Can Prebiotics and Probiotics Really Improve Gastrointestinal Health?

June 3, 2014
Adam Nadelson, MD

Prebiotics and probiotics have been discussed frequently in the media for supposedly improving overall health, especially diseases related to the gut. However, the evidence on the efficacy and use of these dietary supplements is rather complicated.

Prebiotics and probiotics have been discussed frequently in the media for supposedly improving overall health, especially diseases related to the gut. However, the evidence on the efficacy and use of these dietary supplements is rather complicated.

Prebiotics are defined as non-digestible carbohydrates that act as substrates of fermentation for the colonic microbiome. Since they remain undigested during transit through the gut lumen, particular prebiotics can selectively promote the proliferation of beneficial gut bacteria by allowing fermentation in those select bacteria.

In contrast, probiotics are live bacterial cultures available in a variety of preparations, including dairy products and dietary supplements.1 The role of probiotics is to modify the gut microbiome by selectively supplementing bacteria that are beneficial to the host.2 As interventions for gastrointestinal (GI) disorders, prebiotics and probiotics can be administered separately or combined as a symbiotic.1

Prebiotics and probiotics in GI disorders

Since a number of clinical trials have indicated the gut microbiome plays a crucial role in the human immune system, inflammatory response, intestinal wall structural integrity, and fatty acid and glucose metabolism,1 additional studies have been undertaken on the effects of prebiotics and probiotics in GI pathology, including inflammatory bowel disease (IBD), antibiotic-associated diarrhea (AAD), irritable bowel syndrome (IBS), non-alcoholic steatohepatitis (NASH), and metabolic syndrome (MetS).

Ulcerative colitis (UC) and Crohn’s disease (CD)

Both UC and CD are thought to have multifactorial etiologies involving host genetic susceptibility, abnormal intestinal wall integrity, and gut flora imbalance — the very areas the gut microbiome is believed to influence.

Nevertheless, systematic reviews on the use of probiotics to induce UC remission have been inconclusive, and although smaller studies have indicated possible improvement in UC with probiotic administration, a general consensus based on current evidence remains unavailable.3 However, probiotics do appear to be beneficial as maintenance therapy in preventing UC recurrence, and compared with standard mesalamine treatment, they may be equally effective in the maintenance of UC remission, as no statistical difference in relapse rates between the therapies has been discovered thus far.3

In UC patients, pouchitis following colectomy is typically attributed to bacterial imbalance. Based on this hypothesis, investigations were conducted to study the effects of probiotic supplementation to prevent this complication. Now, the evidence strongly suggests probiotics prevent chronic pouchitis — as well as remission of chronic pouchitis — in UC patients following ileal pouch-anal anastomosis (IPAA).4

But although the use of probiotics showed promise as maintenance therapy for UC, there is little to no evidence supporting their efficacy in inducing remission and preventing recurrence of CD.5-6

AAD

Most commonly related to Clostridium difficile overgrowth, AAD results from an imbalance of gut microflora. Although the bacterium is a minor component of the normal gut flora, broad-spectrum antibiotics — particularly clindamycin and fluoroqinolones — eliminate beneficial gut bacteria, which causes C. difficile to proliferate uncontrollably, resulting in diarrhea, colitis, or even death.

Several studies set out to determine whether probiotic supplementation prevents AAD by restoring the balance between beneficial and pathogenic bacteria in the gut microbiome, and their evidence strongly supports the use of probiotics with an antibiotic regimen to prevent AAD. In fact, a systematic review of more than 4,400 patients found the risk of developing C. difficile infection decreased by 64% with minimal side effects when probiotics were administered alongside antibiotics.7 Further studies involving antibiotic therapy with prophylactic probiotics with specific bacterium from Lactobacillus and Saccharomyces also showed reduced AAD with probiotic supplementation.8

IBS

IBS is a functional bowel disorder that presents with various abdominal symptoms, including abdominal pain or discomfort associated with changes in bowel habits. Hypotheses on the cause of IBS range from dysregulation of the brain-gut axis9 to overgrowth of intestinal flora within the small intestine.10 As the imbalance of intestinal bacteria has been flagged as a cause of IBS, studies have evaluated the role or prebiotics and probiotics on relieving IBS symptoms.

