Healing The Gut: Restore the Spleen Qi Part 4 – More Insights Into The Human Microbiome And Small Intestinal Bacterial Overgrowth (SIBO)

Introduction

In this article we will explore and evaluate the empirical research-based knowledge to date and attempt to integrate this with TCM theories and practice. In order to do this effectively we need to clearly define our terms, understand the concepts embodied in these terms, and also appreciate the implications and limitations of each of these concepts. The following section deals with a few of the more important ones.

Technical Terms And Critical Issues

As mentioned towards the end of Part 3, a uniform standardised terminology is yet to be adopted by the new breed of ‘microbiome scientists’; (1, 2) and the situation only gets worse when we look at the published information from healthcare practitioners of different modalities, who seek to popularise the knowledge gained from research in this area. Below are definitions of some key terms together with a brief outline of the critical issues that surround them.

Microbiota: This refers to the micro-organisms that are present in a particular bodily region (i.e. the GIT in the present discussion). Microbiota include bacteria, archaea, fungi, protozoa and viruses. The term may be used as a singular noun to denote the totality of micro-organisms in a given region of the body, or it may be used as a plural noun when used in reference to the variety micro-organisms that are inhabiting a particular site.

Microbiome: The microbiota together with the immediate environment, within which the mass of micro-organisms lives and interacts, is referred to as the microbiome. This includes the intestinal wall with related muscular, nervous and immune cells and tissues. It also includes the intestinal contents, with substances derived from the diet, digestive enzymes, bile acids and other secretions from the intestinal epithelial cells, each of which has a profound influence in shaping the microbiota. Additionally, as pointed out in a recent review paper, the network of glial cells within the enteric nervous system also play a very important role in this regard. The glial cells do much more than provide structural support. Just when we were getting comfortable with the idea that the microbiota have essential and variegated roles in health maintenance and disease causation, we are now finding that the enteric glial network carries out many of the same functions. In addition, the glial cells help to maintain a healthy balance between anti-inflammatory and pro-inflammatory bacterial lineages within the microbiota. (3, 4, 5)

Looking at the microbiota together with the environmental factors, within which they live and by means of which they may be profoundly influenced, it is difficult to establish a limit, and, as far as I have been able to find out, there is very little discussion of this issue. We can define an ‘immediate’ microbiome, from the intestinal lumen through to the outer intestinal wall, taking into account all of the structures and functional units that interact with the microbiota, e.g. the mucous layer, the epithelium with its various specialised cells, the immune cells in the lamina propria, the enteric nervous system, and the smooth muscle network that propels the intestinal contents.  Looking further outward, we have an ‘extended’ microbiome, which would encompass the rest of the body, with various systems that may directly influence the microbiota, or be influenced by their metabolites, or be adversely affected by them (e.g. when there is a leaky gut). But we cannot stop there.  As we shall see below, other people, other living beings, the structures we inhabit, our country of residence, the machines with which we work, personal relationships, the seasons, climate, and lifestyle – all influence our microbiota; there is a constant and continual interchange of micro-organisms between us and our external environment. (21) It is, therefore, important that any discussion of ‘the microbiome’ should clearly define the specific portion of the microbiome that is under examination – otherwise the term is too broad to be used in a meaningful way. 

Dysbiosis: Technically this term is focused exclusively on the microbiota and is generally thought to comprise three interrelated aspects: loss of diversity, increase in pathogens and decrease in probiotic organisms. Moreover, the term may also be applied to regional specific abnormalities, e.g. in small intestinal bacterial overgrowth (SIBO), where, amongst the various definitions by various researchers, a substantial increase in numbers of ‘normal’ inhabitants may be considered pathogenic. 

While ‘dysbiosis’ it is an easy idea for a layperson to understand, when examined closely, each of its three aspects, mentioned above (i.e. ‘diversity’, ‘pathogen’, and ‘probiotic’ micro-organism), is very difficult to define, as they are not in any sense fixed. They vary from person to person, region to region within the gut itself, and each item may change depending on a variety of circumstances (as discussed previously in Part 1). The concept of dysbiosis carries within it the promise that we can wipe out the pathogens, introduce a healthy variety of probiotics and solve a patient’s clinical problems. Unfortunately, the problem itself has not yet been adequately defined – and this invalidates any ‘solution’ even before it can be applied. Moreover, all of the solutions that are being considered, i.e. antibiotics, prebiotics, probiotics, and fecal transplant, have serious limitations and potential adverse effects.

Additionally, ‘dysbiosis’ has too broad a meaning and lacks the specificity required for clinical usefulness. In much the same way as we look at the symptom of pain: we need to know the location, severity, duration, previous normal state for the individual, prior condition/s that may be related as well as any aggravating or relieving factors, before we can begin to diagnose and treat it. 

We know that ‘dysbiosis’ means different things in different locations: in the mouth it may lead to gum disease; in the stomach to ulcers, in the small intestines (SI) to irritable bowel syndrome (IBS) and fibromyalgia, in the colon to ulcerative colitis and Crohn’s disease. But does an observable and measurable disturbance in the microbiota always cause these conditions?; in cases where a putative ‘dysbiosis’ does not cause any pathology, can it really be called a dysbiosis?; is the dysbiosis really caused by the conditions with which it is associated, and not the other way around? We do not, as yet, have definite answers to any of these questions.

Metagenome and Metagenomics: Although these terms have not yet been mentioned in this series of articles, an appreciation of their meaning is essential for us to be able to critically evaluate any of the published information on the human microbiome. The fundamental question: ‘how do they know that?’, should always be kept in mind when reading and evaluating such research. As we shall see in the case of small intestinal bacterial overgrowth (SIBO) discussed below, if the methodology that is used in order to gain knowledge is poor and inaccurate, the ideas and theories derived therefrom are no better than a house of cards. 

Metagenomics, the study of the metagenome, is a very sophisticated and accurate method that is used to identify which bacterial species are present, and in what quantities, in any given segment of the GIT. The information is ‘obtained through shotgun sequencing of the DNA extracted from a sample, followed by assembly or mapping to a reference database followed by annotation’ (2, 7, 8). The methodology avoids the pitfalls involved in collecting and culturing samples, e.g. contamination, loss of species on dilution, the inability to culture anaerobic bacteria (the main inhabitants of the colon), inability to identify a cultured species, etc. Metagenomics, as used in the Israeli study on probiotic supplements, discussed below, makes the method of culturing an aspirate of duodenal contents, in order to find out what is going on in the lower SI, look like a primitive backwater in the current research climate. Studies based on such culture methodologies or, even worse, on breath tests, are more likely to be an expression of the authors’ biases than an accurate reflection of anything real. (33, 34)

Empirical Research

The following is a summary of the clinically relevant information, according to empirically based research to date, under the following headings: 

• Diet
• Lifestyle 
• Probiotics supplements
• Fermented foods
• Sources of probiotic micro-organisms
• Bacterial overgrowth in the small intestines (SIBO) 

(References will only be provided for topics that were not discussed in Parts 1 and 2):

DIET

Gut healing

For gut healing in cases with active inflammation, the following should be scrupulously avoided: alcoholic beverages, gluten containing grains, capsicum species (i.e. chilli peppers and sweet peppers), all processed foods, certain pharmaceutical drugs (specifically: proton pump inhibitors and non-steroidal anti-inflammatories), simple sugars (particularly sucrose and fructose) and possibly also coffee (depends in the individual patient’s response). Additionally, one should avoid any substance to which there is sensitivity or allergy, in spite of that substance’s desirability (e.g. peanut, soybean, dairy, etc.) 

Health maintenance

For maintenance of general health, including gut health, the following should be included in the diet: adequate intake of vitamins A and D, sufficient zinc, a wide variety of plant derived PPT’s (phenols, polyphenols and tannins), a variety of MAC’s (microbe accessible carbohydrates, i.e. fiber, glycans and resistant starches), omega-3 fatty acids and a range of unpasteurised fermented foods (yoghurt, sauerkraut, kimchi, miso, etc.). Things to be avoided include processed foods and pharmaceutical drugs (as mentioned above), excessive amounts of simple sugars, non-organic produce and conventional meats (which may be contaminated with glyphosate or antibiotics, respectively), excessive amounts of animal protein and substances to which an individual has sensitivity or allergy. Meals should be taken only when the stomach is empty, and one has a clear sensation of hunger. This allows the stomach and SI to carry out their important self-cleansing activities.

High fat diets

Studies on ‘high fat diets’(HFD) are generally done in people consuming larger amounts of the commonly available ‘foods’ in the Western diet that are high in fat. These are mostly processed foods, containing various chemicals that are known to disrupt the intestinal barrier, as well as containing trans-fats and potential allergens. (6) Thus, the widely promulgated association between HFD and dysbiosis/ impaired intestinal barrier function is very likely invalid and does not apply to naturally occurring healthy fats (e.g. organic butter, ghee and coconut oil). 

LIFESTYLE

Excessive stress contributes towards dysbiosis and leaky gut, as does high intensity exercise and overuse of alcohol. Consuming meals too frequently and snacking between meals increases the risk of motility related dysbiosis within the SI, and this is more critical with advancing age. This issue is discussed in more detail below, under the heading ‘small intestinal bacterial overgrowth’. 

