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Life on the edge: the clinical implications of gastrointestinal biofilm.

Introduction to Biofilm

In the microbiology world, a revolution in how microorganisms are perceived has been occurring that is only now catching the attention of medical practitioners. Much of what has been commonly accepted about microbial structure, function, and ecology are laboratory artifacts. (1) Microbes do not normally live as free-floating, planktonic organisms in enriched media on agar plates or in flasks. They naturally prefer life on the edge, in protected communities nestled within biofilm. (2) Biofilm is a gathering of sessile microorganisms encased by a self-generated hydrated matrix, strongly attached to a surface. (2), (3) Bacteria and fungi living within biofilm differ substantially from their free-living, planktonic fellows. (2) Genes mediating adhesion, growth, and motility are downregulated, while those mediating exopolysaccharide synthesis and antibiotic resistance are upregulated. (4-6) Microbes within biofilms communicate with each other, display metabolic specialization, and even sometimes appear to undergo apoptotic programmed cell death so as to benefit the greater biofilm community. (7) Biofilms are ubiquitous in nature, including the human body.

[ILLUSTRATION OMITTED]

Biofilms and Microbial Survival

Biofilms increase microbial survival. (2), (8) Within biofilms, microorganisms are protected from bacteriophages, amoebas, and other predators. (9) Biofilm shields microbes from humoral and cell-mediated immune responses. (8) Resistance to antimicrobial agents is intrinsic to the biofilm mode of life. (2) Depending on the species and antibiotic, biofilm phenotypes are from 10 to over 1000 times more resistant to antibiotics than their planktonic comrades. The mechanisms of antibiotic resistance are not well understood. Reduced antimicrobial diffusion into biofilms is one means. (10-13) Other proposed mechanisms include exopolymer antibiotic neutralization, reduced growth rates, nutrient limitations, and persister cell development. (14-16) Finally, in some organisms such as Candida albicans, surface adhesion and biofilm formation activate expression of genes mediating classical antimicrobial resistance. (17) All of these mechanisms combine to provide biofilm communities with a multifaceted defense system.

Biofilm Formation

Microbes must adhere to an edge or interface for biofilm genesis to occur. Adhesion triggers a host of changes in gene transcription as microorganisms transform from planktonic to sessile phenotypes. (3) These genetic alterations lead to changes in electron-transport activity, exopolymer synthesis, substrate uptake and catabolism, oxygen uptake, diminished heat generation, and reduced growth rates. Adhesion is quickly followed by exopolymer matrix synthesis, proliferation of adherent microbes, and attachment of other organisms. As cell density increases, an essential biofilm cell-to-cell communication phenomenon known as quorum sensing occurs. (18) Quorum sensing is mediated by small hormonelike molecules called autoinducers. (19) One highly conserved quorum-sensing molecule, called autoinducer-3 (AI-3), is central to microbial interspecies communication as well as mediating interkingdom messaging. (20) AI-3 crosstalks with the eukaryotic hormones epinephrine and norepinephrine, allowing microbes to sense host metabolic status and stress levels. AI-3 may allow the highly pathogenic enterohemorrhagic Escherichia coli to switch on virulence factors when it detects host stress. (21) Mature biofilms are heterogeneous compositions of microorganisms, exopolysaccharides and other exopolymers, water, metals, and debris resembling tiny mushroom-shaped turrets or towers. (2)

Biofilm Matrix Exopolymers

Biofilm matrix is predominately composed of exopolysaccharides. (3) Different species synthesize differing biofilm polysaccharides. (22), (23) While the dominant matrix exopolysaccharides vary from species to species, two common components have been described, poly-[beta]-1,6-N-acetylglucosamine (PNAG) and cellulose. (24) PNAG is a highly conserved biofilm matrix constituent among eubacteria. Cellulose, a polymer of [beta]-(1[right arrow]4) linked D-glucose sugars, is a ubiquitous component of biofilms made by microorganisms in the Enterobacteriaceae family, some Gram-positive organisms, and cyanobacteria.

Health Implications of Biofilms

Biofilm is increasingly recognized as a major factor in chronic, persistent diseases including periodontal disease, endocarditis, osteomyelitis, and otitis media. (2), (9), (25) (See Table 1) Infections related to medical devices invariably involve biofilm. Biofilm explains why many common infections are difficult to treat with antimicrobials and are characterized by recurrent relapses. Antimicrobials may transiently improve symptoms as planktonic pathogens are killed, but the underlying source of the infection, sessile pathogens within biofilm, cannot be eradicated. Biofilm also explains why infected medical devices do not respond well to antibiotic treatment. Persistent biofilm may cause chronic symptoms as the body's immune responses are deflected and inflammation damages tissue.

