Mucosal barrier function and the commensal flora
R J Kennedy,1 S J Kirk,1 and K R Gardiner1
Mucosal barrier function and the commensal flora
R J Kennedy, S J Kirk, K R Gardiner
Gut. 2002 March; 50(3): 441–442.
Includes additional comments & authors
PMCID:
PMC1773146
We read with interest the article by Garcia-Lafuente et al (Gut 2001;48:503–7). Their results
demonstrate that strains of endemic gut bacteria can affect gut mucosal barrier function, as measured
by intestinal permeability, and that the effect may be potentially beneficial or harmful depending on the
specific bacterial strains administered.
These findings help to explain and corroborate the interesting findings that have been emerging from
clinical and experimental studies investigating the use of probiotics in inflammatory bowel disease (IBD).
It is known that development of colonic inflammation in genetic models of IBD is dependent on the
presence of intestinal bacteria. In human studies, an imbalance in colonic bacteria has been described in
patients with IBD with a reduction in potentially protective organisms such as bifidobacteria and
lactobacilli and an increase in Escherichia coli. Furthermore, treatment with probiotics such as
lactobacilli has been shown to reduce intestinal inflammation and inflammatory response in
experimental models of colitis and to reduce symptoms and inflammatory scores in patients with IBD.
We have recently investigated the effect of Lactobacillus plantarum species 299 on the gut mucosal
barrier both in patients with ulcerative colitis and in the interleukin 10 knockout mouse model of
colitis.1, 2 This probiotic was found to improve gut mucosal barrier function in the mouse model, as
measured by a reduction in gut permeability and a reduction in the concentration of circulating antibody
to endotoxin. These changes correlated positively with a reduction in colonic inflammation. In a study of
patients with ulcerative colitis, Lactobacillus plantarum probiotic therapy was also found to improve gut
mucosal barrier function, as measured by a reduction in the circulating antibody to endotoxin.2 The
findings of our studies and those of Garcia-Lafuente et al suggest that probiotics such as Lactobacillus
plantarum are capable of improving gut mucosal barrier function in both normal and inflamed bowel. It
is possible that this probiotic induced enhancement of the gut barrier may be a mechanism by which
probiotics are effective in reducing intestinal inflammation in experimental models of colitis and IBD.
References
1. Kennedy RJ, Hoper M, Weir H, et al. Probiotic therapy stabilises the gut mucosal barrier in the IL-10 knockout mouse
model of colitis. Br J Surg 2000;87:669.
2. Kennedy RJ. The effect of Lactobacillus plantarum species 299 on intestinal inflammation and associated gut mucosal
barrier dysfunction, MD Thesis. Belfast: The Queen's University of Belfast
Postgrad Med J. 2006 June; 82(968): 376–382.
PMCID: PMC2563748
doi: 10.1136/pgmj.2005.040899
Copyright ©2006 The Fellowship of Postgraduate Medicine.
Probiotics and inflammatory bowel diseases
A‐P Bai and Q Ouyang
A‐P Bai, Q Ouyang, Department of Gastroenterology, Huaxi Hospital, Sichuan University, Chengdu, Sichuan Province, China
Correspondence to: Professor Q Ouyang
Department of Gastroenterology, Huaxi Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China;
qin.ouyang@163.com
Received August 24, 2005; Accepted November 10, 2005
Abstract
Enteric microflora profiles vary considerably between active inflammatory bowel diseases (IBD)
and healthy conditions. Intestinal microflora may partake in the pathogenesis of IBD by one or
some ways: specific pathogenic infection induces abnormal intestinal mucosal inflammation;
aberrant microflora components trigger the onset of IBD; abnormal host immune response loses
normal immune tolerance to luminal components; luminal antigens permeate through the
defective mucosal barrier into mucosal lamina propria and induce abnormal inflammatory
response. Preliminary studies suggest that administration of probiotics may be benefit for
experimental colitis and clinical trials for IBD. Researches have been studying the function of
probiotics. Introduction of probiotics can balance the aberrant enteric microflora in IBD patients,
and reinforce the various lines of intestinal defence by inhibiting microbial pathogens growth,
increasing intestinal epithelial tight junction and permeability, modulating immune response of
intestinal epithelia and mucosal immune cells, secreting antimicrobial products, decomposing
luminal pathogenic antigens.