Meta-analyses indicate probiotics are beneficial in treating the symptoms of IBS, some of which are known to be treated by specific bacteria.11 In fact, one systematic review found “probiotics were statistically significantly better than placebo with a number needed to treat (NNT) of 4.”12 However, in light of the strong placebo effect with IBS, studies conflict on the true effects of probiotics in IBS symptoms; thus, further research is still needed.12

The possible mechanisms through which probiotics improve IBS symptoms include roles in modulating the brain-gut axis13 and producing bacteriocins, which may limit the overgrowth of the pathogenic bacteria thought to be associated with IBS pathophysiology.14 Particularly, the transgalactooligosaccharide prebiotic was shown to yield symptomatic improvement in bloating, stool consistency, flatulence, and subjective improvement reported by IBS patients.15

NASH

NASH, a disease known for inflammation and fatty infiltration of the liver that can eventually progress to cirrhosis and hepatocellular carcinoma, is one entity where prebiotic studies are still in preliminary phases.1 Plasma endotoxemia has been implicated as a possible etiology of NASH, as it involves the absorption of gram-negative bacteria from the gut — along with the lipopolysaccharides (LPS) on the bacterial wall — into the bloodstream. LPS can stimulate inflammation in particular organs and can worsen cirrhosis, obesity, and insulin resistance. Thus, maintaining a proper intestinal barrier with prebiotics and probiotics can inhibit penetration of gram-negative bacteria through the intestinal wall, decreasing the associated inflammatory response.1

Prebiotics may also aid in decreasing triacyl-glycerols in the liver and further reduce inflammation.1 Although only a few small randomized control trials (RCTs) have been carried out, their results indicate beneficial effects of prebiotic and probiotic supplementation on the liver in NASH patients. Furthermore, one study involving the administration of a symbiotic of fructo-oligosaccharide and Bifidobacterium longum showed reduced levels of aspartate aminotransferase, inflammatory markers, and LPS, with liver biopsy also demonstrating decreased steatosis.16

Obesity, diabetes, and hyperlipidemia

Current research indicates gut microflora differ between lean and obese individuals, as well as between those with and without type 2 diabetes.17-19 Gut bacteria play a role in energy absorption, intestinal wall integrity, inflammatory response, and glucose and fatty acid metabolism — each of which can have an impact on obesity and diabetes.1 Based on this evidence, investigations have begun to focus on the effects of prebiotics in modifying the gut microbiome of obese and diabetic patients.

Recent studies indicate inulin-type fructans and galactans consumed over a time period of 2 days to 2 weeks resulted in earlier satiety in subjects, although significant weight loss was not noted.1 However, studies of prebiotic use over 12 weeks did result in significant weight reduction, indicating the need for longer-term prebiotic supplementation to achieve weight loss. Prebiotic supplementation has also shown to result in decreased postprandial insulin and glucose concentrations in both healthy and overweight individuals.

Nevertheless, researchers have not analyzed prebiotics for an adequate length of time to determine whether the supplementation is effective in preventing the development of type 2 diabetes among patients with pre-diabetes.1 Additionally, the effect of prebiotics on serum cholesterol levels is currently unclear, and available evidence shows prebiotics administered in patients with hypercholesterolemia over a 3-8 week period do not significantly change low-density lipoprotein (LDL) or high-density lipoprotein (HDL) levels. Similar to diabetes, studies to determine the long-term effects of prebiotics on cholesterol levels are not yet available 1

Future directions

Based on current trial results, prebiotics and probiotics appear to have utility in the treatment and prevention of numerous GI disorders. As noted in numerous RCTs and systematic reviews, there is already mounting evidence on the supplements’ benefits in inflammatory, infectious, functional, hepatic, and metabolic GI processes. Currently, research clearly supports the benefit of probiotic supplementation with the administration of antibiotics to prevent C. difficile infection. However, data regarding the induction of remission in UC and symptomatic improvement of IBS have been conflicting in RCTs, so larger trials and longer treatment studies in those GI disorders are needed.