PROBIOTIC SUPPLEMENTS

Normal healthy microbiota colonies

As previously discussed, a healthy microbiome may contain several hundred naturally occurring, and individual specific, probiotic species. Moreover, it appears to be important for an individual’s health that several species that are capable of carrying out the same or similar functions should be present within the microbiome. This is the concept of ‘functional redundancy’ discussed in Part 1. 

Landmark research

In September 2018 a group of Israeli researchers published what I believe are landmark and definitive studies on the mechanisms of action of probiotics involving both murine (mice) and human subjects. (7, 8) Each study consisted of two parts where the same procedure was followed in experimental mice and human volunteers. Below is a summary of the human findings.

Probiotic supplement taken under normal conditions

Utilising deep endoscopy and colonoscopy techniques the microbiota at several different regions of the small and large intestines was mapped, using state of the art metagenomics techniques. The investigators were thus able to map the mucosal colonies, which are relatively more permanent, as well as those within the luminal contents, which are relatively transient, along the important areas of the GIT. As we know, each of these areas show characteristic differences, specifically: the stomach, the upper SI, the lower SI, the proximal colon, and the distal colon. The initial mapping was carried out in healthy human subjects, all eating a similar diet, and was used as a baseline. 

The first study looked at what happens to the microbiota after four weeks administration of a commercially available probiotic supplement containing 11 strains of bacteria, including Bifidobacteria, Lactobacillus, Lactococcus and Streptococcus species, taken twice daily. The pills were enterically coated and each contained a minimum of 25 billion active bacteria; their content was validated as part of the study. Both the stool and the intestinal microbiota were mapped and measured. 

Probiotic supplement after a course of antibiotics

The second study focused on what happens to the microbiota when, after a 7 days’ course of broad-spectrum antibiotics: 1) no specific treatment is given 2) the same probiotic supplement (as per the previous study, described above) is given, and 3) autologous faecal microbiome transplant (aFMT) is given (i.e. stool samples were taken from each individual before the administration of the antibiotics, to be transplanted into the colon of the original donor after the course of antibiotics). Here again, both the stool and the intestinal microbiota were mapped and measured, both at baseline (before antibiotic treatment), after antibiotic treatment but before probiotic treatment, after the four weeks course of probiotics and at follow up after three months. 

Colonisation by introduced probiotics in normal subjects

The first group of experiments showed that while flourishing colonies of most of the introduced probiotic species were found in the stools of all subjects taking the probiotic supplement, there was considerable variation in the degree to which these probiotic species colonised different segments of the intestinal tract. In some of the subjects there was no colonisation at all (‘resistant’ individuals). However, in those subjects in which colonisation did occur (‘permissive’ individuals), there was an observed reduction in variety of bacterial species, overall (i.e. the probiotic supplement caused a reduction in bacterial diversity). Moreover, the stool of resistant individuals rapidly returned to baseline after cessation of probiotics supplementation, while in the permissive subjects, there was a more gradual decline before they too returned to baseline. 

Of note is the fact that in permissive individuals (i.e. those in whom the native population of microbiota allowed some degree of colonisation by the introduced probiotic species) there were observable, potentially therapeutic effects, such as enhancement of immune system function, whereas in the resistant subjects there was evidence of immune system rejection of the introduced probiotic strains. In addition, the researchers found that permissiveness or resistance to probiotic supplements could be predicted from analysis of the native microbiota of an individual.

Post antibiotic effects of probiotic supplements

The second study showed that:

1. Antibiotics considerably thinned out the native population of microbiota, as expected
2. Because there were fewer species present in the intestines after antibiotic treatment, probiotic supplementation resulted in colonisation of the intestinal mucosa in all subjects (i.e. there were no longer any resistant subjects; they all became permissive). This provides evidence supporting the microbiota mediated rejection of introduced probiotics in resistant individuals.
3. Baseline microbiota composition was achieved most rapidly in subjects who underwent aFMT, some within a few days after cessation of the antibiotics. Second were the group who received no treatment, who returned to baseline within 21 days. The group who received the probiotic supplement had still not retuned to baseline by the end of the study (after 8 weeks) and still exhibited dysbiosis after a further 5 months. Their microbiota composition remained significantly different from baseline at five months, in spite of the fact that some of the administered probiotic species were found at elevated levels in the stools. This indicates that, although the effects of antibiotic treatment had allowed some degree of permanent colonisation by a few of the introduced species, the degree varied from significant to insignificant, and was mostly in relation to the Bifidobacterium species. In addition, there was a considerably longer delay in returning to baseline (normal) microbiota composition, compared to the no treatment group. Thus, it appears that the supplemented species, or rather some of these introduced species of bacteria, actively prevented the return to microbial diversity that would have occurred naturally, through normal eating and a normal daily routine. 

The dark side of probiotic supplements

Questions about the clinical efficacy as well as the safety of probiotic supplements have only very recently begun to emerge. (9, 10, 11)  Against a backdrop of numerous studies touting their benefits – both actual and potential – there have been few voices, to date, that express the common-sense perspective of caution and scepticism when it comes to the issue of deliberately ingesting a life form that is able to transmute quite rapidly, is closely related to known pathogens, and that may readily transfer genetic material that can confer virulence or antibiotic resistance. 

In addition, studies showing benefit of probiotic supplementation in immune system disorders, cardiovascular disease, cancer metastases, type 2 diabetes, obesity, depression and anxiety are generally too heterogenous, small scale or poorly conducted to provide conclusive evidence of benefit; moreover, there is widespread under-reporting of adverse events (10). To date the only validated uses of probiotic supplements are for the improvement of symptoms in oral disorders (periodontal disease, halitosis) improvement of symptoms in gut conditions (rotavirus diarrhea, antibiotic associated diarrhea, IBS, food allergies), and prevention of upper respiratory tract infections. (12, 13, 14, 15) However, even these results are now being questioned. (61)

Marketing scams, dangers and misleading information

Meanwhile, the heavy marketing continues to encourage people of all ages and health conditions to take probiotic supplements, (11) promulgating the same big lie to professionals and the general public alike: that there are only a dozen or so probiotic species. However, in truth there are several hundred of them and each person has their own specific set of probiotic organisms within which there needs to be several species capable of performing the same or similar functions under various conditions. 

Nor are probiotic supplements without their dangers. It should come as no surprise that there are serious safety issues involved when colonic bacteria are introduced into the SI in numbers that are several thousand times more than that which the small bowel usually has to accommodate. The dark side of probiotic supplementation has been described as: transfer of hostile genetic material to the host microbiome (that may support the development pathogenicity and antibiotic resistance); infections (including sepsis, infective endocarditis, liver and lung infections); various metabolic disturbances (e.g. production of biogenic amines); and also allergic responses (allergic rhinitis and asthma). (9, 10, 11) 

Further risks may arise from the ability of some of the supplemented probiotic species to produce D-lactic acid. The D-isomer of lactic acid is very poorly metabolised in humans and may readily reach toxic levels in the blood. These issues have only recently been investigated.  The title of one study says it all: ‘Brain fogginess, gas and bloating: a link between SIBO, probiotics and metabolic acidosis’. (52, 53) Moreover, the vulnerable populations, in which studies have shown some benefit (e.g. critically ill patients, pre-term infants, elderly and immunocompromised patients) are also the most susceptible to adverse events. (10, 11) 

Looking through the literature, many studies that are intended to support the benefits of probiotic supplements include traditional foods (which are a rich source of probiotic organisms) together with the probiotic supplements without drawing any distinction between them. In fact, it is still not established whether or not the same or increased benefits may be derived from food sources alone, e.g. in the area of oral health. (13, 14) More importantly, studies on the benefits of probiotic supplements are almost universally poorly designed, lack standardization, show a high level of data variance from one study to another (i.e. there is a lack of repeatable data), are biased, have very high drop-out rates and are often incompletely reported. (9, 10) A recent review of probiotic supplements, published in May 2019, has the telling title: ‘The pos, cons and many unknowns of probiotics.’ (62) I encourage readers to review this paper as it provides the most up-to-date and balanced perspective on these issues. 

FERMENTED FOODS

If you do an online search for ‘manufacturers of probiotics’ it will become obvious, within a very short time, that this industry has all the trappings of the multinational pharmaceutical companies, and it becomes readily apparent how their marketing activities have contributed to the many shortcomings, described in the previous section on probiotic supplements. As most commercial providers of high quality traditional style fermented foods are, comparatively or literally on the level of cottage industries, we are unlikely to see a large body of theoretical and clinical research emerge in relation to these foods, which, in my opinion, deserve to be classified nutritionally as a separate and essential food group. Therefore, it is not surprising that ‘despite the wide array of beneficial mechanisms deployed by probiotic bacteria and fermented foods and beverages, relatively few effects have been supported by clinical data’. (16) However, the very modest evidence to date does support the beneficial effects of regular consumption of fermented foods in the following areas: maintenance of normal weight and glucose metabolism, reducing the risk of cardiovascular disease and type 2 diabetes, reduction of post exercise muscle soreness, improvements in mood and brain activity as well as reduction in all-cause mortality. If we follow the ‘best available evidence’, which includes patterns of traditional usage, then we must regard fermented (or rather ‘fermenting’) foods as an important source not only of readily absorbable nutrients, but also of probiotic microorganisms, an important factor in the maintenance of a healthy microbiome and general health. (16, 17, 18) 

OTHER SOURCES OF PROBIOTIC MICRO-ORGANISMS

Lack of comprehensive knowledge

Now that we are aware of the serious limitations of commercially available probiotic supplements, what are some other practical, readily available sources of probiotics?