Keywords: inflammatory bowel diseases, probiotics, enteric microflora
Decomposing luminal pathogenic antigens
Intestinal inflammation resulting in disruption of mucosal barrier function has been proposed as a cause
of increased incidence of allergic diseases.74,75 Dietary antigens may trigger aberrant immune response
in mucosa and flare the onset of colitis.76 Some studies have shown that probiotics can decompose
luminal pathogenic antigens, and induce hyporesponsiveness of mucosal immune system to dietary
antigens.
Enteric microflora become aberrant in IBD patients, with a decrease in bifidobacterium and
lactobacillus, and a significant increase in pathogenic and potential harmful enterobacteria. The
aberrant microflora may partake in the pathogenesis of IBD. Preliminary studies suggest that oral
administration of probiotics may be effective in treating intestinal inflammation in animal colitis
and clinical trials. Probiotic mixture often contains bifidobacteria, lactobacilli, and some
non‐pathogenic bacteria as escherichia and enterococci. The effect of probiotic administration is
often different in each clinical trials as probiotic use differs in those respects: the dose used, the
frequency and duration of use, and the use of concomitant treatment with other drugs as
corticosteroids and antiobiotics. More controlled trials are needed to search the best efficient use
of probiotics for treating the diseases.
Recent researches are enlarging the insight into the composition and function of probiotics. Oral
introduction of probiotics can normalise of the properties of aberrant indigenous microflora and
reinforce the various lines of intestinal defence. However, different probiotic bacteria may be
distinct in immunological effects, and have special properties when normalising in the inflamed
mucosal of IBD patients or in the healthy. In the respect, the properties of different probiotics
strains might be intensively explored to determine and screen the optimal probiotics strains and
proper ingredients for therapeutic intervention of IBD in the future.
Mucosal barrier
Allergies are overreactions of the immune system. The immune system is a very complex
interconnected network, comprising the various different white blood cells (lymphocytes,
granulocytes, macrophages, mast cells), as well as the entire system of mucous membranes
throughout the body, but especially in the digestive system, where specialized lymphatic tissue,
called Peyer’s patches, and an immunoglobulin called secretory IgA play an essential role in the
Gut Associated Lymphoid Tissue or GALT. Secretory IgA is essential for the healthy immune
functioning of the gut because it will form antigen antibody complexes within the digestive tract
allowing the complex to be excreted in the stool, thus preventing the adhesion of antigens to the
epithelial lining. Another essential component of the immune system is the normally present
bacterial colonies in the mucous membranes of the gut.
An allergy begins long before the manifestation of allergic like symptoms. The body has to be
set up to respond to an allergen. This usually begins in early childhood. It takes a disturbed
intestinal environment, the internal terrain of the body, for the body to react allergenically.
Unfortunately this disturbance to the intestinal environment often goes unnoticed, since it is
chronic, and tends to build up over many years.
Dysbiosis is one of the major disturbances to the intestinal environment leading to the
presentation of allergenic symptoms. Dysbiosis can be described as an abnormal intestinal flora
and an abnormally permeable intestinal mucous membrane. The intestinal flora, comprising of
billions of bacteria, forms a fine film on the inside of the intestines. Everything you eat passes
through this bacterial layer, which alters and filters the foodstuffs. The build up of pathogenic
bacteria, yeast and parasites severely impairs the absorptive ability of the intestinal mucous
membranes.
Functional hypochlorhydria and pancreatic insufficiency cause the maldigestion of
carbohydrates, fats and proteins. Large macromolecules are left undigested and form the
substrate for dysbiosis formation. Over time the villi, the large absorptive surface of the
intestines, becomes irritated and inflamed due to the production of destructive enzymes and
toxins from the dysbiotic pathogens. This causes the villi to become less dense and the intestinal
lining to become “leaky”. With the destruction of the villi comes the reduction of the GALT and
the secretory IgA, the body’s first line defense against “foreign” invaders. Large, incompletely
digested macromolecules, especially proteins, start to penetrate the hyperpermeable intestinal
mucous membrane and enter the blood stream. Once in the bloodstream, the body’s immune
system recognizes the small, incompletely digested macromolecules as foreign, and produces
antibodies against it. These antigen-antibody complexes circulate in the blood stream, migrating
to various tissues in the body. It is the reaction of the antibody/antigen complex systemically that
produces the classic allergy symptoms.
The body’s second layer of defense lies in the liver. The liver normally screens the blood for
antigens. On each pass through the body, the blood must pass through the liver for cleaning and
detoxification. The liver normally takes these foreign substances and destroys them or gets them
out of the body. Unfortunately, liver dysfunction is a very common occurrence in our society.
