Antibiotics Can Cause Gut Related Diseases

Michael Ash BSc (Hons), DO, ND FDipION reviews the current understanding of the role of antibiotics in the initiation of gut associated inflammation and local and systemic health problems, and briefly explores some strategies to prevent and manage this.

What is perhaps the greatest medicinal discovery in the last 100 years has a sting in its tail, the tremendous success in managing bacterial infection has encouraged over and inappropriate use of antibiotics, the problems of which have been well documented. This review explores the developing comprehension that even a single day of antibiotic use has consequences that may produce transient and long term effects that compromise the health and well being of the patient and their bacterial co-habitants.

Sir Alexander Fleming discovered the antibiotic substance penicillin in 1928 and was awarded a co share in the Nobel Prize in Medicine in 1945.

It was a discovery that would change the course of history. The active ingredient in that mould, which Fleming named penicillin, turned out to be an infection-fighting agent of enormous potency. When it was finally recognised for what it was—the most efficacious life-saving drug in the world—penicillin would alter forever the treatment of bacterial infections. By the middle of the century, Fleming’s discovery had spawned a huge pharmaceutical industry, churning out synthetic penicillin’s that would conquer some of mankind’s most ancient scourges, including syphilis, gangrene and tuberculosis. (Time Magazine April 1999)

However, as the combined benefits of decent engineering for sanitation, prevention via vaccination and bacterial infection control through antibiotics have contributed to life extension, they have also produced microbe and human disturbances. The incidence of immune mediated disorders is continuing to increase and the gastrointestinal tract is continuing to gain traction as a site of significant origination.[1]^,[2]

Most healthcare professionals are now aware of the complication of prolonged antibiotic therapy and the risk of developing antibiotic resistance or trans/bacterial development.[3] Patients are often less comfortable with this notion and will still seek antibacterial treatments for primary viral illness, follow the treatment protocol badly and continue to apply dubious standards of self care.[4]

The Journal of Mucosal Immunology in March 2010, ran an editorial and paper on the adverse effects of antibiotics beyond those previously understood.[5] Most Nutritional Therapists and clinicians will agree that there may be some level of bacterial disruption after a course of treatment. Most conservative researchers had suggested that the ‘fingerprint’ of species in the gut, maintained through bacterial communication techniques would ensure the bacterial architecture resolves a short time after cessation. Bonnie Basler PhD describes this quorum communication in an informative film from one the famous TED presentations.

Some intestinal bacteria are mutualists that promote normal human physiology including proper digestion, metabolism, epithelial cell function, angiogenesis, enteric nerve function, and immune system development. Although bacterial communities in the intestine promote normal immune homeostasis, patients with inflammatory bowel disease or allergies have altered intestinal bacteria, indicating that microbial populations might influence disease pathogenesis and in particular those linked with adverse immune driven inflammation.

It is now understood that the composition of the microbiota is significantly altered by the use of antibiotics including the increase in urinary tract infections, diminished carbohydrate fermentation, loss of bile acid metabolism, pathogenic bacterial colonisation, immune disturbances, barrier defects and mucin degradation.

Microbe Associated Molecular Patterns (MAMP’S) are the molecular signatures used by bacteria to impart friendly messages to the mucosal immune receptors. They are also used to promote defence when a pathogen’s sticky patterns are identified.[6] It is proposed that a change in the concentrations of these messengers by antibiotic therapy could disrupt the homeostatic health of the gut contributing to various significant changes in the competence of the gut related immune responses.  It is becoming clear that a large part of our bacterial bedfellows have similar MAMP’S allowing them to operate in a symbiotic manner for immune tolerance and gastrointestinal health.[7] It is this strategy used by probiotics to impart different messages to maintain a healthy digestive tract, and may also be used in the resolution or management of more complex immune mediated diseases.

Mucins

Our mucins are a vital part of the overall management, composed of an inner layer, a dense composition and free of bacteria, and the outer layer, made up of a looser matrix and offering a home to bacteria.[8] The inner layer acts like a muffler, diminishing contact with the intraepithelial lining and yet still able to allow MAMP’s via dendritic cells to communicate with the immune system. The use of probiotics; L.plantarum and L.Rhamnosus (LGG) have shown a beneficial increase in this mucin layer, adding volume to the material and improving resistance to pathogen adhesion.[9]

A loss of this layer as shown in the diagram above may increase the total information load on the lining cells by loss of the muffling mucins in effect increasing the frequency and noise of the bacterial chatter, and may also facilitate translocation of bacteria across the lining, inducing an inflammatory response and additional loss of barrier quality. This increase in inflammation may induce local damage such as IBD but may also induce collateral damage to tissues far distant from the gut, such as the brain, joints and skin as described in a previous post.

Bacteriotherapy (the treatment of disease by the use of bacteria or their products)

The use of certain strains of probiotics have demonstrated barrier protection and cell survival. The opposite effect of loss of barrier integrity has many potential health complications related to inflammation as explained in a previous article. Antibiotic therapy offers the reverse scenario and contributes to pro-inflammatory cytokine production and loss of antimicrobial proteins, used by the gut tissues to maintain microbiota colonies and prevent pathogens binding.[10] The use of selected probiotics (MAMP’s) during and post antibiotic therapy to selectively agitate the mucosal immune system represents a safe strategy.

