastation wreaked by the Mongols as they took the other capital cities of the Jin, as well as the destruction inflicted on the peasantry, not only impelled the urgent move, but also provided Dr Li with valuable information about patterns of disease under the extreme conditions of siege warfare. (55)

Although we have no records of their ever having met, another highly influential figure in the Jin-Yuan medical reforms, Zhang Cong-zheng, a.k.a. Zhang Zhi-he, (1156 – 1228), who lived and practiced in Henan province, was living in Kaifeng for a short period during the time that Dr Li was there. (56) Zhang Cong-zheng’s presence, however, was not voluntary; he had been summoned to serve in the newly established imperial court, soon after the capital’s relocation to Kaifeng. Zhang apparently preferred the more down-to-earth nature of life in the countryside and only lasted two or three years, before returning to his roots and practicing as an itinerant physician, mostly treating the common people.  He had received a classical education and had studied medicine as well as the Confucian classics in his youth. Although he passed the necessary examinations, he chose not to enter civil service, but to devote his life to medicine. Predominantly influenced by the teachings of Liu Wan-shu (ca.1120 – 1200), his approach to treating disease involved a primary focus on the assisted expulsion of pathogens, generally through the induction of sweating, purgation and emesis. He is thus credited with founding the Attack and Drain (the Pathogens) School (gong xie pai). The extent of his clinical successes in the countryside was such that his renown extended to the imperial court. This, together with his presence, albeit quite brief, in Kaifeng no doubt influenced the local practitioners at all levels to adopt his methods. (54, 58, 59)

The unfortunate consequences of this emphasis on vigorous expulsion of pathogens was seen during the epidemic of 1232, which occurred just after a temporary lifting of the Mongol army’s siege of the city. In his two books, ‘Treatise on the Differentiation of Endogenous and Exogenous Injuries’ (nei wai shang bian huo lun), and ‘Treatise on the Spleen and Stomach’ (pi wei lun), published respectively 15 and 17 years later, Dr Li observed, perhaps with the benefit of hindsight, that victims of the epidemic who were treated with these rather drastic methods, in the belief that they were suffering from an Exogenous Cold disorder, almost always took an immediate turn for the worse and soon died. Noting that the population within the walled city was under severe emotional and physical stress, with food restrictions (eating once a day in the evening), insufficient time for resting and lack of adequate shelter, he concluded that the main underlying disorder in this epidemic was severe deficiency of the Spleen and Stomach, and not invasion by an exogenous Cold pathogen. We do not have any information regarding Dr Li’s own approach to treating patients at this time, nor the outcomes of his treatments. Moreover, it is very likely that this and other recent epidemics associated with the Mongol sieges were, in fact due to the bubonic plague, carried by rodents that had been stowed away in the Mongolian army’s supplies. (55) Such being the case, we would expect a death rate of between 50 – 60%, in the absence of treatment with antibiotics. (65) Therefore, we may presume that Dr Li had to endure, once again, an experience of helplessness and frustration in the face of this appalling epidemic, and that his clinical successes were with the 40 – 50% who would have survived without treatment. One thing that is apparent, however, is that this experience provided the impetus for him to develop his theories regarding the difference between Endogenous and Exogenous disorders, as well as disorders due to Spleen and Stomach deficiency. 

Dr Li’s contribution to TCM: the Yi Shui School and beyond

Dr Li may have got it wrong at the time of the epidemic of 1232, but he had the opportunity to observe at first hand an entire community living under extreme conditions for a prolonged period. After the epidemic had burned itself out, the situation continued to deteriorate; once the city had surrendered to the Mongols and the Jin empire had collapsed, life for the Han Chinese did not return to normal. (55, 58) It is therefore most likely that Dr Li’s clinical experience during this time not only confirmed his previous line of thinking, but also gave him the opportunity to test out and elaborate on his new theories. Thus, his observations during the time of the epidemic served mainly as a starting point, from which he was able, by careful clinical observation to define the causes, clinical manifestations and appropriate treatment for these new syndromes that he had recognized. 

In spite of the fact that the new Mongol rulers gave preferential treatment to doctors and rewarded apostate elite officials from the previous regime, Dr Li held to the prevailing Confucian belief that true loyalty demands allegiance to only one dynasty. Together with his friend, Yuan Hao-wen, he was transported from Kaifeng as a political prisoner to be resettled in Dong-ping county, Shandong province. Yuan Hao-wen (1190 – 1257) was one of the leading lights of the Jin literati, who left for posterity detailed chronicles of the events of this time, together with exquisite poetry lamenting the destruction of the culture, to which he was a major contributor, and the suffering inflicted by the Mongol wartime atrocities. (80, 81, 82) Yuan had connections in Dong-ping, where the leaders welcomed and encouraged the settling of many of the exiled elite from Kaifeng. This area subsequently become a major cultural centre, within which Dr Li was introduced into the literati community by his friend Yuan, and where he lived and worked for the next decade.  Returning to his hometown, Zhending, in 1243, Dr Li remained there until his death in 1251. During this time, he wrote eight books on TCM, only four of which are extant. (80, 81)

Dr Li observed that syndromes characterized by fever may, indeed, sometimes arise due to deficiency of the Spleen together with imbalance within the Spleen-Stomach axis. Furthermore, he clearly described the distinction between febrile illness due to interior injury (specifically relating to the Spleen and Stomach) and febrile illness due to invasion by exogenous pathogens. In his discussions on the clinical approach to making this distinction, Dr Li championed a far more detailed and precise system of clinical examination together with interpretation of symptoms and signs, setting the standard for future generations. He also noted that extremes of emotion deplete the body’s reservoir of Qi and engender Heart Fire, i.e. induce a state of over-excitement, further depleting the Qi and causing injury to the Stomach. In the Treatise on the Spleen and Stomach he discusses how this newly described group of syndromes, characterized by what he called ‘Yin-Fire’, may be generated by three main pathogenetic pathways: emotional extremes, unsuitable diet, and failure to achieve a healthy balance between work and rest. These factors all tend to weaken and disrupt Spleen and Stomach function, which then may develop into a febrile illness. He denoted this type of pathological change (i.e. a febrile illness that arises due to internal injury) as ‘Yin Fire’, because it is a type of pathological (yin) Fire that arises from the interior of the body (yin) and is due to deficiency (yin). (51, 59) In this way Dr Li continued to develop his theories along the lines of his preceptor, emphasizing the key role of the middle Jiao (i.e. the Spleen and Stomach considered together as a single unit) in the maintenance of vigorous good health, as well as in the recovery from illness. Moreover, in developing and elaborating these key points of theory, Dr Li and his followers have been credited with founding their own great school (or ‘current of thought within TCM), named the ‘Tonifying Earth (Spleen-Stomach) School (bu tu pai). 

