Beneficial Microbe Repairs and Protects Against Aspirin-Induced Injury

A randomized, double-blind, placebo-controlled trial

By Rebecca Lovejoy, ND, LAc

Reference

Suzuki T, Masui A, Nakamura J, et al. Yogurt containing Lactobacillus gasseri mitigates aspirin-induced small bowel injuries: a prospective, randomized, double-blind, placebo-controlled trial. Digestion. 2017;95(1):49-54.

Objective

To evaluate the efficacy of Lactobacillus gasseri (LG) in reducing aspirin-induced small bowel injuries in patients taking low-dose aspirin (LDA) for at least 1 month

Design

Prospective, randomized, double-blind, placebo-controlled trial

Participants

Sixty-one patients completed the study. They had been randomized to LG (n=30; 25 male: 5 female; mean age 71.1±7.4 years) or placebo (n=31; 27 male: 4 female; mean age 70.4±9.4 years).

The 2 groups had no statistically significant differences in baseline parameters evaluated by the study.

Patients eligible for the study must have been taking LDA daily for more than 1 month. All patients were recruited from a single study site at a university hospital in Japan between July 2013 and June 2015.

Intervention

Participants were randomized to receive 112 mL of yogurt containing LG (109 colony-forming units [CFUs] ) or placebo twice daily for 6 weeks while continuing with daily LDA use. The authors did not describe the placebo formulation.

Study Parameters Assessed

Changes in lesions of the small intestine mucosa and in small bowel transit time were evaluated by capsule endoscopy (CE) at baseline and after 6 weeks of yogurt consumption.

Changes in gastrointestinal symptoms such as reflux, abdominal pain, indigestion, constipation, and diarrhea were assessed using the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG) and Gastrointestinal Symptom Rating Scale (GSRS) questionnaires at baseline and after 6 weeks of yogurt or placebo consumption.

Primary Outcome Measure

Improvement in mucosal lesions of the small intestine.

Key Findings

After 6 weeks of treatment, compared to baseline, the LG group showed significant improvement (P<0.002) of mucosal lesions (including injuries such as breaks in the mucosa and erythemic lesions) and significantly fewer mucosal breaks, such as ulcers or erosions (P<0.01). No changes in mucosal lesions were observed in the placebo group. Neither group showed changes in small bowel transit time.

No patients were found to have active bleeding or stenosis in the small intestine during the study.

The LG group also showed significant improvement in GSRS and FSSG scores after 6 weeks of treatment (compared to baseline scores), while no change in assessment scores was seen in the placebo group. Further analysis of GSRS scores in the LG group showed that reflux, abdominal pain, indigestion, and constipation were significantly improved (P<0.05), with no change in diarrhea scores.

Practice Implications

It is well-known that LDA use increases risk of bleeding in the stomach and duodenum. Research continues to emerge on the adverse effects of aspirin use on the small intestine as endoscopic methods for small bowel evaluation become more available. There is evidence that short-term LDA use causes mild inflammation in the small intestine mucosa; research on long-term LDA use shows a variety of adverse effects on small bowel mucosa, such as loss of villi, development of petechiae, erosions, ulceration, and stricture.1 Some studies have shown a greater than 80% prevalence of LDA-induced small bowel injuries in patients with occult gastrointestinal bleeding.2,3 Prevalence of small bowel injuries in this study by Suzuki et al was 60% in patients with occult gastrointestinal bleeding and 75% in asymptomatic patients.

Perhaps use of live beneficial microbes might also be paired with any of our traditional mucilaginous agents such as Ulmus rubra, Althea officinalis, or Glycyrrhiza.

