Small Intestinal Bacterial Overgrowth, or SIBO as it has become known, is a pathology which can cause complications in gastrointestinal function, and beyond.
SIBO occurs when colonic bacteria are provided with an opportunity to populate the small intestine from the colon, which disrupts the delicate balance of flora, having functional consequences.
It is defined as ‘an increase in the number and/or alteration in the type of bacteria in the upper gastrointestinal tract’ (*).
Typically, the small intestine contains mainly gram positive and aerobic bacteria, whereas the large intestine contains predominantly gram negative and anaerobic bacteria (*). Colonic bacteria or Coliforms ferment carbohydrates into gases like hydrogen and methane, and active metabolites like short chain fatty acids.
But, when these coliforms swim upstream as it were, their very specific function being distinct from that of the comparatively sparse small intestinal bacteria, causes problems.
Some common bacteria associated with SIBO are:
Escherichia coli, Enterococcus spp., Klebsiella pneumonia and Proteus mirabilis
SIBO can be characterised in terms of bacterial population within the small intestine:
Finding of ≥1 × 103 Colony Forming Units (CFU)/ML coliform bacteria of proximal jejunal (*).
Although SIBO is also found at 105 CFU/ml for some, a healthy measure seems to lay below 103 CFU/ml for the majority.
How does SIBO happen
Colonic bacteria are able to populate the small intestine given a number of factors which may occur exclusively or in combination with one another. Typically, you have regulatory mechanisms which attempt to prevent the scenario where SIBO is able to propagate.
Natural defences preventing SIBO:
- Sufficient strength and secretion of gastric acid
- Intestinal motility – healthy peristalsis (contraction and movement of the bowel to propel food and bacteria through)
- Ileocecal valve function (the junction where the small intestine meets the colon)
- Production of secretory immunoglobulins (sIgA) on the surface of the gastrointestinal mucous membrane
- Bacteriostatic properties of pancreatic juice and bile
Hypochlorhydria is a term given to reduced stomach (gastric) acid secretion. Gastric acid plays an important role in neutralising bacteria taken in from food, and naturally prevents them from being overly disruptive in the small intestine. Without sufficient GA, an environment now exists where increased bacteria can populate the small intestine.
Hypochloridia can occur:
- After Helicobacter pylori colonisation
- As a consequence of ageing
- After histamine receptor 2 blockers & proton pump inhibitor extended use
- After extended periods as a vegan or vegetarian
- Due to sympathetic nervous system dominance (stress). Gastric acid production is normally stimulated when parasympathetic nervous activity predominates, in response to acetylcholine
Stress can disrupt gastric acid output in a myriad of ways:
- Psychological stress drives sympathetic dominance and vagal (parasympathetic) inhibition
- Food sensitivities (IgG) induce activation of sympathetic nervous activity (adrenaline)
- Eating when under stress, in a rush, or when highly caffeinated means that you are not in an optimal state to digest and absorb that food
The mechanical process of digestion is also highly important for maintaining the bacterial ecosystem. The stomach has to contract and churn food to break it down in combination with gastric acid. This movement is also essential for gastric emptying (into the small intestine) where food propels further down the GI tract.
Delayed gastric emptying, where peristalsis (muscular movement) is inhibited, allows for food (and bacteria) to stagnate in the upper small intestine. This is known as Gastroparaesis.
Gastropariesis can occur:
- Because of dysfunctions between PNS & SNS (stress based)
- Due to hyperglycemia – high blood sugar may inhibit the movement of the stomach. AGE’s are formed in response to high blood sugar, and can inhibit nNOS, which is a cell signalling molecule which synthesises NO (a neurotransmitter involved in gastric relaxation).
The movement and contraction of the intestines is also a vital step in the digestive process, and is also under control from the same network that controls gastric acid secretion, contraction and relaxation.
Coordinated and rhythmic contraction and relaxation of the small intestine typically moves food and bacteria down the GI tract. This movement is known as motility.
Small intestinal dysmotility is exactly what it sounds like, a lack of intestinal movement. Therefore, bacteria are not swept into the colon, due to the dysfunction of contractions that normally keep them moving. As a result, they stagnate and grow within the SI.
Dysmotility can occur:
- As a consequence of/in concert with hypothyroidism (*), which is associated with SIBO (*).
- Downstream of gastroparesis (possible due to shared innervation of contractions/relaxation)
- SNS dominance reduces bowel motility (stress)
- Lack of exercise/movement reduces bowel motility
- Due to lack of fibre, which facilitates bowel transit
- Deoxycholic acid is a bile acid and can affect intestinal smooth muscle activity. Alterations in bile acid metabolism may contribute to dysmotility and constipation (*). Constipation is a risk factor for SIBO.
Another way SIBO can proliferate, is through changes to the ileocecal valve. The ileocecal valve is the gateway where the end of the small intestine (ileum) meets the start of the colon (ceacum). It essentially keeps traffic moving one way, and prevents back flow from the colon.
Reduced ileocecal valve pressure is significantly associated with SIBO (*), and is what allows translocation of bacteria from the colon into the small intestine.
