Probiotics for Gastrointestinal Intervention: What About Direct Delivery?
July 1, 2014
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Gastrointestinal Disease
Probiotics for Gastrointestinal Intervention: What About Direct Delivery?
By Luke Fortney, MD, and Rian Podein, MD
Dr. Fortney is a physician with Meriter Medical Group, Madison, WI. Dr. Podein is a family physician, Group Health Cooperative of South Central Wisconsin, Madison, WI.
Dr. Fortney and Dr. Podein report no financial relationships relevant to this field of study.
Summary Points
- Probiotic therapies appear to be safe and may be helpful for various health problems.
- The strongest evidence is for use as an adjunctive supportive therapy forgastrointestinal-related disorders.
- Although direct colonic probiotic delivery therapies appear promising, further research
is needed.
Probiotics are defined by the World Health Organization as live microorganisms that, when administered in adequate amounts, confer a health benefit.1 Probiotics are available in "functional foods" that contain live active cultures of various bacterial species — such as yogurt, sauerkraut, tempeh, kombucha, and others — or as dietary supplements in the form of capsules, tablets, and powders. Governmental regulation in the United States depends on the product’s intended use: a food ingredient, dietary supplement, or a drug.
Interest in probiotics has proven to be a growth industry for both consumers and the supplement industry. In 2011, U.S. sales of probiotic supplements totaled nearly $770 million and they continue to be one of the fastest growing dietary supplements.2 Since the early 20th century when Russian Nobel Laureate Elie Metchnikoff first proposed the idea of ingesting microbes for health benefits, there has been ongoing investigation into both the basic and applied clinical sciences.3 The National Institutes of Health launched the Human Microbiome Project in 2008 with the mission to identify and characterize the microbial communities that inhabit both healthy and unhealthy people.
Probiotic Clinical Research
More than 100 trillion microbes reside within the human gastrointestinal (GI) tract. This GI microbiota is acquired at birth and develops quickly during the early newborn period with subsequent windows of susceptibility and alteration throughout childhood development prior to the establishment of a relatively stable "adult" gut microbiota.4 This established gut ecosystem can shift due to influences such as aging, diet, geographical location, intake of food supplements and medications, infectious disease, chronic illness, and likely other yet unknown factors.5 There is increasing evidence to support an association between the composition of the human microbiome and a wide range of diseases, including Clostridium difficile infection (CDI), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colonization with multidrug-resistant organisms, cancer, osteoporosis, cardiovascular disease, obesity, allergic diseases, autoimmune disorders, and neuropsychiatric illnesses.5,6,7,8 However, ongoing research and therapy challenges include what probiotic strains should be used for what conditions, in which people, for how long, and at what dose and type of delivery.
IBS and Other Gut Disorders
The prevention and treatment of various GI disorders by manipulation of the microbial ecosystem with orally administered probiotics has been widely studied with varying strengths of evidence. However, overall the strongest evidence for use of probiotics includes GI-related disorders such as IBS, IBD, CDI, antibiotic-associated diarrhea (AAD), and various other forms of infectious diarrhea.9,10 Unfortunately, there have been significant limitations and variation among studies that raise many more questions regarding efficacy, viability, optimal species and genus selection for specific conditions in specific people, single vs combination products, optimal colony forming units dosing, and adequate treatment duration.11
Although incompletely understood, purported mechanisms of benefit from probiotics use include the direct remodeling of microbial communities, competition to/suppression of pathogens, enhanced immune function/modulation, up-regulation of anti-inflammatory factors, suppression of pro-inflammatory factors, and proliferation and promotion of intestinal epithelial barrier function.10 Interestingly, however, few studies have actually documented the survival of orally administered probiotics after passage through the caustic upper GI tract environment. Further, probiotic effects have been demonstrated using both viable and non-viable bacteria.12,13 What’s more, colonization of the GI tract from orally administered probiotics appears to be temporary at best, with noted disappearance of introduced strains from the stool soon after discontinuation. In general, oral probiotics appear to have their effects via regulating the function — including gene expression and metabolism — of the already established GI microbiota ecosystem, rather than actually changing the existing microbial composition itself.14