Not only for restoring a dysbiotic microbiota to a healthy state, but also – we may presume – for daily replenishment, which appears to be necessary in order to maintain gut health. (21) Outside of the regular consumption of fermenting foods, there is little information available at present. As mentioned above, fecal microbiota transplantation (FMT) has been shown to rapidly restore the microbiome after a course of antibiotics (8) and is now regarded as the most effective therapy for treating recurrent Clostridium difficile colitis. (19) Although studies on its scope of application, while encouraging are far from definitive, it may eventually prove to be a useful therapeutic intervention for some other conditions as well. (20) Unfortunately, FMT must be limited to the colon, as the introduction of colon specific micro-organisms into the SI can be problematic. (22, 23)

Likely sources of readily available probiotics

Getting back to the problem of replacing or replenishing the gut microbiota – at present we know very little about this potentially critical health issue.  It seems reasonable to presume that the good micro-organisms spread in much the same way as the pathogenic ones. Importantly, it appears that: ‘transmission of commensal intestinal bacteria between humans could promote health by establishing, maintaining and replenishing microbial diversity in the microbiota of an individual. Unlike pathogens, the routes of transmission for commensal bacteria remain unappreciated and poorly understood, despite the likely commonalities between both. Consequently, broad infection control measures that are designed to prevent pathogen transmission and infection, such as oversanitation and the overuse of antibiotics, may inadvertently affect human health by altering normal commensal transmission.’ (21) 

It may take a radical change of perspective for us, as a society, to understand that bacteria overall do us much more good than harm. Perhaps now we can appreciate the additional benefits of hugging our friends, keeping a pet, working outdoors in the garden, and, controversially, of not being overly concerned with sanitation.

Bacterial Overgrowth In The Small Intestines (SIBO)

Historical background and definition

The phenomenon of bacterial overgrowth in the SI was inferred, initially, by surgeons and gastroenterologists who noted characteristic clinical features in patients who had some sort of disruption to the structure and/or function within the SI and associated organs, slowing down the transit of the intestinal contents. This was seen in patients with post-surgical or other conditions that adversely affected intestinal motility, e.g. gallstones, blind loop syndrome and patency of the ileocecal valve. In these patients there were the obvious sights, sounds and smells that were the hallmark of this condition: abdominal bloating, increased bowel sounds, flatulence, the presence of methane, hydrogen sulphide or ammonia on the breath, loose stools and, in extreme cases, steatorrhea with signs of malnutrition. (22, 23, 24) Clinically, this syndrome., due to bacterial overgrowth within the SI, was recognised as the cause of steatorrhea and malnutrition in patients with structurally or functionally compromised SI. (23) 

SI bacterial overgrowth (SIBO) has been variously defined as a significant increase in numbers of bacteria that are able to be cultured from an aspirate of the luminal contents of the upper SI; and/or the presence of gram-negative colonic bacteria, even with relatively normal amounts of total bacteria. (24, 25) It was not until the mid-1970’s that the medical community became aware that other factors besides gross structural abnormalities could lead to SIBO, principally disorders of small intestinal motility. In their seminal study on intestinal motility, Vantrappen et al. described normal and abnormal states of motility, linking the latter with bacterial overgrowth. (44)

When good bacteria turn bad 

The pathological consequences of SIBO are manifold, particularly when there are gram-negative bacteria that normally reside within the colon. Most importantly, toxins and fermentation products from colonic bacteria, which would normally be dealt with effectively within the colon, damage the small intestinal mucosa and impair the breakdown and absorption of nutrients. More importantly, mucosal damage allows the entry of toxins, bacteria, and incompletely digested food molecules into the blood stream (i.e. causes leaky gut). As discussed in Part 2, this can lead to inflammation in distant organs and may overwhelm the liver’s detoxification pathways. These extra colonies of bacteria within the small bowel, where most of our digestion takes place, compete with their host for nutrients. Thus, there may be significant disruption to fat, carbohydrate and protein metabolism, and there may be loss of fat-soluble vitamins, increased amounts of toxic products from protein breakdown by bacteria (which are then absorbed into the blood stream) and diminished absorption of nutrients in general, with loss of vitamin B12, other B vitamins, vitamins D, K and folate. (23, 24, 27) Additionally, the combined effects of bacterial overgrowth, and particularly when colonic bacteria proliferate within the SI, is to further disrupt small intestinal motility, creating a vicious cycle that tends to perpetuate and worsen the condition. (27)

Clinical symptoms of SIBO

Although the symptomatology of SIBO is not specific, a combination of the following three classes of symptoms should raise clinical suspicion. 

• Symptoms due to malabsorbed nutrients or metabolites in the GI tract and changes in intestinal permeability: bloating, flatulence, distention and discomfort, increased volume of loose stools or diarrhea or steatorrhea, pale stools
• Malabsorption of nutrients: weight loss, anemia, retarded growth in children
• Systemic effects of gut inflammation and immune activation: generalised aches and pains, fatigue, fibromyalgia. (27, 51)

Table 1: Symptoms associated with bacterial overgrowth in the small intestines. (Dukowicz et. al., 2007)

• Bloating
• Flatulence
• Distention and discomfort
• Increased volume of loose stools or diarrhea or steatorrhea 
• Pale stools
• Weight loss
• Anemia
• Retarded growth in children
• Generalised aches and pains
• Fatigue
• Fibromyalgia

Difficulties defining and measuring SIBO

In the early 1970’s the medical understanding of this condition was based on a common-sense approach, incorporating the basic sciences of bacteriology together with human anatomy, physiology and pathology. In this way, the likely sites within the SI for bacteria to breed and colonise, when normal motility was disrupted, were accurately described.  Notably, bacteria may proliferate within the intestinal lumen, may colonise within the mucous layer or may invasively colonise on or within the epithelium. (22) According the most recent data, stable colonies of micro-organisms colonise in the more diffuse outer portion of the mucous layer (i.e. closest to the lumen), while the more dense inner layer is, for the most part, sterile due to the presence of immunoglobulins and anti-microbial proteins.  The concentration of bacteria progressively increases from stomach to colon: 10¹ in the stomach, 10³ in the duodenum, 10⁴ in the jejunum, 10⁷ in the ileum and 10¹² in the colon. (26) 

One should bear in mind, however, that these putative numbers of bacteria (given as colony forming units per gm or ml of luminal aspirate) have mostly been derived from culturing a small quantity of material that has been collected by endoscope from the lumen of the bowels, and then diluted down, so that discrete colonies of bacteria may be observed on a culture medium. (27). However, in regard to sampling within the SI, only around 30% of the bacteria thus collected are able to be cultured. Moreover, this method does not account for any bacteria that may have colonised within the mucous layer or on the epithelial surface, nor can it show what might be going on in the ileum, as sampling is restricted to the duodenum and upper jejunum. 

In spite of these facts, this method has been considered, up until now, to be the gold standard for the diagnosis of SIBO. However, not being practical for every day clinical application, because it is complex, expensive and invasive, various breath tests are routinely used instead. Breath tests measure the increase in hydrogen (and sometimes also methane) after ingestion of a carbohydrate load (usually glucose or lactulose), which is fermented by the microbiota to produce hydrogen gas, which can then be measured in the expired air. (31) Not only is this method considerably less accurate than the culture method, which is already flawed, none of these tests have been standardised, nor is there universal agreement on the significance of test results with respect to the diagnosis of SIBO. Of more concern, as has only quite recently been pointed out, is that the widely used breath tests, upon which are based the findings in almost every paper published on the subject of SIBO in the last 20 years or so, are extremely inaccurate, with false positives up to 40%. (32) 

SIBO is not restricted to patients with structural abnormalities 

In the mid to late 1970’s researchers noted that SIBO (and specifically SIBO with colonic bacteria present) could be detected in patients without any mechanical obstruction within the small bowel or associated structures. This finding grew out of the early studies on small intestinal motility in humans, specifically investigations of the ‘interdigestive motor complex’, (44, 47) now referred to as the ‘migrating motor complex’ (MMC, discussed below). As we shall see below, disturbances in the MMC may occur (and commonly do) as a consequence of various lifestyle factors, or after an infection within the GIT. Indeed, it has been recently shown that once bacterial overgrowth has been established (particularly with colonic bacteria present), the MMC become attenuated through several different pathways, thereby worsening and perpetuating the condition. (27, 47)

The rise and rise of SIBO 

Not surprisingly, since the mid 2000’s the clinical scope of this condition has expanded considerably.  Some medical experts are now proposing that SIBO is the underlying cause of a vast and ever-increasing number of chronic diseases, citing the many studies (all based on extremely unreliable ‘evidence’) that have been published in recent years. (30, 31) However, as the pendulum once more swings back to a more common-sense perspective, some medical researchers have noted that due to the extreme inaccuracy of the diagnostic methodology, we need to approach these proposed connections with extreme caution. (33, 34) Additionally, in many of the disorders linked to SIBO, the bacterial overgrowth has been ‘shown’ to occur in 30 – 40% of patients with the disorder. (34) Unfortunately, this is a statistical ‘iceberg’: the unrevealed portion may well conceal the fact that, while approximately one third of patients have SIBO, another one third do not have it, while in the remaining one third the test results are equivocal. In other words, these findings are not significant – they are the ideal expression of a random (i.e. non causal) association. What this comes down to is that in studies that attempt to show some kind of relationship (usually causal) between a disease and a treatment or a proposed cause, when the results are in the 30 – 40% range we must conclude one or more of the following: the disease diagnosis is invalid; the treatment does nothing; the causal factors are not relevant; the measuring methodology is inadequate.