Pathogenesis and symptomatology of Yin Fire syndromes

Although Dr Li’s theoretical discussion on the pathogenesis of Yin Fire is complex, detailed and highly nuanced, the basic idea is quite simple. All physiological functions depend on the Qi, and Qi is seen as both the capacity for activity as well as the activity itself. In this sense we can regard Qi as the energy that gives rise to all the various physiological processes. This physiological Qi requires the presence of a force that both drives it and regulates it, and this function is carried out by a specific type of ‘Fire’, or Yang Qi (these terms are mostly interchangeable). In much the same way that an army is characterized by both explosive force as well as meticulous precision, the essential Yang Qi or Fire in the body provides the impetus and direction for all bodily functions. This physiological Fire (referred to as the ‘Minister’ Fire, because it is charged with getting things done) is compared to the fire from wooden logs in a hearth. The hearth, in which the logs are burning, is situated in the lower part of the trunk (the ‘lower Jiao’), the domain of the Kidney (and the Colon), while the flames of the fire ascend to drive and regulate the Qi throughout the whole body. The fire may be regarded as having its root in the logs, while its flames, spreading upwards, provide warmth and light to the rest of the house. The Minister Fire, thus, has its root in the lower Jiao and is regarded as an essential component of the Kidney, while the Yang Qi rises upwards from there to enliven the whole body. To return to the image of burning logs in the lower abdominal cavity: as long as the logs are in place and burning in an even way, all is well with the whole body; the Qi functions as it should, and the physiological processes proceed in a smooth and orderly fashion. According to Dr Li, when the Spleen and Stomach have become deficient, together with other related imbalances (e.g. stress, emotional strain and other types of deficiency), the logs tumble out of the fire-place and instead of warming and lighting the house, they set fire to it, wreaking destruction. The Five Elements associations here are as follows: one of the attributes of the Earth element is stability and holding things in place. When Earth in the body (Spleen and Stomach) becomes weakened, Earth is unable to provide the stabilizing force to keep the Minister Fire in place, and thus the source of the body’s normal physiological Fire becomes displaced and hence pathogenic. Normal healthy Fire, also referred to as the Yang Qi, is responsible for driving the body’s physiological activities, catalyzing the transformation of substances and promoting separation of the ‘clear’ (physiologically useful substances) from the ‘turbid’ (i.e. waste materials). Furthermore, when Fire becomes pathogenic, it behaves in much the same way as a bushfire burning out of control: it desiccates and destroys all in its path and may readily translocate from one site to another. 

As mentioned above, this is all quite complex and nuanced, relying on the axioms of macrocosmic-microcosmic correlations together with a deep understanding of Yin Yang and the Five Elements. However, the image that illustrates this pathological process is relatively simple and easy to grasp. 

Now, one may well ask: why doesn’t this happen to everyone whenever they become fatigued or lack adequate nourishment? As we know, there are various ways in which Spleen Qi deficiency may manifest, most of which do not involve clinical manifestations associated with fever. The first reason is that this is due to differences in body constitution and that various inherent weaknesses may predispose a person to respond in a specific way to a particular pathological change. However, this explanation is rather too broad for our purposes and doesn’t tell us very much. Dr Li and his followers provide another, more intricate explanation. In essence, this explanation posits a combination of factors, that may be present in different proportions, but are all required to be present together, in order for Spleen Qi deficiency to generate a Yin Fire syndrome. As he observed in Kaifeng and in the turmoil after the city’s fall, there is a combination of malnutrition (‘improper diet’, which includes consuming too many heating or cooling items, over-eating, under-eating, eating while in a hurry or stressed and engaging in taxing activities immediately after eating), physical exhaustion (overwork and lack of adequate rest), together with emotional overstimulation (‘injury by the seven emotions’). These factors generate several concomitant pathological imbalances, primarily affecting the Spleen and Liver. In addition, these imbalances lead to the formation of the critical endogenous pathogens, Damp and Damp-Heat. (51, 66) 

Although not mentioned specifically, intemperate use of alcohol was surely (and still is) an important contributing factor. Indeed, Dr Li’s Treatise on the Spleen and Stomach contains a chapter devoted to the herbal treatment of ‘Damage Due to Excessive Drinking of Alcohol’. Beginning with the admonition that alcoholic beverages are very Hot (in nature) and create Toxin, the chapter goes on to describe 19 different syndrome patterns and their herbal treatment. This amount detail on the differential diagnosis and treatment for a single type of disorder is only surpassed by the number of modifications described for his famous formula, Bu Zhong Yi Qi Tang (Supplement the Center and Boost the Qi Decoction, a.k.a. Ginseng and Astragalus Formula) in the treatment of various clinical scenarios that may be seen in patients with Yin Fire syndromes. (51)

We do not need to pursue the TCM pathogenetic pathways very much further before we start to get a  picture, although not quite so extreme, of the modern Western lifestyle: poor dietary habits, physical and mental overstrain, sleep deprivation and emotional overstimulation, often together with immoderate use of alcohol. Regrettably, this represents our cultural norm, and the diseases related to dysbiosis and leaky gut, as discussed in part one, are dramatically on the rise. (47, 67) Although these gut-related conditions are quite disparate, especially in the advanced stages, for the most part they share a common core symptomatology in their early stages. (68, 69) These symptom patterns are virtually identical to those of the Yin Fire syndromes described in the Treatise on the Spleen and Stomach:

• ‘Fever’ relating to the upper body, such as feelings of heat in the head, face and hands, red cheeks, thirst/dry mouth, dry nasal passages, mouth ulcers, headache.
• Clinical features of Spleen-Stomach deficiency, such as poor appetite, fatigue, loose stools, bloating after meals, spontaneous sweating.
• Some clinical features of Cold, such as pale tongue, sensitivity to the cold, chills.
• Some respiratory signs, such as dyspnea or nasal congestion. 