The opening and closing of the ICV is under both muscular and hormonal (gastrin) control. When pressure is exerted on the colon, the valve closes, and when peristalsis occurs in the small intestine, the valve opens (*). An upstream disruption of nervous system signalling may disrupt both the muscular and gastrin control of ICV function.
Gut Immune Function
Complications in gut immune function may also be a factor in the development of SIBO;
SIgA is an antibody of the adaptive immune system which coats the mucosa on the intestine, providing an immunological wall which prevent pathogens from activating inflammatory and complement responses.
Typically SIgA regulates gut inflammation by preventing infections, neutralising viruses and clearing antigens from the GI tract, which is of particular significance when we are considering changes to bacterial living arrangements in the intestine.
If SIgA becomes depleted, then opportunistic bacteria may be able to populate and proliferate in the small intestine.
In addition to SIgA deficiency, reduced T cell response may also increase the likelihood of bacterial overgrowth (*), and mice with reduced T cell control had impaired SIgA selection, which severely disrupted the balance of bacterial communities (*).
T cells also influence the composition of the microbiome via their modulation of inflammation. An absence of Foxp3+ T cells alters the gut microbiome composition due to T helper cell 2 mediated inflammation (*).
In fact, the microbiome and T cells exist as a regulatory loop. Foxp3+ T cells repress inflammation and support SIgA selection, and subsequently promotes diversification within the gut microbiome. In turn, balanced and diverse gut microbiota stimulate the immune system with bacterial antigens, promoting expansion of Foxp3+ T cells, and SIgA production (*).
So, if this regulatory loop becomes disrupted through, say a depletion of gut microbes from so many of the environmental disruptors we encounter today, this may in fact drive the development of SIBO.
Anatomical alterations of the GI tract from surgery may indeed play a role in the development of SIBO. For example;
Surgeries where a section of SI is bypassed and reattached with the stomach may induce bacterial stagnation and overgrowth due to abnormal motility and ineffective clearance of retained foods and secretions (*).
Also, strictures of the small intestine which develop after surgery, or as a result of Crohn’s may also predispose to the development of SIBO (*).
Resection of the Ilieocecal valve may also permit bacterial migration from the colon into the small intestine. Again, this is prevalent in Crohn’s patients after ICV resection (*).
Ghoshal, U. C., Shukla, R., & Ghoshal, U. (2017). Small Intestinal Bacterial Overgrowth and Irritable Bowel Syndrome: A Bridge between Functional Organic Dichotomy. Gut and Liver, 11(2), 196–208.
As a list, the risk factors for SIBO are:
- Small intestine diverticula
- Small intestine strictures (radiation, medications, Crohn’s disease)
- Surgically created blind loops
- Resection of ileocecal valve
- Fistulas between proximal and distal bowel
- Gastric resection
- Small bowel dysmotility
- Celiac disease
- Chronic intestinal pseudo-obstruction
Irritable Bowel Syndrome
Organ System Dysfunction
- Renal failure
- Immunodeficiency states
- Crohn’s disease
- Celiac disease
- Recurrent antibiotics
- Gastric acid suppression
How does SIBO cause constipation?
Is a frequently asked question, which can be answered simply by flipping the script. Constipation causes SIBO as we have already mentioned above with regards to reduced bowel motility.
However, an overproduction of methane in the small intestine could also account for constipation. Archaea are like bacteria, but more ancient. A product of their metabolism when they feed on carbohydrates is methane, particularly the species Methanobrevibacter smithii (M. smithii).
Other bacterial metabolites, both ‘good’ and ‘bad’ can also affect gut motility. The bacterial endotoxin LPS, which is produced by gram negative bacteria may impair gut motility. LPS activates TLR4 receptors within the enteric nervous system (gut), increasing their signalling which has been suggested to degrade myenteric neurones, altering intestinal motility in mice (*).
Additionally, SCFA production by bacteria has been found to decrease gut motility. SCFA bind to G protein-coupled receptors in the gut, and cause a subsequent release of the hormone PYY. This hormone reduced gut motility in the ileum of rats (*). However, PYY also increases intestinal transit time, and a deficiency of Gpr41 (G-protein c receptor) reduced intestinal transit rate in mice.
SCFA production depends very much on the species and amounts of microbes present, and where those microbes lie, which may dictate whether they serve to be beneficial or counterproductive for bowel movement.
SCFA tend to be beneficial in the colon, but when overproduced in the small intestine put the brakes on motility.
The underlying theme here is that SIBO can be a result of poor motility and further perpetuate constipation. A solution may therefore lie in addressing non-bacterial causes of reduced motility, such as stress reduction and exercise. Additionally, making dietary changes to level the bacterial playing field may help address constipation perpetuation, e.g. FODMAPS, ketogenic, low sugar, antimicrobial agents, fasting.
How does SIBO cause diarrhea?
There are a few mechanisms that tie microbial composition together with diarrhea:
Because SIBO interferes with enzymatic, absorptive and metabolic actions, maldigestion and malabsorption can occur, which often encompasses diarrhea. Water/ion balance is a key player in diarrhea, and below are a few ways which it can be poorly regulated.