Pursuit of the modulation of intestinal microflora is an intuitive therapy for many gut disorders. Foremost is IBS, which involves disruption of the colonic microbiota in various ways. There are various manifestations of IBS, such as constipation, diarrhea, bloating, and mixed symptom variations. Overall, IBS is a heterogeneous disorder characterized by abnormal GI motility, altered GI microbiota composition, low-grade chronic inflammation, visceral hypersensitivity and hyperalgesia, and disruption of the gut-brain communication axis. However, specific identification of biologic markers based on genetic polymorphisms remains undetermined and inconsistent.15 It is also important to keep in mind that IBS is a functional bowel disorder with many contributing factors, including a significant association with adult and childhood abuse and trauma. The pathogenesis of IBS is multidimensional and is heavily influenced by biopsychosocial dysfunction in various forms. Stress, although not considered a cause of IBS, is nonetheless a significant trigger that is often present with IBS flares for many patients.15
Specifically regarding altered gut microbiota, there does appear to be a consistent theme of reduced Bacteroides and increased Firmicutes strains in IBS,16 but actual characterization of individual gut flora remains difficult and inconsistent. Nonetheless, research suggests that targeted treatment using certain antibiotics and select probiotics based on individual differences in intestinal microbiota composition may be effective in alleviating IBS symptoms.16 A recent meta-analysis reported that overall, all probiotic species and strains appear to improve flatulence and bloating in patients with IBS compared with placebo.17 Two other meta-analyses concluded that probiotics in general improve overall IBS symptoms for most patients.17 However, one RCT found no significant benefit from using a multispecies probiotic oral supplement for 6 weeks among 35 patients diagnosed with IBS. In this placebo-controlled trial, visceral hypersensitivity decreased significantly for both the probiotic group as well as the control group, but overall pain scores and mean symptom scores did not differ.18
When it comes to iatrogenic AAD, one study found that older hospitalized patients being treated with antibiotics for various reasons were less likely to contract AAD when given Lactobacillus paracasei fermented milk prophylactically. This was also found to be very cost effective, with a total estimated cost savings of more than $575 per hospitalized patient > 65 years of age, which is a particularly vulnerable demographic.19 This finding is consistent overall in terms of using probiotics for the prevention of gut-associated disorders of nearly every kind, noting that one study concluded an average risk reduction of 35% compared to placebo in maintaining gut homeostasis for various GI conditions.20
In more severe disease states, such as IBD, altered gut microbiota — also called dysbiosis — appears to be a key player in the prolonged and stubborn course of these disorders. Several studies have found an association with polymorphisms in genes that are involved in autophagy — a process that involves cell degradation of unnecessary or dysfunctional cellular components that helps maintain healthy cells — which is thought to be a result of the innate relationship of host cells with adjacent luminal gut bacteria. The inverse also appears to be true, that specific gut pathogens may have a negative impact on the gut microbiome, which in turn generate protracted inflammation and immune dysfunction, which may result in the pathogenesis of IBD.21
In the setting of pouchitis among patients who underwent restorative proctocolectomy for various reasons including severe IBD, prolonged probiotic administration appears to be helpful. In a study of 43 randomized patients given a daily probiotic consisting of L. acidophilus, delbrueckii, bulgaricus, and Bifidobacterium bifidus for 9 months, the average severity and incidence of pouchitis decreased significantly compared to placebo. Objective biomarkers for pouchitis were also lower in the treatment group, noting lower levels of fecal pyruvate kinase and calprotectin. This study also demonstrated that long-term probiotic use is safe and effective in preventing pouchitis episodes.22
Fecal Transplantation
Microbiota restorative therapies, such as fecal microbiota transplantion (FMT), provide direct anatomical delivery of various healthy microbial species to diseased or dysfunctional colons. While FMT has yet to be fully approved by the FDA, it is permitted for use in select patients for the treatment of recurrent and treatment refractory CDI. Risk of recurrence of CDI is high with use of oral antibiotics such as vancomycin and metronidazole, particularly in recurrent disease. Despite use of new novel antibiotics, such as fidaxomicin, the threat of growing resistance continues. For this and other reasons, FMT is attracting increased attention from physicians and patients alike. There are currently more than 500 case reports of FMT for the treatment of CDI, with greater than 91% efficacy.7,23
Given its impressive success with severe CDI, there is growing interest for the use of FMT for additional GI disorders such as IBS and IBD, as well as other "extra-intestinal" conditions such as diabetes, obesity, multiple sclerosis, and idiopathic thrombocytopenic purpura among many others.24 While the potential application of FMT is expanding, there are concerns for risk of inadvertent transmission of various pathogens and infectious diseases. Appropriate donor selection, standardization of donor stool preparation, insurance reimbursement, and long-term safety and efficacy are ongoing concerns.7 Additionally, there is a general cultural aversion to the idea of "stool sharing." Ideally, a clearer understanding of the optimal probiotics composition for specific disorders will likely lead to strategic microbiota "mining" from healthy donor stool samples vs production and selection of various specific bacterial strains in microbiology laboratories without the need for and potential risks of FMT.