(51, 57, 59, 66)

Obviously, once the disease has become established, particularly in the case of the various auto-immune disease, the clinical features related to the affected organ/s become manifest. It should be noted, however, that in most autoimmune conditions it has been observed that the disease process tends to remit and recur over a variable time period before the overt features of a full-blown auto-immune condition become apparent. (69) Moreover, various researchers convincingly argue that the production of auto-antibodies is secondary to organ or tissue damage by bacteria or toxins escaping from an inflamed gut or caused by cross reaction to undigested large protein molecules or microbes that have passed into the blood stream from a leaky gut. (1, 2, 31, 34, 38, 70, 71, 72) This lends support to our thesis that the Yin Fire syndromes described by Dr Li correlate very closely with the triad of dysbiosis, inflammation and leaky gut. This is also borne out if we examine the approach to the diagnosis and treatment of allergies, auto-immune diseases, and inflammatory bowel disorders within contemporary TCM. (73 – 79) 

Radical approach to therapeutics

The unique ideas of Dr Li discussed so far are essentially a further development of traditional concepts: the critical importance of the Spleen and Stomach is discussed in the Yellow Emperor’s Classic of Medicine (huang di nei jing), as is the difference between illnesses due to exogenous pathogens and those due to internal imbalance; even fever due to deficiency was described by Zhang Zhong-jing (circa 150 – 219 CE) in the ‘Synopsis of Prescriptions of the Golden Cabinet’ (jin gui yao lue fang lun). Dr Li’s radical departure from the accepted standards, as variegated as they were within TCM during his time, is seen very clearly in the novel therapeutic applications that he developed. In order to clear Heat, when that Heat was due to Spleen-Stomach deficiency, he initiated the use of sweet warming herbs, specifically ginseng (ren shen), honey-fried or dry-fried astragalus (zhi huang qi) and honey-fried licorice root (zhi gan cao). Additionally, he used small doses of the ‘exterior releasing’ class of herbs (i.e. diaphoretics), pre-prepared by dry-frying to eliminate the diaphoretic action and harness their inherent Yang properties, to promote the functions of the Minister Fire and thereby reduce the pathological Yin Fire. This therapeutic equivalent of ‘fighting fire with fire’ went completely against the grain of the traditional medicine as practiced by his contemporaries: conditions due to Heat or Fire were always treated with Cold and Cooling medicines, generally in combination with strong methods of expulsion, such as purging, sweating or emesis. Dr Li and his followers argued that once you have made the critical distinction between a febrile illness due to exogenous factors and one due to internal factors, if you treat the latter by the standard methods of expelling pathogenic factors, you will make the condition worse and risk killing the patient. (51, 54, 57) 

Analysis of Ginseng and Astragalus Combination (bu zhong yi qi tang).

Perhaps the best known and most popular formula that Dr Li developed to treat Spleen deficiency leading to Yin Fire syndrome is Bu Zhong Yi Qi Tang (Ginseng and Astragalus Formula). Although it forms the basis for treating variants of the Yin Fire syndrome, it is also frequently used for treatment of Spleen Qi deficiency with ‘sinking Qi’, clinically manifesting with organ prolapse. A brief analysis of this formula follows: 

Formula ingredients:

• Astragalus membranaceus, root (huang qi)
• Codonopsis pilosula, root (dang shen)
• Atractylodes macrocephala, rhiz. (bai zhu)
• Angelica polymorpha, root (dang-gui)
• Glycyrrhiza uralensis, root (gan cao)
• Actaea cimicifuga, rhiz. (sheng ma)
• Bupleurum falcatum, root (chai hu)
• Citrus reticulata, fruit peel (chen pi)
• Zingiber officinale, rhiz. (sheng jiang)
• Ziziphus jujuba, fruit (da zao)

Formula composition, according to Scheid, Bensky et al. (86):

• Astragalus (huang qi) is the principal herb; as such it’s actions encompass the main actions of the whole formulation. It is generally lightly dry fried to enhance the actions of tonifying the Qi of the Spleen and Stomach as well as promoting the ascending movement of the Qi. Its secondary action is to tonify the Lung Qi and strengthen to defensive Qi, in order to consolidate the Exterior and stop excessive sweating.
• Panax ginseng (ren shen), which is nowadays substituted by Codonopsis pilosula, root (dang shen), is the ‘deputy’ herb, assisting some of the actions of the principal herb. It strongly tonifies the Qi and is assisted in this function by Atractylodes macrocephala, rhizome (bai zhu) and honey-fried Glycyrrhiza uralensis, root (zhi gan cao). Together, these three sweet-warm medicinals act on the Spleen and Stomach promoting all of their functional activities, including the elimination of Damp through the descending action of the Stomach Qi. 
• Angelica root (dang-gui) and Citrus peel (chen pi) are ‘assistants’, which supplement and modify the main actions of the formula. The former herb nourishes the Blood. This is an important consideration in applying any treatment that aims to tonify the Qi. This is one of the innovations that was developed by Dr Li’s teacher, Zhang Yuan-su, and is designed to boost the Blood so as to counterbalance and support the increased Qi, because Blood is the Yin counterpart of the Qi, and they always act together. Citrus has the actions of regulating the Qi and drying Damp, thus assisting digestion and absorption of the Qi tonifying herbs. Additionally, the Qi regulating action assists in promoting the ascending and descending movements of the Spleen and Stomach, respectively. 
• The two Wind expelling, exterior releasing (i.e. diaphoretic) herbs: Actaea  rhizome (sheng ma) and Bupleurum root (chai hu) are prepared by lightly dry frying so as to redirect the therapeutic action from the exterior to the interior of the body and accentuate their Yang nature. Thus, these two herbs assist the principal herb in raising the Yang Qi.  
• Subsequent physicians have often included two additional ingredients: Zingiber officinale, rhizome (sheng jiang) and Ziziphus jujuba, fruit (da zao), which in combination are also warm and sweet, serving to provide additional support to the middle Jiao (i.e. Spleen and Stomach), allowing the other herbs in the formula to be more easily absorbed.

Chen and Chen provide a summary of the pharmacological effects of this formula (87): 

• Regulatory effect on intestinal peristalsis (i.e. increases or decreases, depending on the condition)
• Increase in gastric acid secretion (dose dependent effect)
• Adaptogenic for physical stress
• Anti-ageing (improves endurance, learning, memory, neuromuscular co-ordination, and brain mono-amine levels)
• Immunostimulant (immune enhancing effect)
• Anti-allergic
• Anti-cancer (induces apoptosis of human hepatoma cell cultures, and enhances natural killer cell activity)
• Radioprotective 
• Antibiotic (against H. pylori)
• Antiviral (by enhancing host immune responses)
• Prevention of bone loss (in ovari-ectomised rats)
• Antidepressive and antinociceptive (animal experiments)

Additionally, they also report that clinical studies, carried out in China, have shown that this formula is useful in the following medical conditions: chronic fatigue syndrome, gastric prolapse, rectal prolapse, uterine prolapse, nephroptosis, gastritis, nausea and vomiting, constipation, diarrhoea, fever, leukopenia, compromised immunity in the elderly, common cold, MRSA (Methicillin-resistant Staphylococcus aureus) infection, hypertension, dysuria, urinary frequency, incontinence, seizures and epilepsy, myasthenia gravis, depression, excessive menstrual bleeding, male infertility, tinnitus, allergic rhinitis, cataract in the elderly (modified formula), chronic hepatitis. 