If, however, we remain hopeful, based on the assessment that the results in this 30 – 40% positive group appear to be very convincing, then we may look for a subgroup (which requires a new definition) in which these findings may be relevant. This is, in fact, what has been happening in recent studies on IBS, where it is postulated that in a small subgroup of patients the clinical symptoms may, in fact, be due to SIBO. (28, 32, 34) Unfortunately, even in the case of IBS, which has become the flag-ship condition linked to SIBO, the so-called ‘proof of concept’ argument is very weak. Namely, that because IBS symptoms (in a subgroup of patients) improve after a course of antibiotics, the disorder must be due to SIBO in these particular cases. (28, 35) However, it has recently been observed that there are other mechanisms by which an antibiotic is able to alleviate IBS symptoms. (36) Additionally, the placebo effect in trials of IBS is quite large, with an average of 40% or more (there’s that pesky statistic again!) and reaching to over 70% in some studies. (37, 38) Not to put too fine a point on it, the statistics involved here point to several conundrums: the diagnosis of IBS may not be valid (i.e. what we call IBS may, in  fact encompass several different disorders); the condition called SIBO may not be valid (i.e. SIBO may also be a mixed bag); the measuring methodology is very inaccurate. In these circumstances, to look for a causal link between two ‘entities’, both of which are poorly defined, would appear to be futile. There are two take-home messages here: firstly, this line of thinking is applicable to most, if not all, of the other conditions linked to SIBO, and secondly, there is a high degree of uncertainty surrounding these issues. 

At this point in time it appears that in SIBO we have a condition that is apparently only matched in its pathogenetic ubiquity by its diagnostic elusiveness. Perhaps future researchers will be able to gain a clearer picture of SIBO using the metagenomics techniques that were applied by the Israeli researchers in their studies relating to probiotic supplements, discussed above. (7, 8, 33) 

Table 2. Risk Factors for the Development of Small Intestinal Bacterial Overgrowth

Structural/anatomic

• Small Intestinal diverticula
• Small Intestinal strictures (radiation, medications, Crohn’s disease)
• Surgically created blind loops
• Resection of ileocecal valve
• Fistulas between proximal and distal bowel
• Gastric resection

Motility disorders

• Gastroparesis
• Small bowel dysmotility
• Celiac disease
• Chronic intestinal pseudo-obstruction

Irritable bowel syndrome

Metabolic disorders

• Diabetes
• Hypochlorhydria

Elderly person

Organ system dysfunction

• Cirrhosis
• Renal failure
• Pancreatitis
• Immunodeficiency states
• Crohn’s disease
• Celiac disease
• Malnutrition

Medications

• Recurrent antibiotics
• Gastric acid suppression

Table 2. Risk Factors for the Development of Small Intestinal Bacterial Overgrowth (Dukowicz et. al., 2007)

Clinical considerations

But that is not the end of the story. Perhaps these conundrums only speak to the limitations of the Western analytical research paradigm.  There may indeed be something very important here after all. As stated above, SIBO is a real condition with recognisable (but not very specific) clinical features. After all, in terms of digestion and absorption of nutrients, the small bowel is where most of the action occurs (literally! – see below). (39) And, for the purposes of this discussion, if any one physical organ can be correlated with the Spleen in TCM, the SI are at the top of the list. (40) Let us briefly review what is known about the SI, focusing on normal motility and bacterial contents. 

Physiology of the small intestines

Our understanding of the physiology of digestion within the SI has progressed considerably in recent years, with clarification of various modes of gastrointestinal motility, along with a more detailed understanding of how nutrients are broken down and transported across the intestinal epithelium. (41, 42) 

After the stomach has finished its part in the process of digestion, delivery of gastric chyme into the duodenum must be carried out in small, measured doses. Due to the marked difference in size and capacity between the stomach and the SI, it is necessary that the pyloric sphincter strictly controls the efflux of contents from the gastric antrum, preventing the larger peristaltic waves of the stomach from sending an overwhelming flood of chyme into the duodenum. When this mechanism fails in certain pathological states, the rapid emptying of gastric contents into the SI (‘dumping syndrome’) is characterised by nausea, pallor, sweating vertigo and sometimes fainting within minutes after a meal. On the other hand, we also want to avoid delayed gastric emptying, e.g. in gastroparesis, which causes early satiety, abdominal bloating and nausea. This important function, the control of gastric emptying, is shared between the entero-endocrine system, the enteric nervous system and the central nervous system, each of which, in addition to having direct action on the stomach itself, also interact with one another. 

When the various endocrine cells within the mucosa of the duodenum detect low pH, osmotic changes, fats and the products of fat digestion, they release several different hormonal factors that slow down gastric emptying. Similarly, the specialised nerve endings within the duodenum – mechanoreceptors, chemoreceptors and osmoreceptors – provide feedback to the ganglia of the enteric nervous system in order to put a brake on gastric emptying in response to the rate of flow into the duodenum. Finally, the central nervous system is able to slow gastric emptying through decreasing parasympathetic activity or increasing sympathetic activity, as well as through direct effects on the enteric nervous system. Outside of these finely co-ordinated physiological responses, emotional states such as anger, resentment, fear, anxiety and sadness may also affect the motor activity of the stomach. (42)

Small intestinal motility during digestion

Motor activity within the small bowel is directed towards two major functions: mixing and propulsion. The former is facilitated by segmentation, while the latter is accomplished by peristalsis. Segmentation involves short segments of the SI becoming sealed off by narrow annular constrictions. Within each of these small bowel segments the luminal contents are effectively churned by being propelled in a to-and-fro motion, allowing thorough mixing of the chyme with bile acids, pancreatic secretions and epithelial cell secretions. Peristalsis is the co-ordinated contraction and relaxation of the muscles of the small bowel to propel the contents in an aboral direction (i.e. away from the mouth and towards the colon) under normal circumstances, or in an oral direction when the vomiting reflex has been activated. Retrograde power contractions (i.e. reverse peristalsis) begin in the upper SI (i.e. the jejunum), allowing removal of both intestinal and gastric contents through vomiting. (42) 

In order to allow sufficient time for digestion and absorption within the SI, transit of the meal through the gastrointestinal tract is regulated by a complex integration of signals generated in response to nutrients, leading to what is known as the ‘jejunal brake’ (to slow emptying of the stomach) and the ‘ileal brake’ (to slow aboral motility in the proximal SI). As a means of monitoring the progress of digestion, different neuropeptides are released in response to the presence of various nutrients within the lumen of the SI, slowing transit when levels of nutrients, which should have already been absorbed, are detected. The most potent of these mechanisms if provided by the ileal brake, when unabsorbed fats are detected in the lumen of the ileum. (75)

Interdigestive small intestinal motility 

Of special interest in this discussion is a specific type of peristalsis: the migrating motor complex (MMC). This is a critical aspect of gastro-intestinal motility, the disruption of which has been closely linked with gastro-oesophageal reflux (GERD), functional dyspepsia (FD) and SIBO. (43) Under normal circumstances (which will be clarified below), when the stomach has emptied its contents into the duodenum and the lumen has become less acidic, there occurs a co-ordinated, rhythmic burst of smooth muscle contractions. This is the beginning of a peristaltic wave that proceeds all the way from the stomach to the terminal ileum, the purpose of which is to serve a ‘housekeeping’ function, i.e. to remove residual contents of food, mucous, dead cells and, importantly, bacteria that are feeding on and breeding within these materials. 