Direct Colonic Probiotic Delivery
Concurrent with the rising interest in FMT is the more facile idea of direct colonic delivery of probiotic supplements, in single or combination strains. The direct anatomical delivery of probiotics has also been explored in oral and vaginal disorders with some reported benefit.25,26 However, research into the rectal application of probiotic supplements for GI disorders has been largely absent with the exception of a few small trials of an enema supplied single-species probiotic for ulcerative colitis, which was well tolerated and showed some benefit.27,28
For gut-related disorders, such as IBS and AAD (and likely others), the direct delivery of multistrain probiotics is a reasonable, safe, inexpensive, and effective adjunctive therapy to standard of care. Furthermore, it circumvents the challenge of orally administered probiotic destruction by the caustic upper GI environment. Although research supporting direct colonic probiotic delivery (DCPD) use is surprisingly lacking, anecdotal evidence and case reports are promising. In the clinical setting, for non-immunocompromised patients who struggle with various GI-related disorders but who find only limited success from standard of care therapies, it is reasonable to recommend DCPD as an adjunctive therapy option when prescribed with careful and clear instruction for proper use.
DCPD should use a saline solution transport medium, which is the preferred delivery agent for FMT.29 While further research is needed, this approach has been used successfully and safely in the clinic setting. In addition to implementing a healthy diet and regular exercise (see www.meriter.com/wellness for exercise and nutrition prescriptions), DCPD can be considered and used under clinical supervision with properly screened patients who are willing and able (see Table 1).
Table 1. How to Arrange a Probiotic Fleet Enema at Home
Avoid use if feeling ill (fever, chills, sweats, current use of corticosteroids, or recent GI procedure).
This is best used after a bowel movement to allow better retention and distribution of the multistrain probiotic saline solution.
Obtain one saline Fleet enema (133 mL, or smaller 59 mL volume pediatric version).
Unscrew the enema applicator tip to access the saline liquid inside.
Open and directly pour into the saline solution two probiotic capsules from three different probiotic brands/varieties (e.g., Culturelle, Florajen3, VSL#3, etc.) A variety of different probiotic strains is key.
Re-apply the probiotic tip applicator, tighten, and shake the saline probiotic enema solution a few times.
Lay down (left or right side, bent knees flexed into the abdomen) and insert the probiotic fleet enema applicator tip rectally, firmly squeeze the bottle to deliver the entire contents into the rectum, and then remove the applicator.
Suggested body positions for improved probiotic distribution in the colon: laying on your left side, then right side, cat-cow, child pose, bridge, half shoulder stand, repeat.
Try to retain the entire probiotic enema contents rectally (hold the probiotic enema as long as you can), but stay near a toilet.
Repeat monthly as needed for gut symptom relief.
Adverse Effects of Probiotics
A 2011 Agency for Healthcare Research and Quality assessment of the safety of probiotics concluded that current evidence does not suggest widespread risk or negative side effects associated with probiotics. However, the data on safety and long-term safety are limited, and the risk of serious side effects may be greater in people who have underlying health conditions.30 Although probiotics fall under an FDA category of generally recognized as safe, or having been adequately shown to be safe for general consumption, avoidance or close medical supervision and caution are recommended for several conditions, including immunocompromised state, premature infant patients in the neonatal period, presence of any type of intravascular catheter, impaired intestinal epithelial barriers, and advanced cardiac valve disease.31
Conclusions
There is accumulating evidence regarding the relationship of the GI microbiota with GI health and disease. Limitations of orally administered probiotic supplements — along with the impracticalities, cost, and concerns of inadvertently introducing pathogens through widespread FMT — support further investigation into the direct rectal delivery of various probiotic preparations (DCPD) for various GI disorders.
References
- (WHO) Joint Food and Agriculture Organization of the United Nations/World Health Organization Working Group report on drafting guidelines for the evaluation of probiotics in food, London, Ontario, Canada, April 30 and May, 2002. Available at: ftp://ftp.fao.org/es/esn/food/wgreport2.pdf. Accessed March 28, 2014.
- Reddy S. Probiotics’ benefits may be more than a gut feeling. The Wall Street Journal Nov. 26, 2012. Available at: http://online.wsj.com/news/articles/SB10001424127887324784404578143402702878118. Accessed March 28, 2014.
- Podolsky SH. Metchnikoff and the microbiome. Lancet 2012;380:
1810-1811. - Petschow B et al. Probiotics, prebiotics, and the host microbiome: The science of translation. Ann N Y Acad Sci 2013;1306:1-17.