The destruction of foreign substances will not occur if the liver is not functioning as it should, if
there is too much of the substance to get rid of easily or the liver’s phase I and II detoxification
pathways cannot destroy it.
Over 80% of the human immune system is situated alongside the intestines. It is therefore
understandable that disturbances of the intestines and the intestinal flora place a tremendous
overload on the immune system, which then often reacts “allergically” to otherwise quite
innocuous proteins. Allergies are usually indirect ailments of the intestinal mucous membrane.
Thus, in treating allergies, the greatest attention needs to be given to assessing the health of the
mucosal barrier, identifying whether or not the patient has dysbiosis, restoring the intestinal flora
and repairing the intestinal mucous membrane.
In our experience working with physicians, the health of the mucosal barrier is not routinely
assessed. The key is to identify the primary cause and extent of increased intestinal
hyperpermeability. The test we recommend is the Mucosal Barrier Function Test.
The Mucosal Barrier Function Test
The Mucosal Barrier Function Test measures the serum levels of IgG, IgM and IgA antibodies to
five combined dietary proteins (wheat, corn, soy, milk, and eggs), yeast (Candida albicans), two
aerobic bacteria (Bacteroides fragilis and Clostridium perfringens), and two anaerobic bacteria
(E. coli and Enterococcus) using the ELISA method of analysis.
How is the Mucosal Barrier Function evaluated?
The Mucosal Barrier Function Profile measures the health of the mucosal barrier lining of the GI
tract from a functional standpoint. A healthy mucosal barrier will have secretory IgA (sIgA)
levels in normal range and will show normal recognition of food proteins, enteric yeasts and
enteric aerobic and anaerobic bacteria. This means that IgA, IgM and IgG levels to food proteins,
enteric yeasts and enteric aerobic and anaerobic bacteria are all within normal range.
What if the mucosal barrier does not recognize normally encountered antigens?
If the mucosal barrier has shut down, the results for IgA, IgM and IgG levels to food proteins,
enteric yeasts and enteric aerobic and anaerobic bacteria will all be <400. A continuum of events
can lead to the complete shutdown of the mucosal barrier. When a healthy mucosal barrier is first
challenged by an infectious agent, sIgA rises and elevations of specific antibodies may occur. At
this point the antigen load is compartmentalized within the GI tract. As the infection begins to
overwhelm the mucosal barrier defenses, the humoral immune system becomes more involved
by increasing the number of circulating antibodies.
As an infection overpowers the mucosal barrier defenses, at some point the tight junctions
between the intestinal cells open up and antigen penetration into the general circulation increases
resulting in an increase in allergy and inflammation. Also, if any one of the three antibodies
(either IgA, IgM or IgG) are elevated in each of the four compartments on the Mucosal Barrier
Function Test (dietary proteins, yeasts, anaerobic bacteria, and aerobic bacteria) this would
indicate hyperpermeability in the intestinal mucosal lining.
If no intervention occurs, eventually the mucosal immune response begins to weaken and can
eventually shut down. As time goes on it loses its ability to recognize and process antigens
properly. Ever increasing antigen penetration can eventually result in overstimulation of the
humoral immune system leading to hyper-immune response and eventually the humoral immune
system burns out.
If a hyper elevated or shut down mucosal barrier and/or leaky gut is confirmed, it is extremely
important to identify the cause.
Suspect: Increased intestinal permeability or “leaky gut”
Possible Causes
1. Exposure to toxic substances (drugs such as NSAIDS and alcohol, chemical exposure)2.
Food allergy/intolerance
2. Intestinal dysbiosis
3. Parasite, yeast, viral, or bacterial infection
4. Maldigestion (includes hypochlorhydria, pancreatic insufficiency, and disaccharidase
insufficiencies)
5. Bacterial overgrowth of the small bowel
6. Prolonged fasting/nutrient insufficiencies
7. Inflammatory bowel disease, e.g. Crohn’s disease
8. Insufficient mucosal glycocalyx and/or sIgA
Finding the cause of a patient’s intestinal impermeability will help you determine the direction of
treatment. It’s important to remember that correcting intestinal hyperpermeability can take quite
a long time, especially as it’s often taken years to develop. Fortunately, the gut tends to be a
responsive organ, and correcting its imbalances can reverse longstanding, painful symptoms.
N.A.(2012) Mucosalbarrier. Retrieved from website: http://www.mucosalbarrier.com/