This interdigestive activity begins to take place at a variable time after a meal has been eaten; it may occur as soon as 2.75 hours or as late as 4.35 hours in normal healthy subjects, (44) most likely depending on age, physical condition, stress levels, and other lifestyle factors. During the fasting state, (and most of the research has been carried out on subjects who have been fasting around 12 hours), MMC’s occur approximately every 80 to 90 minutes. (44, 45, 46) It has been observed that patients with SIBO very often have disturbances, or even a total absence of MMC’s (when observed during the fasting state). The other important thing to note is that as soon as food is eaten the MMC’s abruptly cease to occur. (42, 45)

Each burst of MMC activity sets in train a peristaltic wave that clears the stomach and small bowel, taking 1.5 to 2 hours to propagate from stomach to terminal ileum. As soon as food is taken in, distention of the stomach causes MMC’s to cease in the stomach and upper SI, and as soon as fluid and nutrients begin to enter the duodenum, the MMC activity over the entire small bowel is curtailed. (45) This is an important aspect of MMC activity because, while most MMC’s begin in the stomach (about 70%), a smaller percentage (30%) begin in the SI, allowing small intestinal MMC activity to continue while the stomach is receiving food and is therefore no longer generating MMC activity. (45) This highlights the importance of the MMC in controlling bacterial growth within the SI. In the absence of the gross structural and functional disorders previously recognised as causes of SIBO, attenuated MMC activity is now regarded as a major pathogenetic factor for this condition. (46, 47)

Things that interfere with the interdigestive MMC’s

Returning to the idea of ‘normal circumstances’, mentioned above, we can now more clearly understand why eating before the stomach has emptied completely and been allowed a good hour or two to conduct its cleansing activities, is potentially deleterious to health. This has already been explored in connection with a lifestyle-based treatment for medically diagnosed GERD, the idea being that disruption of normal MMC cycles between meals, because of eating too frequently, is a primary etiological factor in both GERD and functional dyspepsia (FD). Although these studies were small, the results were impressive, lending credence to this idea. (48, 43) If we consider the fact that the combined incidence of GERD and FD in the Western world is 40 – 60% (allowing for over 50% of suffers who self-medicate), (49, 50), then it is apparent that the overnight 10 – 12 hours fasting during sleep is not sufficient for ‘good housekeeping’ of the stomach and small bowel in most people. 

If we look at the common clinical manifestations of mild SIBO (i.e. without steatorrhea and malnutrition): bloating, flatulence, abdominal discomfort, brain fogginess, loose stools or diarrhea, fatigue, weakness and reflux (51, 52, 54), we can readily infer that the small intestinal microbiome is in a constant state of flux, moving in and out of a ‘heathy zone’ in most people. Moreover, this is particularly pertinent when these symptoms are associated with changes in stress level, food intake, or other disruptions to one’s normal dietary routine.  Additionally, patients with various chronic conditions, such as overweight/obesity, chronic diarrhea or loose stools, long term use of PPI’s, as well as those of older in age, are much more likely to have SIBO when these symptoms are present. (51) Unfortunately, in many such patients the misguided use of probiotic supplements may worsen rather than correct the dysbiosis. (52) 

Dangers of introducing colonic bacteria into the small intestines

It bears repeating that the main problem in SIBO is in the deleterious effects arising from colonic bacteria breeding and fermenting within the SI. (27, 31). The bacteria in probiotic supplements are all colonic type bacteria that produce (amongst other things) short chain fatty acids (SCFA) and D-lactic acid, which is poorly metabolised and may readily accumulate to toxic levels. When these bacteria reside within the colon, their products are beneficial within that environment. However, when they flourish within the SI, the SCFA’s damage the intestinal lining, predisposing to leaky gut, and the D-lactic acid may enter the bloodstream leading to lactic acidosis. (52) We need to bear in mind that probiotic supplements are designed to release their contents into the intestines, allowing vast numbers of colonic bacteria to be liberated within the small bowel. No wonder recent studies have found that a large proportion of subjects who regularly consume probiotic supplements suffer from bloating and abdominal pain as well as lactic acidosis, which leads to brain fogginess, fatigue, muscle weakness and cramping. (52, 53)

Things that can go wrong and cause bacterial overgrowth 

Let us now look, briefly, at the factors that help control the growth of bacteria within the SI. Beginning in the mouth, these are: salivary IgA, gastric acid, bile, normal gastro-intestinal motility, secretory IgA in the SI, anti-microbial proteins (a.k.a. ‘defensins’) secreted by the Paneth cells in the intestinal epithelium, and a functioning ileocecal valve. (27) Setting aside the more severe pathological conditions that may lead to SIBO (such as immune deficiency, structural damage, hypothyroidism, diabetic neuropathy, etc.), we can see that there are many factors that may lead to SIBO, some of which are transient and others more long-term. These factors include over feeding (disrupts normal gastrointestinal motility), stress and emotional strain (disrupts motility), presence of sludge or gallstones within the gallbladder (disrupts bile secretion), age related reduction of gastric acid secretion, and age-related loss of intestinal glial cells (disrupts motility), as well as intake of PPI’s and antacids. In addition, once there is an overgrowth of bacteria in the small bowel, for whatever reason, and particularly if colonic bacteria start to proliferate, damage caused to the mucosa and enteric nervous tissue together with the local immune inflammatory response results in reduced SI motility that can lead to or exacerbate any existing stasis, creating a vicious cycle. (27, 46, 47) Additionally, when colonic bacteria become established within the SI, they deconjugate bile acids, leading to varying degrees of fat malabsorption. The presence of unabsorbed fats in the ileum then causes a further reduction in motility over the whole of the SI, via the ileal brake mechanisms. (27)

Figure 1: Summary of the major gut defence mechanisms preventing small intestinal bacterial overgrowth. (Ghoshal & Ghoshal, 2016)

SIBO is likely to be a very common condition

Let us put together what we have discussed so far and see how it applies to our ‘normal’ population – particularly in the more vulnerable middle and older age groups.  Firstly, consider the cultural eating pattern of three meals per day, plus morning and afternoon tea. It should be apparent that in the majority of people following a Westernised lifestyle the stomach is never empty during the day, and in the middle-aged and elderly the stomach may not have completed emptying, even after the evening fast during sleep. Disturbed or abnormal gastrointestinal MMC’s would thus be the norm, and this is evidenced by rising rates of overweight and obesity together with the high prevalence of GERD and FD. Consider also that undiagnosed gallstones are present in about 12% of this age group (55), and that pathogenic levels of stress, anxiety and depression are at an all-time high (statistics on this vary widely depending on the definitions adopted and the source of funding). One may, therefore, readily conclude that SIBO is an ubiquitous condition with considerable variation in severity, and which very likely underlies a multitude of clinical and subclinical conditions. Within the Western evidence-based medical paradigm, however, the data is at present insufficient to support such a statement. (34) Fortunately, there are other clinical paradigms, within which we can explore the clinical ramifications of this condition. 

CORRELATIONS WITHIN TCM 

The most important factor leading to, as well as perpetuating SIBO – both in patients with medically diagnosed pathology as well as in a very large at-risk ‘normal’ population – is stagnation within the Small Intestine. This concept of stagnation ties in very closely with the theories and practical techniques developed by Li Dong-yuan, previously discussed in Part 2, and Zhu Zhen-heng (a.k.a. Zhu Dan-xi), who is regarded as the fourth of the Jin-Yuan medical masters. 

The phenomenon of MMC’s discussed above are an example of a very close, if not one-on one correlation between the findings of Western research and some of the key pathophysiological theories elaborated within TCM. In the Nei Jing, there is a detailed discussion on macrocosmic-microcosmic correlations in relation to medicine. Looking at the natural cycles of change on the earth’s surface – the biosphere (the ‘microbiome’ of Nature) – the early TCM philosopher-physicians attributed to the earth and the Earth element a descending as well as an ascending movement of Qi (in  this context ‘Qi’ can be understood as essential energies, tendencies or influences). The descending Qi was seen in the way water from rainfall soaked into the earth and seeped downward; also, in the way the roots of plants move downwards. The ascending movement was observed in the steam that rises from the earth’s surface and ascends to form clouds, and also in the direction of growth of trees and other plant life, with the Yang upward movement supported by the Yin below ground parts. (56) The bodily organ systems that pertain to Earth are the Stomach and Spleen; anatomically, the small intestines are also included. 

Li Dong-yuan’s theories

In the 13^th century, Li Dong-yuan further elaborated on these seminal ideas from the Nei Jing. He described the middle Jiao (i.e. the middle body cavity, with the chest above and the pelvis below), conceptualised as both the locus as well as the combined physiological activities of the Spleen and Stomach – the organ systems that are involved in digestion, absorption and distribution of nutrients. Dr Li regarded the ascending and descending movements of the body’s physiological Qi as the most important factors in health maintenance and recovery from illness. Specifically, these two complementary groups of physiological functions are centred in the middle Jiao: the Spleen Qi having an ascending direction of activity and the Stomach Qi having a descending direction. (57) The ascending (Yang) Qi has the functions of moving the products of digestion upwards, specifically to the Lung for the production of vital energy (correlating with the release of energy from the combination of glucose with oxygen), as well as spreading them outwards to distribute the absorbed nutrients throughout the body. Thus, ‘ascending Qi’, within this context, refers to a Yang type of movement that is directed upwards and also spreads outwards from the centre. The Stomach Qi, on the other hand, moves downwards and has the tendency to contract and become more concentrated. This is a Yin type of movement that descends and contracts, clearly seen in the passage of the more liquid gastro-intestinal contents through to the colon to be formed into compact stools.  