Effects on the on microbiota

The therapeutic actions of the herbs in this formula are mediated by a variety of pathways. Over the past 50 years much attention has been given to the effects of ‘active’ constituents within these herbs (85), often resulting in commercially available extracts with standardised concentrations of these organic compounds. However, from the above discussion it is apparent that components that are only poorly absorbed may, in fact, contribute substantially to the clinical effects in vivo, via metabolites produced by the microbiota. Moreover, it is now apparent that some of the therapeutic actions are produced through direct action on the microbiota community itself, through promotion of probiotic species. (88 – 92)

It bears repeating that in TCM ‘Spleen-Stomach theory emphasizes functional integration rather than the individual anatomical organs. Notably, these organs are mainly involved in digestion, as well as immunity, hematopoiesis, and metabolism, which is functionally consistent with the roles of the gut microbiota’. (90) Additionally, intestinal dysbiosis may produce the classic signs of Spleen deficiency and Damp retention: poor appetite, loose stools, bloating and thickened tongue coat. (90, 93)

One important caveat: as discussed above, it is all very well to study herbal medicines, or their components, in isolation; but this is artificial and may not accurately reflect real-world clinical scenarios. In TCM, herbal medicines are always prescribed in synergistic groups, and the small amount of data that is currently available generally shows that the putative actions of a single herb are significantly modified by the actions of the other herbs in a multi-herb formula.  Take, for example, the berberine containing herbs Coptis rhizome (huang lian) and Scutellaria root (huang qin). We know that these two herbs have broad spectrum antimicrobial properties, (94, 95) meaning that they are poorly selective and may act against both probiotic and pathogenic bacteria in the gut. Therefore, we are cautioned against their general use in patients with dysbiosis. (84) However, when Coptis and Scutellaria are administered in combination with Pueraria root (ge gen) and honey-fried Glycyrrhiza root (zhi gan cao), as in the traditional formulation ‘Ge Gen Qin Lian Tang’, the effects on the gut microbiota are both selective and favourable. (91)

Astragalus root (huang qi)

On its own, extract of Astragalus root inhibits Clostridium perfringens (a pathogen), (96); increases probiotic species including Lactobacilli (97); promotes proliferation and function of intestinal intraepithelial T cells. (98) In combination with Atractylodes rhizome: induces an increase in cellulolytic bacteria and decrease in Streptococci and Enterococci, improves intestinal microbiota homoeostasis and maintains intestinal barrier functionality and integrity. (91)

Panax ginseng root (ren shen)

On its own, decoction of P. ginseng induces an increase in Lactobacilli and various species of Bacteroides, (91) as well as a shift towards increased numbers of probiotic species relative to potential pathogens (99) In contemporary TCM practice Codonopsis root is generally used as a substitute as Panax ginseng, with a three-fold increase in dosage. (86)

Codonopsis root (dang shen)

The polysaccharides and saponins from Codonopsis increase intestinal mucosal immunity, increase lactobacilli and short chain fatty acid production (through enhancement of probiotic bacteria), reduce intestinal inflammation, inhibit the growth of pathogenic or potentially pathogenic intestinal bacteria (e.g. Bacteriodes species) and increase the proportion of beneficial species of Bifidobacteria and Ackermnasia (100, 101)

Atractylodes rhizome (bai zhu)

The active polysaccharide of Atractylodes rhizome restore diversity and balance of the intestinal flora in rats treated to induce chronic diarrhea, and improve recovery time from associated symptoms of listlessness, loss of appetite and weight loss. (64)

In combination with Citrus fruit (similar constituents to Citrus peel): enhances intestinal motility, improves and excretion of intestinal bacterial together with their toxins, reduces toxin absorption, improves intestinal barrier function. (102)

Citrus peel (chen pi)

Citrus peel extract stimulates intestinal motility (103). Due to its content of phenols, polyphenols and tannins (PPT), (104) its main therapeutic actions, as discussed above, would be derived from three mechanisms: direct action on the microbiota, promoting beneficial species and suppressing pathogens; direct action on the intestinal epithelial cells enhancing barrier function (33); and thirdly via PPT metabolites, derived from the microbiota. (16, 37)

Angelica root (dang-gui)

More than 70 compounds have been isolated and identified from Angelica danggui, including organic acids and polysaccharides. The whole herb, extract or components exhibit anti-inflammatory, immunomodulatory, cardioprotective, neuroprotective, and anti-oxidant effects, amongst others. (105)  It appears likely that some of these effects, particularly the anti-inflammatory and immunomodulatory effects are due to therapeutic action on the gut microbiota and intestinal barrier function. (106)

Glycyrrhiza  root (gan cao)

Recent in vitro studies have shown that Glycyrrhiza root modulates the gut microbiota in a manner predicted to improve colonic epithelium function, reduce inflammation, and promote protection from bacterial opportunistic pathogenic infection. (107)

Actaea rhizome (sheng ma)

To date, more than 457 compounds have been isolated from Actaea species, and clinical research has mainly been focused on the plant’s activities for treatment of menopausal syndrome and its anti-osteoporosis, antiviral, antitumor, antioxidant and antiangiogenic actions. (108) Actaea species also contain a variety of phenolic compounds, (85, 108) which, as discussed above, mainly exert their anti-oxidant action through their actions on, and metabolism by, the microbiota. 

Bupleurum root (chai hu)

The polysaccharides from Bupleurum root (BPs) have been shown to significantly decrease levels of blood glucose and also to increase levels of serum insulin and liver glycogen in a diabetic murine model. In addition, BPs protected the pancreas and liver from oxidative and inflammatory damage. (109) These effects are at least in part likely to be due to actions mediated by the gut microbiota as BPs are a type of MAC (microbe accessible carbohydrate). 

Zingiber rhizome (sheng jiang)

Ginger rhizome is included mainly for its anti-nausea and carminative actions. (110)

Ziziphus fruit (da zao)

Ziziphus fruit has antioxidant, neuroprotective, anti-cancer, anti-inflammatory, immunomodulatory, anti-obesity, as well as cardio-, hepato- and gastrointestinal protective actions. The compounds responsive for its bioactivity include nucleotides, triterpenes, flavonoids and polysaccharides. (111) The latter two components are known to have reciprocal interactions with the gut microbiota.  

Concluding remarks: ‘Weed, Feed and Seed’ 

The clinical application of TCM formulas to address gut health follows essentially the weed and feed components of the naturopathic protocol for dysbiosis, together with the additional therapeutic actions encompassed by the term ‘tonification’: strengthening smooth muscle, regulating peristalsis, improving gastric relaxation, improving gastric and intestinal motility, increasing secretions, facilitation of gastric emptying, and promotion of mucosal blood flow. (112). 

In regard to the ‘seed’ component, as the herbal extracts have undergone prolonged decoction, they are virtually sterile, and therefore not a source of beneficial bacteria. As discussed above and in part one, a healthy individual may have several hundred different probiotic species living in symbiosis with the gut, in a dynamic state of balance with potential pathogens from the local environment. It is therefore very difficult to design a probiotic supplement that would cover the scope and individual variation necessary to provide a healthy gut microbiota population in a dysbiotic patient. Although supplementation with a limited number of specific probiotic species may be beneficial in the short term, long term gut health is best maintained through the regular consumption of a varied diet that includes a variety of fermented (in realty ‘fermenting’) live (i.e. non-pasteurized) foods. Fortunately, these are now becoming more widely available; moreover, they are quite easy to make at home. 