- Bäckhed F, et al. Defining a healthy human gut microbiome: Current concepts, future directions, and clinical applications. Cell Host Microbe 2012;12:611-622.
- Mai V, et al. Recent advances and remaining gaps in our knowledge of associations between gut microbiota and human health. World J Gastroenterol 2009;15:81-85.
- Khanna S, Tosh PK. A clinician’s primer on the role of the microbiome in human health and disease. Mayo Clin Proc 2014;89:107-114.
- Parvaneh K, et al. Effect of probiotics supplementation on bone mineral content and bone mass density. Scientific World J 2014;ePub doi: 10.1155/2014/595962.
- Goldin BR, Gorbach SL. Clinical indications for probiotics: An overview. Clin Infect Dis 2008;46(Suppl 2):S96-S100.
- Preidis GA, Versalovic J. Targeting the human microbiome with antibiotics, probiotics, and prebiotics: Gastroenterology enters the metagenomics era. Gastroenterology 2009;136:2015-2031.
- Verna EC, et al. Use of probiotics in gastrointestinal disorders: What to recommend? Therap Adv Gastroenterol 2010;3:307-319.
- Kailasapathy K, Chin J. Survival and therapeutic potential of probiotic organisms with reference to Lactobacillus acidophilus and Bifidobacterium spp. Immunol Cell Biol 2000;78:80-88.
- Jijon H, et al. DNA from probiotic bacteria modulates murine and human epithelial and immune function. Gastroenterology 2004;126:1358-1373.
- McNulty NP, et al. The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins. Sci Transl Med 2011;3:106ra106.
- Chang FY. Irritable bowel syndrome: The evolutiohn of multi-dimensional looking and multidisciplinary treatments. World J Gastroenterol 2014;20:2499-2514.
- Hong SN, Rhee PL. Unraveling the ties between irritable bowel syndrome and intestinal microbiota. World J Gastroenterol 2014;20:2470-2481.
- Cash BD. Emerging role of probiotics and antimicrobials in the management of irritable bowel syndrome. Curr Med Res Opin 2014 [Epub ahead of print].
- Luddi S, et al. Randomized clinical trial on the effect of a multispecies probiotic on visceroperception in hypersensitive IBS patients. Neurogastroenterol Motil 2014;26:705-14.
- Lenoir-Wijnkoop I, et al. Nutrition economic evaluation of a probiotic in the prevention of antibiotic associated diarrhea. Front Pharmacol 2014;5:13 dpo" 10.3389/fphar.2014.00013.
- Vitetta L, et al. Probiotics, prebiotics and the gastrointestinal tract in health and disease. Inflammopharmacology 2014;22:135-154.
- Hold GL, et al. Role of the gut microbiota in inflammatory bowel disease pathogenesis: What have we learned in the past 10 years? World Gastroenterol 2014;20:1192-1210.
- Tomasz B, et al. Long term use of probiotics lactobacillus and bifidobaterium has a prophylactic effect on the occurrence and severity of pouchitis: A randomized prospective study. Biomed Res Int 2014;2014:208064.
- McCune VL, et al. Faecal transplantation for the treatment of Clostridium difficile infection: A review. Int J Antimicrob Agents 2014;43:
201-206. - Smits LP, et al. Therapeutic potential of fecal microbiota transplantation. Gastroenterology 2013;145:946-953.
- Stamatova I, Meurman JH. Probiotics: Health benefits in the mouth. Am J Dent 2009;22:329-338.
- Mastromarino P, et al. Bacterial vaginosis: A review on clinical trials with probiotics. New Microbiol 2013;36:229-238.
- Oliva S, et al. Randomised clinical trial: The effectiveness of
Lactobacillus reeuteri ATCC 55730 rectal enema in children with active distal ulcerative colitis. Aliment Pharmacol Ther 2012;35:327-334. - Matthes H, et al. Clinical trial: Probiotic treatment of acute distal ulcerative colitis with rectally administered Escherichia coli Nissle 1917 (EcN). BMC Complement Altern Med 2010;10:13.
- Borody TJ, et al. Fecal microbiota transplantation: Indications, methods, evidence, and future directions. Curr Gastroenterol Rep 2013;15:337.
- Hempel S et al. Safety of Probiotics to Reduce Risk and Prevent or Treat Disease. Evidence Report/Technology Assessment no. 200. Agency for Healthcare Research and Quality Web site. Available at: www.ahrq.gov/clinic/tp/probiotictp.htm. Accessed May 13, 2014.
- Floch MH. Probiotic safety and risk factors. J Clin Gasteroenterol 2013;47:375-376.
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