The physiological activities of the small bowel (according to Western science) may be regarded as equivalent to the TCM concept of the middle Jiao, i.e. the combined activities of Spleen and Stomach, the TCM Spleen being the underlying motive force for the various bodily functions centred on absorption and distribution of nutrients together with cellular respiration and energy production. The descending movement of the Stomach Qi represents, arguably, one of the closest correlations of a TCM concept to a Western physiological observation – the migrating motor complex (MMC), with all of the ramifications discussed above. However, Dr Li’s main focus was on restoring the Yang ascending Qi of the Spleen in order to cure illnesses due to disordered Spleen and Stomach function. As discussed in Part 2, most likely the times in which he lived and practiced influenced his approach. It was not until about a century later, when China was once again prospering under Mongol rule, that a prominent physician elaborated the TCM concepts that are most pertinent to our discussion of SIBO. 

Zhu Zhen-heng (a.k.a. Zhu Dan-xi) and his theories

Zhu Zhen-heng was born just after the complete conquest of China by the Mongols and grew up in a time of renewed and expanding prosperity under Mongol rule. In contrast to the prolonged period of deprivation and stress that heralded the end of the Jin empire, Dr Zhu practiced medicine in a time of abundance, prosperity and social order. Much attention has been given to his theory that ‘Yang generally tends to become excessive and Yin to become deficient’, leading later commentators to name his school of thought within TCM, the ‘Nourishing Yin’ or ‘Nourishing Yin and Reducing Fire’ School. 

In addition to developing various approaches to the treatment of Yang-excess-Yin-deficiency syndromes, he also elaborated on the various syndromes due to stagnation (‘yu’ in pin yin). Misleadingly, the TCM technical term ‘yu’, as used by Dr Zhu at the time has been rendered into English by some authors as ‘depression’ giving the false impression that this class of disorders is centred on depressed mood. Unfortunately, this is further compounded by the fact that in contemporary TCM, the term ‘yu’ has, in fact, come to have this particular connotation. In modern TCM, the term ‘yu’ is used in reference to emotion-based disorders and is centred on disruption of Liver function due to emotional strain. However, back in the 14^th century, and specifically in Dr Zhu’s writings and those of his students, this term was used in a general way to refer to purely physical types of stagnation. (58, 59) 

Syndromes due to stagnation in the middle Jiao (Spleen-Stomach axis)

The main text that elaborates Dr Zhu’s clinical theories and practical applications is ‘The Heart and Essence of Dan-xi’s Methods of Treatment’ (Dan Xi Zhi Fa Xin Yao). Although attributed to Dr Zhu, this book is actually a compendium of his theories and methods produced after his death and published during the Ming dynasty, some 200 years later. (60) It is basically a collection of Dr Zhu’s cases with explanations that he provided to his students, including comments by some of his senior followers, arranged according to clinical topics and written in a very brief and concise manner to enable easy reference in the clinic. The discussion of stagnation is introduced with the bold statement: ‘The ten thousand diseases of the human body are all generated by stagnation’. This serves to emphasise Dr Zhu’s theory that very many diseases are due to one or more of the six types of stagnation, and that once stagnation has developed, it tends to get worse, with cumulative effects as one type transforms into another. It is also stated that stagnation syndromes always begin in the middle Jiao – the Spleen-Stomach (and this is the crucial difference between these types of stagnation / ‘yu’ syndromes and the modern Liver-based emotional stagnation / ‘yu’ syndromes). If the condition is not resolved in a timely manner, other pathogenic factors such as Damp, Phlegm, Heat and, in extreme conditions, Blood stasis and Fire may eventually develop. Inherent to this theory is the idea (based on the over-arching Yin-Yang paradigm) that disruption to the descending physiological activities tends to also disrupt the ascending physiological activities – leading to reduced absorption of nutrients and mental dullness, amongst other things. This description of the early stages of stagnation, beginning with disruption of the descending and ascending activities of the Spleen-Stomach in the middle Jiao, foreshadowed in the14^th century the clinical descriptions of SIBO in the 20^th century. (61, 62)

Pathogenesis of the six stagnation syndromes 

The brief exposition referred to above has been considerably elaborated by subsequent TCM physicians, and the current view asserts that Qi stagnation (relating to Liver dysfunction and hence emotional strain) is the primary syndrome, from which other types may develop. (62, 64) I suspect that this is mostly because of the confusion over the use of the technical term ‘yu’. My own interpretation of Dr Zhu’s original discussion is that it specifies the middle Jiao (Spleen-Stomach) as the origin of the various types of stagnation and describes stagnation of food in the Stomach as the primary syndrome, giving a simple two-herb prescription for its treatment at the early stages. Stagnation of Qi is described subsequently – after discussing stagnation of food and its treatment. (61) The two-herb mini-formula, one herb with a descending direction of activity and the other with an ascending action, provides the basis for clinical formula construction, with the addition of other herbs according to the specific individual condition. Thus, the primary aim of treatment is to restore the normal Qi movement of the middle Jiao (Spleen-Stomach), not to regulate or soothe the Liver (as would be the case in treating emotion-based disorders). The stagnation syndromes discussed here are based on a physical or mechanical type of obstruction due to poor lifestyle habits and not specifically due to emotional strain, although the latter can definitely exacerbate the former. 

Another equally valid reading of Dr Zhu’s text is that the six stagnation syndromes are variations on disordered Qi movement in the Spleen-Stomach axis: sometimes it is related to food consumption (food stagnation), sometimes to metabolic disturbances (Damp), sometimes to emotional strain (Liver Qi), and so on. Once this process has begun, it tends to perpetuate itself and worsen by developing a more complex pathological pattern. In this way we can see that these descriptions of the pathogenesis as well as the clinical manifestations appear to parallel if not fully correlate with our contemporary understanding of SIBO.

The six types of stagnation- reinterpreted

According to Dr Zhu, the key clinical features of each of the six types of stagnation are described as follows (note, I have added in brackets the clinical features that are part of the broader body of TCM theory, and it would have been understood by Zhu’s students that these symptoms or signs may also be present):

• Food type stagnation, characterised by food retention in the Stomach: (worsening of symptoms on eating), reflux, sensation of fullness in the epigastrium, loss of appetite, pulse is normal on the left distal position and tight and excessive on the right distal position. 
• Qi type stagnation, characterised by disorder of Liver Qi spreading functions: pain (i.e. localised discomfort with a sensation of distension, which is difficult to localise precisely and tends to change location) in the chest and hypochondrium 
• Damp type stagnation, characterised by retention of pathogenic Damp in the middle Jiao: (thick tongue coat, bloating), generalised body aches and/or joint pain that is aggravated by cold and wet weather.
• Phlegm type stagnation, characterised by the visible manifestations of Phlegm within the respiratory system: (general signs of Phlegm, such as increased sputum, and nasal discharge, greasy tongue coat) dyspnoea on exertion with a slippery pulse in the distal position
• Heat type stagnation, characterised by the presence of pathogenic Heat (generally due to a febrile illness, i.e. systemic infection): (sensations of heat in the body), blurring of vision, dark urine and a deep rapid pulse.
• Blood type stagnation: weakness of the limbs and loss of appetite.

Notably absent from these brief symptom pictures are any emotional symptoms (which we would expect if this discussion was centred around Liver stagnation due to maladaptive emotional responses). Additionally, the symptoms given for Blood type stagnation appear to be more related to Spleen Qi deficiency syndrome (and hence to Qi and Blood deficiency) rather than to Blood stasis. This becomes more intelligible if we interpret the above list as an enumeration of not only the clinical syndrome-patterns but also the causes of stagnation in the Stomach and Intestines. In this reading we have a gastro-intestinal condition that may be caused by over-eating or having meals too frequently (‘food’ type), ingestion of contaminated foodstuffs (‘Damp’ type), sedentary lifestyle with insufficient exercise (‘Damp’ and ‘Qi’ types), emotional strain (‘Qi’ type), various respiratory disorders (‘Phlegm’ type), febrile illnesses (‘Heat’ type), physical overstrain or over-work with insufficient rest (‘Blood’ type = Qi and Blood deficiency due to Spleen deficiency), age related decline of Spleen-Stomach function (‘Blood’ type). 

The text also provides lists of the key herbs for each of the various types of stagnation as well as formulas to be made into pills to have on hand for general usage. As has been pointed out, these formulas may also be understood to be the starting points or building blocks for clinical prescribing according to the patient’s predominant syndrome-pattern. (70) Some the key herbs include Atractylodes lancea, rhiz. (cang zhu), Ligusticum wallichii, rhiz. (chuan xiong), Cyperus rotundus, rhiz. (xiang fu), Citrus aurantium (a.k.a. Poncirus trifoliata), fruit (zhi shi / zhi ke), Gardenia jasminoides, fruit (shan zhi zi). These particular herbs and several formulas that are built around them have been shown by Asian researchers to have a marked action on promoting small intestinal motility. 