Table 1: Examples of Human Infections Associated with Biofilm

Native tissue infections

Medical device infections

Biliary tract infections

Arteriovenous shunts

Chronic bacterial prostatitis

Artificial heart valves

Chronic Candida infections

Biliary stents

Chronic tonsillitis

Cerebral spinal fluid shunts

Cystic fibrosis pneumonia

Contact lens

Dental caries

Endotracheal tubes

Endocarditis

Endovascular catheters

Kidney stone infections

Intrauterine devices

Osteomyelitis

Orthopedic prostheses

Periodontitis

Penile prostheses

Healthy Gastrointestinal Biofilms

As with virtually all other prokaryocytes, the gastrointestinal microflora prefers life within biofilm. (26), (27) Gastrointestinal biofilm communities are invariably multispecies. (26) Bacteroides, Bifidobacterium, Clostridium, and various Gram-positive cocci predominate healthy gut biofilm. (27) The mucosal biofilm embodies gastrointestinal barrier function. (28) It is directly responsible for colonization resistance to pathogenic organisms, an interface for immune system modulation, a site for gut detoxification, and a source of calories and nutrients. Disruption of the healthy gastrointestinal biofilm facilitates an inflammatory response to normal commensal microflora and compromises host defenses against pathogens.

Pathogenic Gastrointestinal Biofilms

Although research into pathogenic gastrointestinal biofilms is relatively scant, interest is rapidly expanding. Pathogenic biofilms are now implicated in disorders ranging from those associated with Helicobacter pylori to chronic fatigue syndrome. (17), (26), (29-31)

Helicobacter Pylori

H. pylori is a helical Gram-negative, microaerophilic bacterium harbored by about 40% of people in industrialized countries. (32) H. pylori infection of the gastric epithelium results in chronic gastritis. About 10% to 15% of people with H. pylori will develop duodenal and gastric ulcers. H. pylori infection increases the risk of gastric carcinoma by 5- to 90-fold, depending on the distribution and magnitude of the metaplastic response. H. pylori has been long known to form biofilms. (33) H. pylori biofilms have been described in people suffering from peptic acid disease and in one endoscopic study covered an average of 97.3% of the gastric mucosa in urease-positive patients. (30) Despite aggressive antibiotic treatment, H. pylori persists in 10% to 20% of infected patients. (34) Biofilm is hypothesized to play a major role in H. pylori's resistance to treatment and persistence in the gastric mucosa. (35) Disrupting H. pylori biofilm may facilitate gastrointestinal eradication of this class 1 carcinogen.

Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS) consists of debilitating fatigue often associated with arthralgias, myalgias, chills, feverishness, and lymphadenopathy. (36) CFS clinically overlaps with other illnesses such as fibromyalgia. (37) The normal gastrointestinal microbiota are frequently disrupted in people with CFS and fibromyalgia. These disorders are associated with a gut microflora low in Bifidobacterium and high in Enterococcus species. (38) Higher enterococcal counts correlate with more severe neurological and cognitive symptoms. While its etiology is unknown, one long-standing, albeit controversial, hypothesis is that chronic fatigue syndrome is caused by an immune response to intestinal colonization by C. albicans. (39), (40) Increased fecal counts of C. albicans have been described during the early phase of the syndrome. (41) Treatment with antifungal agents, together with a special diet, has been described as improving the symptomatology of patients with CFS. (42) Improvements are often transient, and the role of C. albicans in CFS and related disorders remains contentious, in part because there is no definite test and yeast overgrowth as documented by fungal cultures is uncommon in these patients. A refinement of the C. albicans hypothesis is that CFS symptoms are caused by an immune response to Candida species residing within biofilm in the gastrointestinal tract. Candida species ubiquitously form biofilm communities, and most manifestations of candidiasis are associated with biofilm formation. (17), (43) Genes coding for multidrug efflux pumps are upregulated in Candida biofilms, contributing to treatment resistance. (17) The biofilm characteristics of slow growth and presence of persister microorganisms would explain the tendency for patients to relapse following a beneficial symptomatic response to therapy. (44) The combination of antifungals with agents designed to disrupt biofilm, along with pre- and probiotics to reestablish balanced gastrointestinal microbiota, may offer an innovative approach to treating patients with CFS, fibromyalgia, and other chronic disorders associated with gastrointestinal dysbiosis and Candida biofilms.

Enzymatic Disruption of Pathogenic Gut Biofilm

Biofilm is a protective bunker for pathogens. Successful elimination of harmful microorganisms is usually only possible when the bunker is penetrated and disrupted, leaving the inhabitants vulnerable. One successful approach combines a high-potency, multienzyme formulation with or without chelating agents combined with antimicrobials.