Though the exact mechanisms of small bowel injury by aspirin use are not clearly understood, research suggests dysbiosis is a significant contributing factor, perhaps second only to cyclooxygenase (COX)-1 inhibition and subsequent prostaglandin deficiency, which are considered the most important factors in the pathogenesis of nonsteroidal antiinflammatory (NSAID)-induced enteropathy. The dysbiosis results in increased intestinal motility and decreased secretion of protective mucus (both further potentiated by COX-1 inhibition), thereby promoting enterobacterial invasion into the mucosa.4,5 Studies have shown that enterobacterial invasion is essential for development of lesions in the mucosa.4,5 Inflammatory endotoxin released from the enterobacteria increases nitric oxide production, which interacts with superoxide radicals resulting in peroxynitrite production, further destroying the integrity of intestinal mucosa.4,5

Preclinical research by Wallace et al showed exacerbation of NSAID-induced small bowel damage when proton pump inhibitors (PPIs) were used with NSAIDs and identified worsening of dysbiosis as the cause.6 A 2017 review of several studies further indicates that this seems to be the case.7

Interestingly, PPIs are often used as agents to help protect against NSAID-induced gastric or duodenal ulceration in higher-risk patients.8,9 Gastroprotective agents that have also been shown to have protective benefit for LDA-induced small bowel injury include rebamipide, misoprostol, and polaprezinc.10 Rebamipide is an amino acid analogue of 2 (1H)-quinolinone and upregulates COX-2 and prostaglandin (PG) E2, but is not currently available in the United States.11 Misoprostol is inappropriate for long-term use due to other gastrointestinal side effects experienced with its use.10 Polaprezinc, also known as zinc L-carnosine, is thought to help protect the integrity of the intestinal mucosa and its intercellular tight junctions and reduce inflammation and oxidation.10 It is also useful in decreasing intensity of radiation or chemotherapy-induced mucositis.12-14 Certain antibiotics have been shown to be effective in preventing NSAID-induced small bowel injury, but long-term antibiotic therapy is not a practical option given the rise of multidrug-resistant bacteria and the adverse health effects that accompany the eradication of beneficial gut flora.15

In 2011, a small randomized controlled pilot study evaluated the ability of a different lactobacillus species, Lactobacillus casei, to prevent aspirin-induced small bowel injuries in patients on chronic LDA therapy.16 A total of 25 participants completed the study, 13 in the L. casei group and 12 in the control group. Eligible participants had been taking 100 mg aspirin and 20 mg omeprazole daily and had been diagnosed with unexplained iron deficiency anemia. After 3 months of continued aspirin and omeprazole plus/minus L. casei, CE was performed to evaluate changes from baseline. After 3 months, the L. casei group had significantly fewer mucosal breaks and a decreased CE score compared to the control group (P=0.039). After 3 months, the change in the median CE score from baseline was −228 for the L. casei group and −4 for the control group (P=0.026).

In another paper, published in 2011, Lactobacillus gasseri was studied for its protective role in the gastric mucosa in patients taking aspirin.17 Urinary sucrose excretion (USE) test was used to determine gastric mucosa permeability, with elevation in USE indicating increased permeability. This study evaluated ingestion of 1 cup of yogurt containing 1 billion CFUs twice daily in patients taking high-dose aspirin (330 mg daily for 4 weeks, sandwiched by a 1-day loading dose of 1,320 mg before and after). Urinary sucrose excretion test values were significantly increased immediately after aspirin-loading doses, then significantly decreased following L. gasseri treatment (P=0.018). The study also evaluated ingestion of 1 cup of the same yogurt once daily for 16 weeks in patients taking low-dose aspirin (81 or 100 mg daily). Prior to the period of the yogurt ingestion, patients abstained from intake of probiotics or foods with lactic acid bacteria for a 16-week period, followed by an 8-week resting period. Sucrose excretion decreased significantly during the period of L. gasseri treatment (P=0.033). No change was found during the period of beneficial microbe avoidance. The mean number of positive occult blood tests, which had been performed every 4 weeks using guaiac stool analysis, was 1.16 per person during the period of avoidance and 0.65 during the period of L. gasseri treatment (P=0.007).