An inherent bias within modern TCM

At this point it seems appropriate to briefly discuss an important bias within contemporary TCM, which has arisen out of the unique social and cultural conditions in China during the 20^th century, particularly due to the communist revolution and the subsequent cultural revolution. For detailed descriptions of conditions on the ground during the earlier and later stages of this vast cultural transformation, and the effects upon those who lived through them, I refer the reader to books by Edgar Snow and Jung Chang. (65, 66) In the beginning, and this often happens when people become involved as pioneers in great social or religious movements, a person’s individuality becomes subsumed by the immediate social revolution. There is almost a complete loss of personal perspective as subjective experience gives way to identification with the ‘mutations of collective human destiny as the material of history’ (65) There is a social taboo around the expression of personal opinions and feelings, outside of the limited (but all-encompassing) sphere of the great task at hand. All doubts, criticisms, feelings of discouragement, along with modes of personal expression that are not directly related to one’s role within the revolution are all repressed. This may be fine for a short period when enthusiasm, the sense of novelty and adventure, as well as the requisite physical demands provide an outlet for the human spirit. However, in time the innate limitations and imperfections within both one’s immediate circle of human contacts as well as aspects of the movement itself call forth a strong personal response that cannot be expressed. 

And this only describes conditions in the early stages of the communist uprising! Fast forward to Mao Zedong’s maniacal strategies to assert and hold on to his power (i.e. the cultural revolution) and you have whole communities living in fear, loathing and resentment, unable to express any of these feelings because of the risk of social rejection, loss of employment and transfer to labour camps for ‘thought reform’ (read ‘torture’). (66, 67)

‘Relaxation’ had become an obsolete concept: books, paintings, musical instruments, sports, cards, chess, teahouses, bars – all had disappeared . . . We hardly even thought of going out for a walk. The atmosphere outside was terrifying, with the violent street-corner denunciation meetings and all the sinister wall posters and slogans; people were walking around like zombies, with harsh or cowed expressions on their faces. (66) 

Thus, during the latter part of the 20^th century we have a whole society in a state of extreme emotional strain. The only socially acceptable way in which a person could express sadness, discouragement, anger, frustration and even fatigue was through somaticizing. (76) And the TCM doctors, mostly, were the ones who picked up the slack. All of the modern TCM textbooks, both for use within Chinese universities as well as those translated for Western students, were produced during this period. It is no wonder, therefore, that we see this over-emphasis on the Liver (the organ most affected by stress and emotional strain) within the pathogenetic theories of contemporary TCM. This has unfortunate consequences, because most Western authors and teachers, along with many Chinese interpreters of TCM for Western students appear to assume that all Qi stagnation relates directly to the Liver: thus, implying that stagnation of the Qi (which in itself is a very broad term) is always and only due to emotional causes. Indeed, almost every reference cited above reflects this particular bias. 

The class of disorders under the heading of ‘stagnation syndromes’, first elaborated by Dr Zhu and his followers, is an example of a ‘mechanical’ type of pathology that may be initiated principally by overeating, intake of contaminated foods, inappropriate diet, lack of exercise or over-exertion. While emotional strain may contribute to, or even be the principal cause in some instances, emotional factors, mediated via the Liver, are not central to this discussion. In modern TCM, emotion related disorders, centred on the Liver Qi, are also (quite confusingly) referred to as ‘stagnation (yu) syndrome’ and this topic has been discussed elsewhere. (68, 69, 70)

Pathogenesis of stagnation in the middle Jiao

Now that we have clarified what these syndromes are and what they are not, we can examine their causes and progression. Contemporary TCM clinical discussions centre on the disease categories of Abdominal Fullness (fu man) and Abdominal Distention (fu zhang); the former referring to a purely subjective sensation of fullness, while the latter is accompanied by visible and palpable distention of the abdomen. (71)

Reviewing the symptomatology of SIBO, we have the following major symptoms: bloating, abdominal distention and discomfort, flatulence, loose stools or diarrhea, pale stools, weight loss, anemia, fatigue, generalised aches and pains. High risk groups include those with overweight or obesity, chronic diarrhea or loose stools, long term use of PPI’s, and older age. These clinical features are covered by the following four TCM syndrome-patterns: Obstruction by Damp; stagnation of Food; Liver Qi invading the Stomach, and Spleen Qi deficiency. (71)

Pathogenic Damp may be due to consumption of contaminated food, beverages or from other external sources. In addition, it may be generated by dietary factors, such as excessive consumption of cold and cooling foods, deep-fried foods, overly processed fats and oils, or alcoholic beverages. Depending on body constitution and the types of dietary preferences, the pattern may be either Cold-Damp or Heat-Damp type. The Cold-Damp syndrome is characterised by heavy sensation of the head and body, loose stools, poor appetite with nausea or vomiting, excessive vaginal discharge, pale tongue with a thick white coat. The Heat-Damp type is characterised by reflux, increased appetite, irritability, dry mouth, malodorous stools, dark coloured urine, red tongue with a yellow coat. 

Stagnation of food generally arises due to consuming food in excess of requirements and/or capacity for digestion. This pattern is characterised by malodorous belching, halitosis, nausea in response to the smell of food being cooked in oil, symptoms worsening after eating and improving with passage of stool or flatus.

Liver Qi invading the Stomach is the pattern that is closely related to stress and emotional strain and the key symptoms include: fluctuation of symptoms according to the emotional state and a wiry pulse.

Spleen Qi deficiency may also form part of the picture in an individual patient. The key features are fatigue, muscle weakness, poor appetite, pale tongue and a deficiency type pulse (i.e. one or more of: weak, deep, thready). In patients who are physically overburdened (e.g. over-work or over-training with insufficient rest), this may be an important part of the cause, whereas in long term patients, it may arise as a result of the condition, i.e. due to poor absorption of nutrients.

Additionally, Phlegm retention may be an important component of the clinical presentation. TCM generally places all overweight and obese patients into this category, as the development of Phlegm is generally an inevitable accompaniment to the process of acquiring the extra kilos of body fat. Moreover, the behaviour of visceral fat (in biomedical terms) correlates very closely with the TCM concept of interior Phlegm. (72, 73) Key clinical signs (in patients of normal weight) include excessive mucous production (nose or lungs), chest oppression, dizziness, nausea, greasy tongue coat and slippery pulse.

Treatment protocols for middle Jiao stagnation syndromes

The following is a summary of treatment formulas and treatment protocols for clinical application. These have been developed over the subsequent centuries by TCM physicians, building upon Dr Zhu’s seminal work. The principal treatment strategy here is to promote the descending movement of the Stomach (and Intestinal) Qi, while the secondary principle of treatment is to dispel pathogens. In contemporary medical terms we are aiming to restore and promote the MMC’s, while also reducing the proliferation of hostile bacteria in the small intestines and, in some instances, to counteract the effect of bacterial toxins. Additionally, strategies to promote hepato-biliary function, gastric acid and pancreatic enzyme secretion may also be included, as appropriate. 

In order to avoid repetition, the main clinical features that define this condition are: 

• bloating, 
• abdominal distention and discomfort,
• flatulence, loose stools or diarrhea, 
• fatigue,
• generalised aches and pains,
• brain fog
• symptoms occurring in the context of high-risk patient (based on dietary habits, age group and other illnesses). 

Damp stagnation in the middle Jiao

This pattern encompasses the build-up of bacterial metabolites, inflammation and damage to the intestinal mucosa. There are two subtypes: Cold-Damp and Heat-Damp

1. Cold-Damp stagnation

Key clinical features: heavy sensation of the head and body, loose or irregular stools (sometimes loose, sometimes dry and sometimes initially dry then loose), increased bowel sounds, poor appetite, nausea, excessive vaginal discharge, pale tongue with a thick white coat.

Treatment formula/s: 

Ping Wei San (Magnolia & Ginger Combination) 

or Gut Detox Formula (for combined presentation with food stagnation, Damp-Cold and Damp-Heat)

1. Stagnation of Damp and Heat 

Key clinical features: reflux, increased appetite, irritability, dry mouth, malodorous stools, dark coloured urine, red tongue with a yellow coat, possibly also small stones or sludge in the gallbladder.

Treatment formula/s: 

Yin Chen Hao Wan – Jia Wei (Artemisia & Rhubarb Combination)

Liver Qi invading the Stomach

Key clinical features: Abdominal symptoms brought on or worsened by stress and emotional strain, sense of fullness in the hypochondrial region, premenstrual syndrome, wiry pulse.

Treatment formula/s: 

Chai Hu Shu Gan Tang (Bupleurum & Cyperus Combination), also available as Qi Mover Formula.

Food stagnation in the Stomach 

Key clinical features: Malodorous belching, absence of hunger sensations despite not having eaten for 4 hours or more, worsening of symptoms after eating, improvement of symptoms after passing flatus or stools, irregular (in terms of timing) bowel motions.

Treatment formula/s: 

Bao He Wan (Citrus & Crataegus Formula), also available as Digest-aid Formula

Phlegm retention

Key clinical features: obese or overweight patient, sense of fullness and distention in the epigastrium, excessive mucous production (nose or lungs), chest oppression, dizziness, reflux, nausea, fatigue and sensation of heaviness, sleepiness, thick and greasy tongue coat, slippery pulse.