Multienzyme Formulation

The use of cellulase is critical to an antibiofilm enzyme preparation, as cellulose is found in most biofilms. (24) Cellulase has been shown to significantly reduce biofilm formation by the important pathogen Pseudomonas aeruginosa. (46) Betaglucanase is another important antibiofilm component that provides powerful anticandidal biofilm activity by lysing the [beta]-(1[right arrow]3)- and [beta]-(1[right arrow]6)-glucans that are common in candidal biofilms and compose up to 60% of fungal cell walls. Beta-glucan secreted by Candida cells within biofilms significantly increases the organisms' resistance to antifungals, and enzymatic breakdown of beta-glucan can make Candida more susceptible to treatment. (46) Beta-glucan has also been implicated in antibiotic resistance displayed by biofilm Pseudomonas. (47) The combination of peptidases and proteases with polysaccharidases significantly strengthens an antibiofilm enzyme preparation and broadens its clinical spectrum. Proteases inhibit Staphylococcus aureus biofilm formation and rapidly detach sessile microbes. (48) Serratia peptidase is a particularly important antibiofilm protease. (49) In the laboratory, it effectively disrupts P. aeruginosa and Staphylococcus epidermidis biofilm and augments antibiotic sensitivity to ofloxacin. (50) Serratia peptidase increases antibiotic eradication of biofilm-forming pathogens in animal models. A highly effective, patent-pending antibiofilm formulation of supplemental polysaccharidases, peptidases, and proteases has been developed using the MBEC Physiology and Genetics (P&G) assay developed at the University of Calgary: an elegant batch culture technique for reproducible biofilm growth and antibiofilm intervention assessment. (52) This antibiofilm enzyme formulation has been developed with and without disodium ethylenediamine tetraacetic acid (EDTA). EDTA is a powerful cation chelator and complexes with metals required for cross-linking biofilm matrices. (22), (53) It also causes structural damage to bacterial cell walls, making them more permeable to antimicrobials. (54), (55) MBEC P&G testing has shown that the new supplemental antibiofilm enzyme preparation with or without EDTA is effective at disrupting biofilm produced by H. pylori, E. coli O157:H7, Klebsiella pneumoniae, Candida paratropicalis, S. aureus, and S. aureus MRSA.

Antimicrobial Agents

Successful disruption of pathogenic biofilm must combine agents, such as hydrolytic enzymes and chelators, with antimicrobial agents. Disruption of biofilm alone is unlikely to have a major impact unless the microbes within the biofilm are inhibited and destroyed. Antimicrobials employed span the spectrum from natural agents such as berberine, undecylenic acid, and green tea extract to prescription antibiotics and antifungals. The choice of antimicrobial should be based on the patient's history, the type and location of the biofilm, and the anticipated sensitivities of the pathogen to be treated. The newly developed antibiofilm enzyme preparation has been found to significantly reduce the amount of antibiotics needed to kill the pathogens P. aeruginosa, E. coli O157:H7, S. aureus, and S. aureus MRSA.

Pre- and Probiotics in Treating Pathogenic Gut Biofilm

Probiotics for Upper Gastrointestinal Biofilm

Lactobacillus probiotics have significant antagonistic effects against H. pylori. In adults, L casei together with quadruple therapy augmented eradication of H. pylori after failed triple therapy. (56) In children, intake of a dairy product containing L. johnsonii reduced H. pylori gastric colonization. (57) Other probiotics that antagonize H. pylori include L. acidophilus, L. paracasei, L. plantarum, L. rhamnosus, L. reuteri, L. salivarius, and L. lactis. (58), (59) Seven of nine human studies have shown that probiotics decrease H. pylori populations and improve gastritis. (59) The addition of probiotics to antibiotics significantly improves eradication and reduces side effects by 50%. Selection of probiotics without acid-protective technology is vital so that the organisms may counteract H. pylori within the stomach.

Prebiotics and Probiotics for Lower Gastrointestinal Biofilm

Prebiotics show great benefit in the management of pathogenic biofilms in the colon. Prebiotics uniformly stimulate the growth of endogenous Bifidobacterium species and augment populations of Eubacterium species. (60), (61) Increased populations of healthful commensals displace pathogens residing within biofilm. Probiotics combat pathogens through a number of mechanisms, including secretion of organic acids, hydrogen peroxide, and bacteriocins. (62) Less well appreciated is the ability of probiotic organisms to directly disrupt pathogenic biofilm. Surfactants produced by various strains of L. acidophilus have been shown to significantly reduce biofilm formation by both S. aureus and S. epidermidis. (63) Streptococcocus thermophilus has been found to secrete a surfactant that impairs C. albicans surface adhesion. (64) Much of the ability of probiotics to interfere with pathogen adhesion and displace them may be due to specific antibiofilm activities. (65), (66) In the management of pathogenic lower gastrointestinal biofilms, a combination of pre- and probiotics represents the most comprehensive strategy for the displacement of pathogens and their replacement by healthful microbes.