The TCM approach to ‘weed and feed’ takes into consideration the pathogenic load, versus the host resistance (i.e. xie qi vs zheng qi), which is assessed by clinical observation. In Chapter 2, Book 2 of the ‘Treatise on the Spleen and Stomach’ (pi wei lun), Dr Li presents more than twenty variations (mostly in the form of additions) for his formula, Bu Zhong Yi Qi Tang (Ginseng and Astragalus Formula). Many of these are for the purpose of dispelling different pathogens, with clinical features such as abdominal pain in various locations, signs of Heat, signs of Cold, headaches, signs of Damp, constipation, epigastric or abdominal bloating, loss of appetite and thickened tongue coating. These clinical scenarios can be correlated with the manifestations of dysbiosis, and these manifestations are treated according to signs and symptoms, always weighing up the relative strength of the patient’s health Qi (zheng qi) against the virulence of the pathogenic factors (xie qi). Thus, within the TCM paradigm, the components of the treatment that aim to dispel pathogens will reduce the load of gut pathogens, while at the same time the tonifying components protect the microbiota population from being decimated by the ‘poorly selective’ antibacterial herbs, thus preserving and promoting beneficial species.

In the next part of this series we will discuss various protocols for gut healing using traditional Chinese herbal formulas. 

REFERENCES PART 2

1. Ferreira, C., Vieira, A., Vinolo, M., Oliveira, F., Curi, R., Martins, F. (2014). The central role of the gut microbiota in chronic inflammatory diseases. J Immunol Res, 2014. 689492
2. Kim, D., Zeng, M., Núñez, G. (2017). The interplay between host immune cells and gut microbiota in chronic inflammatory diseases. Exp Mol Med, 49(5), e339.
3. Gilbert, J. (2015). Our unique microbial identity. Genome biology, 16(1), 97.  
4. Lloyd-Price, J., Abu-Ali, G., Huttenhower, C. (2016). The healthy human microbiome. Genome Med, 8(1), 51. 
5. Thursby, E., Juge, N. (2017). Introduction to the human gut microbiota. Biochem J, 474(11), 1823-1836. 
6. Yadav, M., Monika, M., Chauhan, N. (2018). A review of metabolic potential of human gut microbiome in human nutrition. Arch Microbiol, 200 (2): 203-217.
7. Wang, B., Yao, M.,Lv, L., Ling, Z., Li, L. (2017). The Human Microbiota in Health and Disease. Engineering. 3(2017):71-82
8. Maier, L., Pruteanu, M., Kuhn, M., Zeller, G., Telzerow, A., Anderson, E., Brochado, A., Fernandez, K., Dose, H., Mori, H., Patil, K., Bork, P., … Typas, A. (2018). Extensive Impact of Non-Antibiotic Drugs on Human Gut Bacteria Nature, 555(7698), 623-628.
9. Valdes, A., Walter, J., Segal, E., Spector, T. (2018). Role of the gut microbiota in nutrition and health. The BMJ, 361: k2179. 
10. Mao, Q., Manservisi, F., Panzacchi, S., Mandrioli, D., Menghetti, I., Vornoli, A., Bua, L., Falcioni, L., Lesseur, C., Chen, J., Belpoggi, F., … Hu, J. (2018). The Ramazzini Institute 13-week Pilot Study on Glyphosate and Roundup Administered at Human-Equivalent Dose to Sprague Dawley Rats: Effects On The Microbiome. Environ Health; 17(1), 50. 
11. Dubinkina, V., Tyakht, A., Odintsova, V., Yarygin, K., Kovarsky, B., Pavlenko, A., Ischenko, D., Popenko, A., Alexeev, D., Taraskina, A., Nasyrova, R. , Krupitsky, E., Shalikiani, N., Bakulin, I., Shcherbakov, P., Skorodumova, L., Larin, A., Kostryukova, E., Abdulkhakov, R., Abdulkhakov, S., Malanin, S., Ismagilova, R., Grigoryeva, T., Ilina, E., … Govorun, V. (2017). Links of Gut Microbiota Composition with Alcohol Dependence Syndrome and Alcoholic Liver Disease. Microbiome, 5(1), 141. 
12. Engen, P., Green, S., Voigt, R., Forsyth, C., Keshavarzian, A. (2015). The Gastrointestinal Microbiome: Alcohol Effects on the Composition of Intestinal Microbiota. Alcohol Res; 37(2), 223-36.
13. Pandey, K., Naik, S., Vakil, B. (2015). Probiotics, Prebiotics and Synbiotics- a Review. J Food Sci Technol, 52(12), 7577-87. 
14. Vyas, U., Ranganathan, N. (2012). Probiotics, Prebiotics, and Synbiotics: gut and beyond. Gastroenterol Res Pract, 2012, 872716.
15. Singh, R., Chang, H., Yan, D., Lee, K., Ucmak, D., Wong, K., Abrouk, M., Farahnik, B., Nakamura, M., Zhu, T., Bhutani, T., … Liao, W. (2017). Influence of Diet on The Gut Microbiome and Implications for Human Health. J Transl Med, 15(1), 73. 
16. Wilson K, Situ, C. (2017) Systematic Review on Effects of Diet on Gut Microbiota in Relation to Metabolic Syndromes J Clin Nutr Metab 1:2. 
17. Menni, C., Zierer, J., Pallister, T., Jackson, M., Long, T., Mohney, R. et al. (2017). Omega-3 Fatty Acids Correlate with Gut Microbiome Diversity and Production of N-Carbamylglutamate in Middle Aged and Elderly Women. Scientific Reports, 7(1). 11079 
18. Selhub, E., Logan, A., Bested, A. (2014). Fermented Foods, Microbiota, and Mental Health: Ancient Practice Meets Nutritional Psychiatry. J Physiol Anthropol, 33(1), 2.
19. Marco, M., Heeney, D., Binda, S., Cifelli, C., Cotter, P., Foligné, B., Gänzle, M., Kort, R., Pasin, G., Pihlanto, A., Smid, E., Hutkins, R. (2017). Health Benefits of Fermented Foods: Microbiota and Beyond. Curr Opin Biotechnol. 44:94-102.
20. Dueñas, M., Muñoz-González, I., Cueva, C., Jiménez-Girón, A., Sánchez-Patán, F., Santos-Buelga, C., Moreno-Arribas, M. V., … Bartolomé, B. (2015). A survey of modulation of gut microbiota by dietary polyphenols. BioMed Res Int, 2015: 850902. 
21. Sonnenburg, E., Sonnenburg, J. (2014). Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metab, 20(5), 779-786.