Similarly, only a handful of RCTs to date have studied the use of prebiotics and probiotics as supplemental treatment for NASH. Although their results are promising, further research with an increased number of study subjects and longer treatment duration will be necessary to determine the efficacy of prebiotics in NASH. Since obesity, type 2 diabetes, and cardiovascular disease (CVD) are significant causes of morbidity and mortality in the United States, therapeutic options to prevent these complications are needed.

The research findings that gut microflora may play a role in energy metabolism, obesity, and type 2 diabetes are promising for prebiotic and probiotic use, and current studies illustrate improvements in early satiety, weight loss, and postprandial glucose and insulin levels. However, these results stem from treatment durations between 3-12 weeks and appear to be transient effects. Therefore, more studies involving longer treatment duration may yield further improvements in weight loss, glucose control, and cholesterol reduction, with promise in treating diabetes and preventing CVD, which may be critical in the future healthcare system.

Other areas of interest for probiotics include reducing the risk of upper respiratory infections in adults and children, as well as lowering the risk of traveler’s diarrhea, though conflicting data already exists on their use in treating infants with colic. Future studies that analyze stool samples may indicate whether changes in the gut microbiome actually occur following prebiotic and/or probiotic administration, which would also determine whether certain symptomatic improvements in GI disorders such as IBS stem from the supplements or a placebo effect.

As the study of prebiotics and probiotics in treating human GI disorders is relatively new, further investigations are needed to clarify conflicting data on the supplementation. To date, the research indicates a promising future for prebiotics and probiotics in GI health and may revolutionize the treatment of related disorders in the coming years.

References

1. Kellow NJ, Coughlan MT, Reid CM. Metabolic benefits of dietary prebiotics in human subjects: a systematic review of randomized controlled trials. Br J Nutr. 2014 Apr 14;111(7):1147-61. http://www.ncbi.nlm.nih.gov/pubmed/24230488.

2. Molinaro F, Paschetta E, Cassader M, Gambino R, Musso G. Probiotics, prebiotics, energy balance and obesity: mechanistic insights and therapeutic implications. Gastroenterol Clin N Am. 2012 Dec;41(4):843-54. http://www.ncbi.nlm.nih.gov/pubmed/23101690.

3. Sang LX, Chang B, Zhang WL, Wu XM, Jiang M. Remission induction and maintenance effect of probiotics on ulcerative colitis: a meta-analysis. World J Gastroenterol. 2010;16(15):1908-15. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856834/.

4. Holubar SD, Cima RR, Sandborn WJ, Pardi DS. Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis. Cochrane Database Syst Rev. 2010 Jun 16;(6):CD001176. http://www.ncbi.nlm.nih.gov/pubmed/20556748.

5. Butterworth AD, Thomas AG, Akobeng AK. Probiotics for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD006634. http://www.ncbi.nlm.nih.gov/pubmed/18646162.

6. Rolfe VE, Fortun PJ, Hawkey CJ, Bath-Hextall F. Probiotics for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD004826. http://www.ncbi.nlm.nih.gov/pubmed/17054217.

7. Goldenberg JZ, Ma SS, Saxton JD, Martzen MR, Vandvik PO, Thorlund K, Guyatt GH, Johnston BC. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2013 May 31;5:CD006095. http://www.ncbi.nlm.nih.gov/pubmed/23728658.