The present study by Suzuki et al is the first randomized placebo-controlled trial to demonstrate mitigation of specifically low dose aspirin-induced small intestine injury and improvement in gastrointestinal symptoms with L. gasseri. Though a small trial, it certainly leaves compelling support for the use of L. gasseri alongside LDA therapy. Although this trial did not report on adverse effects, a 2011 review conducted by the American Healthcare Research and Quality agency (AHRQ), which included over 600 clinical trials and case reports on the use of probiotics in both adults and children, healthy or ill, found no association with increased risk of adverse events, including infections.18

Clearly, removing the underlying cause of intestinal injury is optimal, but when potential benefit of LDA therapy strongly outweighs potential risk, then its use may be called for. We may continue to see LDA therapy on the rise, as it has long been used for prevention of cardiovascular events, and research continues to also highlight its potential for reducing risk of several cancers, including breast, colon, stomach, esophageal, and prostate.19-21 As more research emerges on the role of dysbiosis in NSAID-induced injury and the benefits of regulating the intestinal microbiota,4,7 consideration for the use of live beneficial microbes to ameliorate and prevent mucosal damage is certainly warranted. Particular attention should be given to individuals with a higher risk for gastrointestinal lesions, such as older patients, patients with a history of ulcers, patients being treated with steroid medications, PPIs, or high-dose NSAIDS, patients who are at increased bleeding risk from anticoagulants or systemic cancer treatments, and younger patients who may be on low-dose aspirin therapy indefinitely. Perhaps use of live beneficial microbes might also be paired with any of our traditional mucilaginous agents such as Ulmus rubra, Althea officinalis, or Glycyrrhiza.

More research is needed to further inform us of the utility of various probiotic strains in treating and preventing LDA-induced small bowel injury, and larger clinical trials are needed to further confirm degree of benefit. In the meantime, there is plenty of evidence to support the incorporation of foods and beverages containing live cultures into the daily diet of just about anyone,22-26 but perhaps if one happens to also be on LDA therapy, we might additionally seek out options that could provide 1 billion CFUs of L. gasseri twice daily.

About the Author

Rebecca Lovejoy, ND, LAc, received her master's degree from the Tri-State College of Acupuncture in New York City and her naturopathic medical degree from the Southwest College of Naturopathic Medicine in Tempe, Arizona. Following completion of a 2-year hospital-based residency in naturopathic oncology at the Indiana University Health Goshen Center for Cancer Care, she joined the staff, with delight, where she currently continues as a proud member of the integrative care team.