22. Koropatkin, N., Cameron, E., Martens, E. (2012). How glycan metabolism shapes the human gut microbiota. Nat Rev Microbiol, 10(5), 323-35. 
23. Sonia, S., Witjaksono, F., Ridwan, R. (2015). Effect of cooling of cooked white rice on resistant starch content and glycemic response. Asia Pac J Clin Nutr; 24(4):620-5
24. Lockyer, S., Nugent, A. (2017). Health effects of resistant starch. British Nutrition Foundation. Nutrition Bulletin, 42(1):10-41
25. CSIRO Website. Nutrition and Health/ Gut Heath/ Case Study: Resistant Starch. Retrieved Nov 8, 2018 from: https://www.csiro.au/en/Research/BF/Areas/Nutrition-and-health/Nutrition-and-gut-health/Resistant-starch
26. Pendyala, S., Walker, J. M., Holt, P. (2012). A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology, 142(5), 1100-1101.e2.
27. Sasada, T., Hinoi, T., Saito, Y., Adachi, T., Takakura, Y., Kawaguchi, Y., Sotomaru, Y., Sentani, K., Oue, N., Yasui, W., … Ohdan, H. (2015). Chlorinated Water Modulates the Development of Colorectal Tumors with Chromosomal Instability and Gut Microbiota in Apc-Deficient Mice. PloS One, 10(7), e0132435.  
28. De Palm, G., Nadal, I., Collado, M., Sanz, Y. (2009). Effects of a gluten-free diet on gut microbiota and immune function in healthy adult human subjects. Br J Nutr, 102(8):1154-60 
29. Sanz, Y. (2010). Effects of a gluten-free diet on gut microbiota and immune function in healthy adult humans. Gut microbes, 1(3), 135-7.
30. Bonder, M., Tigchelaar, E., Cai, X., Trynka, G., Cenit, M., Hrdlickova, B., Zhong, H., et al. (2016). The influence of a short-term gluten-free diet on the human gut microbiome. Genome Medicine. 8. 10.1186/s13073-016-0295-y.
31. Fasano, A. (2012). Zonulin, regulation of tight junctions, and autoimmune diseases. Annals of the New York Academy of Sciences; 1258(1), 25–33. 
32. Ulluwishewa, D., Anderson, R., McNabb, W., Moughan, P., Wells, J., Roy, N. (2011). Regulation of Tight Junction Permeability by Intestinal Bacteria and Dietary Components. J Nutr, 141(5):769–776
33. De Santis, S., Cavalcanti, E., Mastronardi, M., Jirillo, E., Chieppa, M. (2015). Nutritional Keys for Intestinal Barrier Modulation. Front Immunol, 6: 612. 
34. Pastorelli, L., De Salvo, C., Mercado, J., Vecchi, M., Pizarro, T. (2013). Central role of the gut epithelial barrier in the pathogenesis of chronic intestinal inflammation: lessons learned from animal models and human genetics. Front Immunol, 4: 280. 
35. Kedia, S., Ahuja, V. (2017). Epidemiology of Inflammatory Bowel Disease in India: The Great Shift East. Inflamm Intest Dis, 2(2):102-115.
36. Ray, G. (2016). Inflammatory bowel disease in India – Past, present and future. World J Gastroenterol, 22(36):8123-36. 
37. Clifford, M. (2004). Diet-derived phenols in plasma and tissues and their implications for health. Planta Med; 70(12): 1103-1114
38. Lerner, A., Matthias, T. (2015). Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease. Autoimmun Rev; 14(6):479-89.
39. Hollon, J., Puppa, E., Greenwald, B., Goldberg, E., Guerrerio, A., Fasano, A. (2015). Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity. Nutrients, 7(3):1565-76. 
40. Swanson, G. R., Tieu, V., Shaikh, M., Forsyth, C., Keshavarzian, A. (2011). Is moderate red wine consumption safe in inactive inflammatory bowel disease? Digestion, 84(3), 238-44.
41. Patel, S., Behara, R., Swanson, G., Forsyth, C., Voigt, R., Keshavarzian, A. (2015). Alcohol and the Intestine. Biomolecules, 5(4), 2573-88. 
42. Bala, S., Marcos, M., Gattu, A., Catalano, D., & Szabo, G. (2014). Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals. PloS One, 9(5), e96864. 
43. Queipo-Ortuno, M., Boto-Ordonez, M., Murri, M.,  Gomez-Zumaquero, J., Clemente-Postigo, M., Estruch, R., Diaz, F., Andrés-Lacueva, C., Francisco J Tinahones, F. (2012). Influence of Red Wine Polyphenols and Ethanol on the Gut Microbiota Ecology and Biochemical Biomarkers. Am J Clin Nutr, 95(6):1323–1334,
44. Engen, P., Green, S., Voigt, R., Forsyth, C., Keshavarzian, A. (2015). The Gastrointestinal Microbiome: Alcohol Effects on the Composition of Intestinal Microbiota. Alcohol Res, 37(2): 223-36.
45. Denke, M. (2000). Nutritional and Health Benefits of Beer. Am J Med Sci, 320(5):320-6.
46. Duke University: The Alcohol Pharmacology Education Partnership. https://sites.duke.edu/apep/module-1-gender-matters/content/content-how-is-alcohol-absorbed-into-the-body/
47. Cowan, T. (2018). Vaccines, Autoimmunity and the Changing Nature of Childhood Illness. Vermont: Chelsea Green Publishing.
48. Mullin, E. (2011). The Inside Tract. New York: Rodale Press, NY.
49. Sivin, N. (1987). Traditional Medicine in Contemporary China. Ann Arbor, Michigan: U. of M. Center for Chinese Studies. 
50. Ni, M. (1995). The Yellow Emperor’s Classic of Medicine: A New Translation of the ‘Neijing Suwen’ with Commentary. Shambhala Publications 
51. Flaws, B. (2004). Li Dong-Yuan’s Treatise on the Spleen and Stomach. A Translation of the Pi Wei Lun. Boulder, Co: Blue Poppy Press. 
52. Yang, S, (Transl), Flaws, B. (Ed) (1993). The Heart & Essence of Dan-Xi’s Methods of Treatment: A Translation of Zhu Dan-Xi’s Zhi Fa Xin Yao by Zhu Dan-Xi . Boulder, Co: Blue Poppy Press
53. Kurz, J (2001). The Politics of Collecting Knowledge: Song Taizong’s Compilation Project. T’oung Pao International Journal of Chinese Studies.87(4): 289-316
54. Dharmananda, S. (2001). The Jin-Yuan Medical Reforms. From ITM Online website: Articles. Retrieved Nov 2018 from: http://www.itmonline.org/arts/jinyuan.htm 