Our bacterial bedfellows and the single cell lining of the gut communicate through a variety of mechanisms, a loss of the bacterial composition can alter, tight junction expression, mucins, antimicrobial peptides and cytokine ratio’s. The resulting disturbance may then as a result affect the TH17/Treg ratio in the gut leading to increased production of the cytokine (IL-17), associated with inflammatory and autoimmune disease.[11] Interestingly we as humans use our food source to provide control over the adverse production of this protein, Vitamin A derived from our foods, helps to programme the naive T cells in the gut to develop Treg or peacekeeping cells, rather than the inappropriate conversion into TH17 cells. The role of Vitamin A in mucosal health is well understood but it’s unique role in mucosal tolerance is only just being fully elucidated.[12]

Antibiotics used in clinic might be used to remove or suppress undesirable components of the human microbiome. Antibiotic treatment causes significant temporal and spatial alterations in various colonies of bacteria that have been proposed to have causative or therapeutic roles in human diseases. Antibiotic treatment also has significant negative effects on the output of pro-inflammatory cytokines in gut associated lymphoid tissues.[13]

Findings from this paper indicated that even short antibiotic courses can result in dramatic alterations to intestinal bacterial communities. In particular, significant reductions in the frequency of mucosal-associated Lactobacillus species were observed in antibiotic-treated as compared with control-treated animals.

Comment

Probiotics can introduce missing microbial components with known beneficial functions for human health. Prebiotics such as those derived from apple soluble fibre can enhance the proliferation of beneficial microbes or probiotics as well as diminishing total inflammation, to maximise sustainable changes in the human microbiome.

Combinations of these approaches might provide synergistic and effective therapies for specific disorders. The human microbiome could be manipulated by such “smart” strategies to prevent and treat acute gastroenteritis, antibiotic-associated diarrhoea and colitis, inflammatory bowel disease, irritable bowel syndrome, necrotising enterocolitis, and a variety of other disorders in which altered inflammation is a key driver.

Nutritional Therapists and other healthcare practitioners are going to have to consider the interactions of the medicines, foods, Saccharomyces Boulardii, and strain specific probiotics to optimise rather than compromise the restoration of gastrointestinal function – this is an exciting area of opportunity for specialism and research.

The incidence of lactic acid bacterial depletion and its potential role in the health of humans may make the use of a special strain such as LGG or combinations of strains a practical approach to post antibiotic minimisation of adverse immune disruption in the mucosal tissues. The role of SIgA in mucins and bacterial balance is also an area of significant opportunity for treatment, and Saccharomyces Boulardii has been shown to reduce IL-8 and increase SIgA as well as limit adverse effects associated with antibiotic therapy. In the gastrointestinal tract, SIgA exhibits properties of a neutralising agent (immune exclusion) and of an immunopotentiator inducing effector immune responses in a ‘non-inflammatory context’ favourable to preserve local homeostasis and control disease risk.

S. boulardii effectively reduces the risk of antibiotic-associated diarrhoea in children. [14]

Bottom Line

Antibiotics, and most likely other agents of bacterial disruption, can alter the composition of the human gastrointestinal bacteria. In some people this may be enough to cause a loss of barrier quality and other adverse changes. The increase in immunological chatter can then cause damage locally and systemically via numerous routes.

No longer can antibiotics be viewed as a benign self recovering challenge to commensal bacteria. Nutritional Therapists can lead the way in the judicious use of strain specific bacteria and yeast to prevent and restore these damaged tissues.

References

[1] Round JL, & Mazmanian SK (2009). The gut microbiota shapes intestinal immune responses during health and disease. Nature reviews. Immunology, 9 (5), 313-23 PMID: 19343057

[2] Round JL, O’Connell RM, & Mazmanian SK (2010). Coordination of tolerogenic immune responses by the commensal microbiota. Journal of autoimmunity, 34 (3) PMID: 19963349

[3] Andersson DI, & Hughes D (2010). Antibiotic resistance and its cost: is it possible to reverse resistance? Nature reviews. Microbiology, 8 (4), 260-71 PMID: 20208551

[4] Belongia EA, & Schwartz B (1998). Strategies for promoting judicious use of antibiotics by doctors and patients. BMJ (Clinical research ed.), 317 (7159), 668-71 PMID: 9728003

[5] Wlodarska M, & Finlay BB (2010). Host immune response to antibiotic perturbation of the microbiota. Mucosal immunology, 3 (2), 100-3 PMID: 20016473

[6] Hooper LV (2009). Do symbiotic bacteria subvert host immunity? Nature reviews. Microbiology, 7 (5), 367-74 PMID: 19369952

[7] Mazmanian SK, Round JL, & Kasper DL (2008). A microbial symbiosis factor prevents intestinal inflammatory disease. Nature, 453 (7195), 620-5 PMID: 18509436

[8] Johansson ME, Phillipson M, Petersson J, Velcich A, Holm L, & Hansson GC (2008). The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proceedings of the National Academy of Sciences of the United States of America, 105 (39), 15064-9 PMID: 18806221

[9] Mack DR, Michail S, Wei S, McDougall L, & Hollingsworth MA (1999). Probiotics inhibit enteropathogenic E. coli adherence in vitro by inducing intestinal mucin gene expression. The American journal of physiology, 276 (4 Pt 1) PMID: 10198338

[10] Brandl K, Plitas G, Mihu CN, Ubeda C, Jia T, Fleisher M, Schnabl B, DeMatteo RP, & Pamer EG (2008). Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature, 455 (7214), 804-7 PMID: 18724361

[11] Chang SH, & Dong C (2007). A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell research, 17 (5), 435-40 PMID: 17452998

[12] Strober W (2008). Vitamin A rewrites the ABCs of oral tolerance. Mucosal immunology, 1 (2), 92-5 PMID: 19079166

[13] Hill DA, Hoffmann C, Abt MC, Du Y, Kobuley D, Kirn TJ, Bushman FD, & Artis D (2010). Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal immunology, 3 (2), 148-58 PMID: 19940845

[14] Kotowska M, Albrecht P, & Szajewska H (2005). Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea in children: a randomized double-blind placebo-controlled trial. Alimentary pharmacology & therapeutics, 21 (5), 583-90 PMID: 15740542