References

  1. Endo H, Sakai E, Kato T, et al. Small bowel injury in low-dose aspirin users. J Gastroenterol. 2015;50(4):378-386.
  2. Watanabe T, Takeuchi T, Handa O, et al. A multicenter, randomized, double-blind, placebo-controlled trial of high-dose rebamipide treatment for low-dose aspirin-induced moderate-to-severe small intestinal damage. PLoS One. 2015;10(4):e0122330.
  3. Endo H, Hosono K, Inamori M, et al. Characteristics of small bowel injury in symptomatic chronic low-dose aspirin users: the experience of two medical centers in capsule endoscopy. J Gastroenterol. 2009;44(6):544-549.
  4. Syer SD, Blackler RW, Martin R, et al. NSAID enteropathy and bacteria: a complicated relationship. J Gastroenterol. 2015;50(4):387-393.
  5. Takeuchi K, Satoh H. NSAID-induced small intestinal damage – roles of various pathogenic factors. Digestion. 2015;91(3):218-232.
  6. Wallace JL, Syer S, Denou E, et al. Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis. Gastroenterology. 201;141(4):1314-1322.
  7. Otani K, Tanigawa T, Watanabe T, et al. Microbiota plays a key role in non-steroidal anti-inflammatory drug-induced small intestinal damage. Digestion. 2017;95(1):22-28.
  8. Satoh K, Yoshino J, Akamatsu T, et al. Evidence-based clinical practice guidelines for peptic ulcer disease 2015. J Gastroenterol. 2016;51(3):177-194.
  9. Targownik LE, Metge CJ, Leung S, Chateau DG. The relative efficacies of gastroprotective strategies in chronic users of nonsteroidal anti-inflammatory drugs. Gastroenterology. 2008; 134(4): 937-944.
  10. Suzuki T, et al. Yogurt containing Lactobacillus gasseri mitigates aspirin-induced small bowel injuries: a prospective, randomized, double-blind, placebo-controlled trial. Digestion. 2017;95(1):49-54.
  11. Kudur MH, Hulmani M, et al. Rebamipide: a novel agent in the treatment of recurrent aphthous ulcer and Behcet's syndrome. Indian J Dermatol. 2013;58(5):352-354.
  12. Lin LC, Que J, Lin LK, Lin FC. Zinc supplementation to improve mucositis and dermatitis in patients after radiotherapy for head-and neck cancers: a double-blind, randomized study. Int J Radiat Oncol Biol Phys. 2006;65(3):745-750.
  13. Hayashi H, Kobayashi R, Suzuki A, et al. Preparation and clinical evaluation of a novel lozenge containing polaprezinc, a zinc-L-carnosine, for prevention of oral mucositis in patients with hematological cancer who received high-dose chemotherapy. Med Oncol. 2016;33(8):91.
  14. Suzuki A, Kobayashi R, Shakui T, et al. Effect of polaprezinc on oral mucositis, irradiation period, and time to discharge in patients with head and neck cancer. Head Neck. 2016;38(9):1387-1392.
  15. Otani K, Tanigawa T, Watanabe T, et al. Microbiota plays a key role in non-steroidal anti-inflammatory drug-induced small intestinal damage. Digestion. 2017;95(1):22-28.
  16. Endo H, Higurashi T, Hosono K, et al. Efficacy of Lactobacillus casei treatment on small bowel injury in chronic low-dose aspirin users: a pilot randomized controlled study. J Gastroenterol. 201;46(7):894-905.
  17. Akama F, Nishino R, Makino S, et al. The effect of probiotics on gastric mucosal permeability in humans administered with aspirin. Scand J Gastroenterol. 2011;46(7-8):831-836.
  18. Hempel S, Newberry S, Ruelaz A, et al. Safety of probiotics to reduce risk and prevent or treat disease. Evidence Report/Technology Assessment (Full Rep). 2011;200:1-645.
  19. Schor J. Aspirin to prevent breast cancer recurrence: the potential risks and potential benefits of aspirin use with breast cancer. Natural Medicine Journal. 2011;3(12).
  20. Kaczor, T. Daily aspirin may reduce risk of cancer death: study suggests a protective role of aspirin intake on cancers of the colon, stomach and esophagus. Natural Medicine Journal. 2011;3(1).
  21. Schor, J. Aspirin reduces risk of prostate cancer mortality: study assesses the impact of anticoagulants on men previously yreated for prostate cancer. Natural Medicine Journal. 2013;5(4).
  22. Sun J, Buys N. Effects of probiotics consumption on lowering lipids and CVD risk factors: a systematic review and meta-analysis of randomized controlled trials. Ann Med. 2015;47(6):430-440.
  23. Dong JY, Szeto IM, Mikinen K, et al. Effect of probiotic fermented milk on blood pressure: a meta-analysis of randomised controlled trials. Br J Nutr. 2013;110(7):1188-1194.
  24. Hao Q, Lu Z, Dong BR, Huang CQ, Wu T. Probiotics for preventing acute upper respiratory tract infections. Cochrane Database Syst Rev. 2015;2:CD006895.
  25. Rafie N, Golpour HS, Ghiasvand R, Miraghajani M. Kefir and cancer: a systematic review of literatures. Arch Iran Med. 2015;18(12):852-857.
  26. Bourrie BC, Willing BP, Cotter PD. The microbiota and health promoting characteristics of the fermented beverage kefir. Front Microbiol. 2016;7:647.