55. Hymes, R. (2016). Epilogue: A Hypothesis on the East Asian Beginnings of the Yersinia pestis Polytomy. The Medieval Globe: 1(1 ): Article 12. 
56. Simonis, F. (2015). Ghosts or Mucus? Medicine for Madness: New Doctrines, Therapies, and Rivalries. From: Modern Chinese Religion I (2 Vol. set), 601–639.
57. Boyanton, S. (2015). The Treatise on Cold Damage and the Formation of Literati Medicine: Social, Epidemiological, and Medical Change in China, 1000-1400. Columbia University, Ph.D. Dissertation. Retrieved 5^th December, 2018 from: https://stephenboyanton.com/history/ 
58. Prescott, A. (2012). Medical Masters of the Jin-Yuan Dynasties. From Harmonygate website, Articles. Retrieved 4^th December, 2018 from: http://www.harmonygate.com/ 
59. Buck, C. (2015). Acupuncture and Chinese Medicine Roots of Modern Practice. London, Philadelphia: Singing Dragon 
60. Sun H, Dong T, Zhang A, et al. (2013). Pharmacokinetics of Hesperetin and Naringenin in the Zhi Zhu Wan, a Traditional Chinese Medicinal Formulae, and its Pharmacodynamics Study. Phytother Res, 27(9): 1345–51.
61. Chen, K, Chen, T. (2009). Chinese Herbal Formulas and Applications. CA: Art of Medicine Press Inc. (pp.1274-7)
62. Wu, H., Jing, Z., Tang, X., Wang, X., Zhang, S., Yu, Y., Wang, Z., Cao, H., Huang, L., Yu, Y., Wang, Y. (2011). To compare the efficacy of two kinds of Zhizhu pills in the treatment of functional dyspepsia of spleen-deficiency and qi-stagnation syndrome:a randomized group sequential comparative trial. BMC Gastroenterology; 11:81
63. Hawrelak, J., Cattley, T., Myers, S. (2009). Essential Oils in the Treatment of Intestinal Dysbiosis: A Preliminary in vitro Study. Altern Med Rev;14(4):380-384
64. Wang, R., Zhou, G., Wang, M., Peng, Y., Li, X. (2014). The Metabolism of Polysaccharide from Atractylodes macrocephala Koidz and Its Effect on Intestinal Microflora. Evid Based Complement Alternat Med: 2014, 926381. 
65. SA Health: Health Topics: Plague retrieved December, 2018 from: https://www.sahealth.sa.gov.au/wps/wcm/connect/public+content/sa+health+internet/health+topics/health+conditions+prevention+and+treatment/infectious+diseases/plague
66. Maciocia, G. (2012). Maciocia, G. (2012). Yin Fire. From Giovanni Maciocia website. Retrieved December, 2018 from: http://maciociaonline.blogspot.com/2012/08/yin-fire.html
67.  Lerner, A., Jeremias, P., Matthias, T. (2015). The World Incidence and Prevalence of Autoimmune Diseases is Increasing. Int J Celiac Dis, 3(4)151-5
68. US National Library of Medicine. A.D.A.M. Encyclopedia. Autoimmune disorders. Retrieved December, 2018 from: https://medlineplus.gov/ency/article/000816.htm
69. Bliddal, S., Nielsen, C. H., & Feldt-Rasmussen, U. (2017). Recent advances in understanding autoimmune thyroid disease: the tallest tree in the forest of polyautoimmunity. F1000Res, 6, 1776. 
70. Mu, Q., Kirby, J., Reilly, C., Luo, X. (2017). Leaky Gut as a Danger Signal for Autoimmune Diseases. Front Immunol, 8: 598. 
71. Fasano, A. (2011). Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer. Physiol Rev; 91(151-175)
72. Zhang, P., Minardi, L., Kuestetner, J., Zekan, S., Kruzelock, R. (2018). Anti-microbial Antibodies, Host Immunity and Autoimmune Disease. Front Med, 5:153
73. Greenwood, M. (2017). Dysbiosis, Spleen Qi, Phlegm and Complex Difficulties. Med Acupunct, 29(3)
74. Flaws, B., Sionneau, P. (2001). The Treatment of Modern Western Medical Diseases with Chinese Medicine. Boulder, CO: Blue Poppy Press. (pp. 199, 210, 241, 313, 353, 461, 487, 517)
75. Rosenberg, Z. (2004). Chinese Medical Theory and Autoimmune Disease. From Crane Herb Company Website, Articles. Retrieved 28/09/2018 from: https://www.craneherb.com/shared/articles/10_Chinese_Medical_Theory.aspx
76.  Rosenberg, Z. (2004). Li Dongyuan’s Treatise on the Spleen and Stomach and Treatment of Autoimmune Disorders. From Bioethicus website, Articles. Retrieved 10/09/2018 from: http://www.bioethicus.com.br/d_artigos/1182991725.pdf
77.  Shen, P. (2012). Shen’s Textbook on the Management of Autoimmune Diseases with Chinese Medicine. U.K.: Donica Publishing Ltd. (pp. 31-39)
78. Tierra, M. (2018). Bu Zhong Yi Qi Tang to treat a wide range of diseases based in Spleen Qi and Yin Deficiency. East West School of Planetary Herbology website,  Blogs. Retrieved December, 2018 from: https://planetherbs.com/blogs/michaels-blogs/bu-zhong-yi-qi-tang-to-treat-a-wide-range-of-diseases-based-in-spleen-qi-and-yin-deficiency/
79. Tierra, M. (2018). Treating Chronic, Complicated Conditions with Li Dong Yuan’s Pi Wei Lun. Retrieved December, 2018 from: https://planetherbs.com/blogs/michaels-blogs/treating-chronic-complicated-conditions-with-li-dong-yuan-s-pi-wei-lun/
80.  Tillman, H., West, S. (editors and co-authors) (1995). Essays on Chin Intellectual and Cultural History. Albany, NY: State University of New York Press.
81. Shinno, R. (2016). The Politics of Chinese Medicine Under Mongol Rule. New York, NY: Routledge. (pp.131-2)
82. West, S. (1986). Chilly Seas and East Flowing Rivers: Yüan Hao-wen’s Poems of Death and Disorder, 1233-1235. J Amer Orient Soc.106(1):197-210
83.  Hywood, A. (2004). A Bowel Flora Protocol for Dysbiosis Management. Townsend Letter for Doctors and Patients, July, 2004. Retrieved Jan. 2019 from: http://www.townsendletter.com/July2004/phytotherapy0704.htm