8. Johnston BC, Ma SS, Goldenberg JZ, Thorlund K, Vandvik PO, Loeb M, Guyatt GH. Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012 Dec 18;157(12);878-88. http://annals.org/article.aspx?articleid=1390418.

9. Fukudo S, Nomura T, Muranaka M, Taguchi F. Brain-gut response to stress and cholinergic stimulation in irritable bowel syndrome: a preliminary study. J Clin Gastroenterol. 1993 Sept;17(2):133-41. http://www.ncbi.nlm.nih.gov/pubmed/8031340.

10. Posserud I, Stotzer PO, Björnsson ES, Abrahamsson H, Simrén M. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Gut. 2007 Jun;56(6):802-8. http://www.ncbi.nlm.nih.gov/pubmed/17148502.

11. Ortiz-Lucas M, Tobias A, Saz P, Sebastián JJ. Effect of probiotic species on irritable bowel syndrome symptoms: A bring up to date meta-analysis. Rev Esp Enferm Dig. 2013 Jan;105(1):19-36. http://www.ncbi.nlm.nih.gov/pubmed/23548007.

12. Moayyedi P, Ford AC, Talley NJ, Cremonini F, Foxx-Orenstein AE, Brandt LJ, Quigley EM. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut. 2010 Mar;59(3):325-32. http://www.ncbi.nlm.nih.gov/pubmed/19091823.

13. Konturek PC, Brzozowski T, Konturek SJ. Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options. J Physiol Pharmacol. 2011 Dec;62(6):591-9. http://www.ncbi.nlm.nih.gov/pubmed/22314561.

14. Bixquert Jiménez M. Treatment of irritable bowel syndrome with probiotics: an etiopathogenic approach at last? Rev Esp Enferm Dig. 2009 Aug;101(8):553-64. http://www.ncbi.nlm.nih.gov/pubmed/19785495.

15. Silk DB, Davis A, Vulevic J, Tzortzis G, Gibson GR. Clinical trial: the effects of a trans-galactooligosaccharide prebiotic on fecal microbiota and symptoms in irritable bowel syndrome. Aliment Pharmacol Ther. 2009 Mar 1;29(5):508-18. http://www.ncbi.nlm.nih.gov/pubmed/19053980.

16. Malaguarnera M, Vacante M, Antic T, Giordano M, Chisari G, Acquaviva R, Mastrojeni S, Malaguarnera G, Mistretta A, Li Volti G, Galvano F. Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Dig Dis Sci. 2012 Feb;57(2):545-53. http://www.ncbi.nlm.nih.gov/pubmed/21901256.

17. Diamant M, Blaak EE, de Vos WM. Do nutrient-gut-microbiota interactions play a role in human obesity, insulin resistance and type 2 diabetes? Obes Rev. 2011 Apr;12(4):272-81. http://www.ncbi.nlm.nih.gov/pubmed/20804522.

18. Wu X, Ma C, Han L, Nawaz M, Gao F, Zhang X, Yu P, Zhao C, Li L, Zhou A, Wang J, Moore JE, Millar BC, Xu J. Molecular characterisation of the fecal microbiota in patients with type II diabetes. Curr Microbiol. 2010 Jul;61(1):69-78. http://www.ncbi.nlm.nih.gov/pubmed/20087741.

19. Larsen N, Vogensen FK, van den Berg FW, Nielsen DS, Andreasen AS, Pedersen BK, Abu Al-Soud W, Sorensen SJ, Hansen LH, Jakobsen M. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS ONE. 2010 Feb 5;5(2):e9085. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0009085.

About the authors

Adam Nadelson, MD, is a recent graduate of the University of Massachusetts Medical School (UMMS) in Worcester, MA.

He was assisted in writing this article by Frank J. Domino, MD, Professor and Pre-Doctoral Education Director for the Department of Family Medicine and Community Health at UMMS and Editor-in-Chief of the 5-Minute Clinical Consult series (Lippincott Williams & Wilkins).