Bacteria digest carbohydrates, producing gas and osmotically active byproducts. Over production of SCFA in the SI causes osmotic water movement to the intestinal lumen, and then diarrhea.
Again, injury to the brush border of the small intestine (from bacterial metabolites and inflammation) may reduce the activity of disacchardidases, enzymes which break down sugars (*). Sugars have osmotic activity, and if they are not being broken down and absorbed, they can linger and osmotically stimulate diarrhea.
Typically, a large amount of bile is reabsorbed by the small intestine after it has facilitated digestion and transport of fats and fat soluble vitamins. However, malabsoption of bile acids can occur, and both chenodeoxycholic acid and deoxycholic acid inhibit colonic sodium absorption and stimulate chloride secretion, causing diarrhea (*).
In addition, malabsorption of bile salts may also have an impact on small and colonic intestinal permeability, which in itself is another way in which diarrhea can occur (*).
An underlying force in producing malabsorption may indeed be increased motility in both the colon and small intestine. Where constipation is underpinned by an overpopulation of Methane bacteria, diarrhea is associated with an overgrowth of hydrogen producing bacteria (*). Hydrogen producing bacteria may therefore perpetuate malabsorption issues through increasing motility, as hydrogen sulphide acts as a gaseous neurotransmitter (*).
How does SIBO cause Leaky Gut?
To put it bluntly, alterations in intestinal flora, whether that be in the small intestine as SIBO or dysbiosis in the colon, leads to the disturbance of intestinal homeostasis (*).
The concentrations, types of strain and overall composition of the microbiome are a big deal when it comes to gut permeability – aka gut leakiness. There are several ways which bacteria can influence barrier function in the small intestine, and that has to do with the factors above.
Firstly, SCFA – bacterial metabolites regulate barrier permeability by altering the expression of proteins that open and close the tight junctions in the gut wall. They are also the preferred fuel source for gut cells, maintaining their strength.
However, the overall production and concentration of these metabolites is key, as patients with SIBO were found to have significantly elevated levels of Acetate which may actually damage small and large intestinal lining (*). Additionally, in SIBO cases, bacteria have been found to overproduce succinate, which is implicated in the development of ulcerative colitis (*).
This really highlights that specific bacterial diversity and composition is important for metabolite production that is neither insufficient or excessive, and overgrowth may disrupt this delicate balance.
Bacterial overgrowth de-conjugates bile salts (*) through the production of specific enzymes, one of which is B-glucoronidase. Whilst some bile is recirculated, a lot of it harbours toxins and is sent packing in out poop. De-conjugation releases toxicity back into action before it can be evacuated, and damages the intestinal wall through the release of pro-inflammatory cytokines, like IL-8 (*).
The relationship between dysbiotic bacteria and the immune system may promote an inflammatory environment in the gut. Dysbiosis may entail an increased colonisation of gram negative bacteria of the small intestine, which produce an inflammatory metabolite (LPS). LPS is one way that inflammation is triggered in the gut, through releasing IL-6 and TNF-a – two inflammatory cytokines which increase gut permeability through tight junction protein under expression, and are often seen in association with IBS & IBD.
Bacterial overgrowth produces a number of toxic compounds (peptidoglycans, D-lactate and serum amyloid A), which also promote inflammation, and may damage the brush border of the enterocytes and increases small intestinal permeability (*).
Bacterial strains such as bifidobacterium interact with cannabinoid receptor 1 (CB1) in the gut. CB1 is yet another receptor which regulates tight junction protein expression. Mice given probiotics were found to have increased expression of TJ proteins, and a reduced inflammatory marker (LPS), indicative of less gut leakiness. Disorder in the small intestine may interfere with microbe – cannabinoid barrier function.
How does SIBO cause weight gain?
Carbohydrate fermenting bacteria that produce SCFA are usually found in the colon, but when these bacteria proliferate in the small intestine, it may increase energy harvest from carbohydrates.
Thats been a proposed mechanism linking the gut microbiome to changes in weight, although emerging evidence questions the role of SCFA in weight gain. For example, a study in mice found that SCFA were found in equal concentrations in the biomes of both lean and obese mice (*), suggesting a similar rate of SCFA consumption.
Dalby, M. J., Ross, A. W., Walker, A. W., & Morgan, P. J. (2017). Dietary Uncoupling of Gut Microbiota and Energy Harvesting from Obesity and Glucose Tolerance in Mice. Cell Reports, 21(6), 1521–1533.
Because SIBO can also cause a leaky gut, there is a greater susceptibility to inflammatory metabolites and pathogens, which can impair metabolic function.
Endotoxins like LPS, once into circulation can bind to TLR4 (toll like receptors) which are found on liver, muscle, fat and immune cells. The activation of these receptors induces inflammation and reactive oxygen species, which may impact the function of fat and muscle tissue (*), and their regulatory position in metabolism.
This is known as metabolic endotoxemia, and can disrupt metabolism in such a way that influences fat storage.
Also, the over-production of CH4 gas by CH4-producing microflora could lead to an increase in weight gain (*).