84. Hawrelak,. J. (2014). Phytotherapy in the Treatment of Dysbiosis of the Small and Large Bowel. Metagenics International Congress on Natural Medicine. Retrieved Jan 22, 2019 from: http://congress.metagenics.com.au/postcongress/media/presentation-slides/day2-2-jason-hawrelax-treatment-dysbiosis-small-and-large-bowel.pdf. 
85. Chang, H., But, P. (1986). Pharmacology and Applications of Chinese Materia Medica. Singapore: Word Scientific Publishing
86. Scheid, V., Bensky, D., Ellis, A., Barolet, R. (2015). Chinese Herbal Medicine Formulas and Strategies. Seattle, WA: Eastland Press. 
87. Chen, J., Chen, T. (2008). Chinese Herbal Formulas and Applications: Pharmacological Effects & Clinical Research. City of Industry,CA: Art of Medicine Press Inc.
88. Li, H., Zhou, M., Zhao, A., Wei J. W. (2009).  Traditional Chinese Medicine: Balancing the Gut Ecosystem. Phytother Res. 23:1332–1335
89. Zu, X., Nagle, D., Zhou, Y., Zhang, W. (2018). Application of Intestinal Flora in the Study of TCM Formulae, Ch.5 in Systems Biology and its Application in TCM Formulas Research, pp. 97-112. Elsevier B.V. Retrieved December, 2018 from: https://www.sciencedirect.com/science/article/pii/B9780128127445000059
90. Wang, R., Zhang, L., Xu, J., Gu, Z., Zhang, L., Ji, G., Liu, B. (2018). Human microbiome brings new insights to traditional Chinese medicine. J Bio-X Res, 1(1) 41-44
91. Lyu, M., Wang, Y., Fan, G., Wang, X., Xu, S., Zhu, Y. (2017). Balancing Herbal Medicine and Functional Food for Prevention and Treatment of Cardiometabolic Diseases through Modulating Gut Microbiota. Front Microbiol, 8, 2146. 
92. Wang, X., Li, X., Peng, Y. (2017). Impact of Qi-invigorating traditional Chinese medicines on intestinal flora: A basis for rational choice of prebiotics. Chin J Nat Med, 15(4):241-254
93. Liu, J., Peng, Y., Zhang, S. (2010). Investigation on Intestinal Microflora of Elderly Patients with Spleen Deficiency by 165 rDNA DGGE Analysis. Zhonghua Zhongyiyao Zazhi, 25:1566-69
94. Muluye, R., Bian, Y., Alemu, P. (2014). Anti-inflammatory and Antimicrobial Effects of Heat-Clearing Chinese Herbs: A Current Review. J Tradit Complement Med, 4(2), 93-8.
95. Chu, M., Xiao R., Yin, Y., Wang, X., Chu, Z., et al. (2014) Berberine: A Medicinal Compound for the Treatment of Bacterial Infections. Clin Microbiol, 3:150.
96. Ahn, Y., Kwon, J., Chae, S., Park, J., Yoo, Y. (1994). Growth-inhibitory Response of Human Intestinal Bacteria to Extracts of Oriental Medicinal Plants. Microb Ecol Health Dis (7):257-61 
97. Li, S., Zhao, X., Wang, J. (2009). Synergy of Astragalus polysaccharides and probiotics (Lactobacillus and Bacillus cereus) on immunity and intestinal microbiota in chicks. Poult Sci. 88(3):519-525\
98. Vetvicka, V., Vetvickova, J. (2014). Natural immunomodulators and their stimulation of immune reaction: true or false? Anticancer Res.34(5):2275-2282. 
99. Song, M., Kim, B., Kim, H. (2014). Influence of Panax ginseng on obesity and gut microbiota in obese middle-aged Korean women. J Ginseng Res, 38(2), 106-15.
100. Jing, Y., Li, A., Liu, Z., Yang, P., Wei, J., Chen, X., Zhao, T., Bai, Y., Zha, L., Zhang, C. (2018). Absorption of Codonopsis pilosula Saponins by Coexisting Polysaccharides Alleviates Gut Microbial Dysbiosis with Dextran Sulfate Sodium-Induced Colitis in Model Mice. BioMed Res Int, 2018, 1781036. 
101. Fu, Y., Feng, B., Zhu, Z., Feng, X., Chen, S., Li, L., Yin, Z., Huang, C., Chen, X., Zhang, B., Jia, R., Song, X., Lv, C., Yue, G. Z., Ye, G., Liang, X. X., He, C. L., Yin, L. Z., Zou, Y. F. (2018). The Polysaccharides from Codonopsis pilosula Modulates the Immunity and Intestinal Microbiota of Cyclophosphamide-Treated Immunosuppressed Mice. Molecules (Basel, Switzerland), 23(7), 1801.
102. Zhang, J., Chen, Q., Luo, D., You-Li, K., Yang, Y. (2009). Effect of the Zhishu Decoction on the permeability of rat intestinal mucosal barrier. Chin J Integr Tradit West Med Dig; 17:227–9.
103. Lyu, J., Lee, H. (2013). Effects of dried Citrus unshiu peels on gastrointestinal motility in rodents. Arch Pharmacol Res;36(5):641-8
104. Xu, G., Chen, J., Liu, D., et al. (2008). Minerals, phenolic compounds, and antioxidant capacity of citrus peel extract by hot water. J Food Sci;73(1):C11-8 
105. Chao, W., Lin, B. (2011). Bioactivities of Major Constituents Isolated from Angelica sinensis (Danggui). Chin Med. 6:29 
106. Gao, Z., Li, Q., Wu, X., Zhao, X., Zhao, L., Tong, X. (2017). New Insights into the Mechanisms of Chinese Herbal Products on Diabetes: A Focus on the ‘Bacteria-Mucosal Immunity-Inflammation-Diabetes’ Axis. J Immunol Res, 2017: 813086
107. Peterson, C., Sharma, V., Uchitel, S., Denniston, K., Chopra, D., Mills, P., Peterson, S. (2018) Prebiotic Potential of Herbal Medicines Used in Digestive Health and Disease. J Altern Complement Med. 24(7):656-665
108. Guo, Y., Yin, T., Wang, X., Zhang, F., Pan, G., et al. (2017). Traditional uses, phytochemistry, pharmacology and toxicology of the genus Cimicifuga: A review. J Eyhnopharmacol; 209:264-82
109. Pan, L., Weng, H., Li, H., Liu, Z., Xu, Y., et al. (2015) Therapeutic Effects of Bupleurum Polysaccharides in Streptozotocin Induced Diabetic Mice. PLOS ONE 10(7): e0133212.
110. Bode, A., Dong, Z. (2011). The Amazing and Mighty Ginger. In: Benzie IFF, Wachtel-Galor S, editors. Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; Chapter 7. 
111. Pierluigi, P., 2016). (Pharmacological Aspects of Jujubes. Pharmacologia, 7: 243-255
112. Suzuki, H., Inadomi, J., Hibi, T.(2009). Japanese herbal medicine in functional gastrointestinal disorders. Neurogastroenterol Motil; 21(7): 688–696.