Treatment formula/s: 

Ban Xia Hou Po Tang – Jia Wei (Pinellia & Magnolia Combination) – with excessive sputum in the throat 

or 

Wen Dan Tang (Bamboo & Hoelen Formula) also available as Clear the Phlegm Formula – with nausea or vomiting

Spleen Qi deficiency

Key clinical features: fatigue, muscular weakness, poor appetite, craving for sweets, loose stools, brain fog, pale tongue with a thick white coat, weak-slippery or weak-soft pulse.

Treatment formula/s:

Xiang Sha Liu Jun Zi Wan (Saussurea & Cardamon Formula) also available as Digestive Tonic Formula

Clinical Protocols

The treatment should be guided by initial and ongoing assessment of whether the patient has a predominantly excess and deficiency type of pattern. In this condition, the symptom of fatigue is not specific as may be due to excess pathogens (e.g. Damp, or Phlegm) or due to Spleen Qi deficiency – correlating with effects due to increased absorption of bacterial metabolites in the former case and the effects of malnutrition in the latter. Excess conditions are characterised by normal or red tongue body, thickened tongue coat and a full pulse; while deficiency conditions are characterised by a pale tongue body and a weak pulse. 

Because gastro-intestinal motility dysfunction is at the root of the condition, treatment protocols should comprise one formula focused on promoting motility together with another formula to dispel the accumulated pathogens.

Acute stage treatment

• Damp patterns:

1. Cold-Damp: 

Ping Wei San (Magnolia & Ginger Combination) or Gut Detox Formula

Plus 

Chai Hu Shu Gan Tang (Bupleurum & Cyperus Combination) or Qi Mover Formula.

1. Damp and Heat:

Yin Chen Hao Wan – Jia Wei (Artemisia & Rhubarb Combination)

Plus 

Chai Hu Shu Gan Tang (Bupleurum & Cyperus Combination) or Qi Mover Formula.

• Food stagnation:

Gut Detox Formula

• Phlegm retention:

Chai Hu Shu Gan Tang (Bupleurum & Cyperus Combination) or Qi Mover Formula.

Plus 

Ban Xia Hou Po Tang – Jia Wei (Pinellia & Magnolia Combination) or Wen Dan Tang (Bamboo & Hoelen Formula) also available as Clear the Phlegm Formula 

• Spleen Qi deficiency:

Xiang Sha Liu Jun Zi Wan (Saussurea & Cardamon Formula) also available as Digestive Tonic Formula

Plus

Ping Wei San (Magnolia & Ginger Combination)

Follow-up treatments to prevent recurrence:

• Spleen Qi deficiency (low gastric acid and enzyme secretion):

Xiang Sha Liu Jun Zi Wan (Saussurea & Cardamon Formula) also available as Digestive Tonic Formula

Notes: Continue for 2 – 3 months after symptoms have been resolved

• Gallbladder obstruction (small stones or sludge)

Yin Chen Hao Wan – Jia Wei (Artemisia & Rhubarb Combination)

Notes: Continue at high dosage for 4 weeks and confirm that gallbladder is clear with abdominal ultrasound and a computerized tomography

• Food stagnation and Qi stagnation (slow transit through upper GIT):

Digest-aid Formula

Plus

Ping Wei San (Magnolia & Ginger Combination)

Notes: Continue for 2 – 3 months until appetite returns to normal (feels hungry again 4 – 5 hours after eating)

Lifestyle changes

The three main classes of underlying causes need to be addressed, otherwise the condition will soon return. This has been shown to be the case with treatments based on antibiotics, where around half of the patients thus treated had a recurrence within 9 months. (74) Excluding structural abnormalities, the important modifiable causes are based around the maintenance of healthy stomach acid secretion, bile secretion and gastrointestinal motility. The following lifestyle measures will assist in restoring these functions.

• Eating less and allowing the stomach to remain empty for at least one hour before refilling. This becomes more important with advancing age.
• Avoidance of aggravating, irritating or inappropriate foods or combinations of foods (as discussed at the beginning of this article).
• During the initial stages of treatment, drastically reduce intake of plant fibre and other microbe accessible carbohydrates (MAC’s). In SIBO you do not want to be providing ample nourishment to the colonic microbiota, as this may exacerbate the condition.
• Avoidance of prolonged sitting. If at a sedentary job, one should stand up and move around at least once an hour.
• Exercise regularly.
• Manage stress. 
• Avoid the use of antacids and stomach acid reducing medications.
• Include a protein source at each meal.
• Eat the main meal at lunch time.
• Take a soup or stew at dinner some nights with fewer carbs and more protein.
• Avoid fermented foods.

Epilogue: The interstitial cells of Cajal and empirical research

In 1893 a Spanish neuroscientist and pathologist first described a cell type located between the nerve endings and smooth muscle cells of the gastrointestinal tract. He described them as ‘interstitial’ and they were subsequently named after him: the interstitial cells of Cajal (ICC). These specialised cells were originally thought to provide only structural support to the surrounding nerve and muscular tissues. However, about 100 years on, it was discovered that the ICC have spontaneous electrical activity and perform the function of pacemaker for the smooth muscle of the GI tract, eliciting rhythmic contractions of low frequency and long duration, which occur in the absence of any neural stimulation. In addition, the ICC facilitate the transmission of neural impulses from the enteric nerves to the GI smooth muscle cells. As such, the ICC play an important role in maintaining normal gut motility. (78, 79)

Recent studies on human subjects have shown that abnormality or decrease in numbers of ICC, which may occur due to toxins, neurotoxins or viral disease, result in slowed intestinal transit that is seen in many GI motor disorders. (79) Additionally, several animal studies have shown a link between SIBO and reduced density of ICC, particularly when this occurs after an enteric infection. (80, 81) 

Empirical research on TCM herbal medicines

In light of the serious adverse events associated with the use of several pharmaceutical prokinetic agents, and their withdrawal from the market in the early 2000’s, researchers in China, Korea and Japan have been investigating traditional herbal formulas as well as individual herbs for potential in this area. Because herbal medicines form a significant part of the national healthcare systems in these countries (82), the selection of herbs and formulas in studies is based upon traditional usage, i.e. those with a beneficial action on the digestive system. Although favouring this class of herbs and formulas does introduce a particular type of bias into this research, it is considered the most efficient way to proceed. These have been centred on in vitro studies using murine intestinal tissue. 

Interestingly, most of the Dr Zhu’s key herbs for treating stagnation syndromes, mentioned above, and formulas based around these herbs have shown a pronounced dose-dependent action on the ICC, mostly via 5-HT receptors (i.e. receptors for serotonin). (83, 84) In particular, Coptis root (huang lian), Gardenia fruit (shan zhi zi), Ginseng root (ren shen), Ginger (sheng jiang), Cirtrus (Poncirus) fruit (zhi shi, zhi ke) and Magnolia bark (hou po) have marked effects, stimulating the activity of these cells and promoting intestinal motility (84 – 87, 90) Several commonly used formulas for gastro-intestinal disorders that have shown this type of action include Ping Wei San (‘Calm the Stomach Powder’, a.k.a. Magnolia and Ginger Formula) (88); Li Zhong Tang (‘Benefit the Middle Decoction’, a.k.a. Dangshen and Ginger Formula) (89); and San Huang Xie Xin Tang (‘Three Yellow Herbs Decoction to Drain The Epigastrium’) (90). 

In terms of human subjects, the commonly used formula, Xiang Sha Lui Jun Zi Tang (‘Six Nobleman Decoction with Saussurea and Cardamon’, a.k.a Saussurea and Cardamon Formula) promotes gastric emptying in functional dyspepsia and alleviates diarrhea in irritable bowel syndrome; (91, 92) While another  formula in which two of Dr Zhu’s key herbs, Ligusticum, rhiz (chuan xiong) and Cyperus, rhiz. (xiang fu) play an important part, Chai Hu Shu Gan Tang (Decoction with Bupluerum to Soothe the Liver, a.k.a. Bupleurum and Cyperus Formula) has prokinetic activity in functional dyspepsia. (93)

Of course, targeting ICC activity is only one among many different ways in which herbal medicines are able to heal the gut. As discussed previously in Part 3, herbs and formulas may have anti-inflammatory, adaptogenic, immune system modulating, antioxidant, anti-bacterial, and tissue regeneration actions. 

I would like to conclude this series of articles with a quote from one of the books that Dr Zhu, himself wrote, the Extra Treatises Based on Investigation and Inquiry (ge zhi yu lun), which derives its title from the neo-Confucian admonition to ‘investigate things and extend knowledge’ (ge zhi). Right at the beginning of this collection of short essays, the first topic to be discussed concerns eating: ‘Admonitions on Food and Drink’

The human body is precious because it is inherited from one’s parents. Yet there are no end of cases where the body is damaged for the sake of the mouth. Because a person has a body, hunger and thirst arise repeatedly, and subsequently one must eat and drink in order to continue living. However, one can see that, in the muddle headed, it is because of indulgence in delicacies, which leads to an excess intake of one or more of the five flavours (i.e. sweet, sour, pungent, bitter and salty) that diseases spring up in swarms…. Those poor and humble people in the mountains and wilderness, live on a bland and homely diet, yet their movements never show decrepitude and their bodies remain safe and sound their entire lives. (94)

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