A Protocol for Pathogenic Candida Gut Biofilm

A clinically useful protocol to eliminate gastrointestinal Candida biofilm is evolving. Patients may experience significant "die-off" symptoms if therapy is initiated using high doses of enzymes or enzymes together with EDTA. A guiding therapeutic principle is to "Start Low and Go Slow." Therapy should be initiated with 1 capsule twice a day of the antibiofilm enzyme formulation. The enzymes should be taken on an empty stomach and contemporaneously with one or more antifungals. The type and number of antifungals must be individualized. Enzyme dosing should be gradually ramped up based on tolerance. A conservative approach is to increase the dose to 4 capsules twice daily over a month. After 1 month, the enzyme product alone should be discontinued and antibiofilm therapy initiated with the enzyme plus EDTA formula. Again, dosing should begin low at 1 capsule twice daily and titrated up to 4 capsules twice daily over 1 month. Antifungals should be continued throughout a 3-month treatment period. Pre- and probiotics should be administered from the outset. They should be given with food and at a different time of day than the enzymes and antifungals. Again, initiating therapy with low amounts and gradually increasing the dose will provide the greatest patient tolerance. Prebiotics should be started at a dose of 1 gram once a day and gradually titrated up to 5 grams twice daily over 1 month. For treatment of Candida and lower-intestinal dysbiosis, selection of a high-potency, multispecies probiotic with enteric coating or acid stabilization technology ensures that high numbers of viable microorganisms arrive in the distal small bowel and colon. Probiotics should be initiated in the amount of 25 billion CFU daily and increased over 3 to 4 weeks to 50 billion CFU twice a day. Patients with marked gut dysbiosis may benefit from higher doses on the order of 200 to 400 billion CFU daily. This protocol is only a general guideline for eradicating gastrointestinal Candida biofilm, and the recommendations must be adjusted to meet individual needs.

Conclusion

Microbes prefer life within biofilm communities, where they are protected from predation, antimicrobials, and host immune responses. Biofilm is increasingly implicated in a variety of diseases. The normal gastrointestinal microbiota reside within biofilm, and a number of gastrointestinal diseases associated with dysbiosis are related to pathogenic biofilm formation and direct pathogen toxicity or the body's misplaced immune responses to resistance microbes. A combination of hydrolytic enzymes available as nutritional supplements represents a viable approach to degrading pathogenic biofilms by lysing biofilm exopolymers. Hydrolytic enzymes may be combined with chelating agents for a synergistic antibiofilm effect. It is essential to administer enzymes and chelators together with antimicrobial agents, but apart from food to ensure pathogen destruction as biofilm is degraded. Pre- and probiotics are optimally used in an antibiofilm regimen to support the healthy intestinal microflora, displace pathogens, and disrupt pathogenic biofilm. There exists a critical need for clinical biofilm research to define effective combinations of hydrolytic enzymes, chelators, and pre- and probiotics and to work out optimal doses and regimens for various pathogens.

Stephen F. Olmstead, MD

10439 Double R Blvd.

Reno Nevada 89521

Notes

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by Stephen Olmstead, MD; Dennis Meiss, PhD; and Janet Ralston, BS

[C]ProThera Inc. 2009

Stephen Olmstead, MD, is chief science officer at ProThera Inc., where he directs clinical trials of ProThera and Klaire Labs nutraceutical products. His current research focus is the use of enzymes and chelating agents to disrupt pathogenic GI biofilm. Dr. Olmstead graduated from the University of New Mexico with distinction in biology and chemistry. He attended the University of New Mexico School of Medicine, and trained at Harvard Medical School, Massachusetts General Hospital. He is board certified in both internal medicine and cardiovascular diseases.

[ILLUSTRATION OMITTED]

Dennis E. Meiss, PhD, is a founder of ProThera, Inc. and acts as president and CEO. He is the primary formulator of ProThera and Klaire Labs products and directs the company's management team. Dr. Meiss received his PhD in neurobiology from the University of Connecticut.

Janet Ralston, BS, is a founder of ProThera Inc. She serves as vice president of the company, where she directs marketing efforts and client service programs. She is a graduate of the University of California Davis Nutrition and Dietetics program.

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