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Title: No evidence of harms of probiotic Lactobacillus rhamnosus GG ATCC 53103 in healthy elderly-a Phase I Open Label Study to assess safety, tolerability and cytokine responses

item HIBBERD, PATRICIA - Massachusetts General Hospital
item KLEIMOLA, LAUREN - Massachusetts General Hospital
item FLORINA, ANNE-MARIA - Massachusetts General Hospital
item BOTELHO, CHRISTINE - Massachusetts General Hospital
item HAVERKAMP, MIRIAM - Massachusetts General Hospital
item ANDREYEVA, IRINA - Massachusetts General Hospital
item POUTSIAKA, DEBRA - Tufts - New England Medical Center
item FRASER, CLAIRE - University Of Maryland
item Solano-Aguilar, Gloria
item SYNDMAN, DAVID - Tufts - New England Medical Center

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/1/2014
Publication Date: 12/1/2014
Citation: Hibberd, P.L., Kleimola, L., Florina, A.M., Botelho, C., Haverkamp, M., Andreyeva, I., Poutsiaka, D., Fraser, C., Solano Aguilar, G., Syndman, D.R. 2014. No evidence of harms of probiotic Lactobacillus rhamnosus GG ATCC 53103 in healthy elderly-a Phase I Open Label Study to assess safety, tolerability and cytokine responses. PLoS One. 1:9(12):e113456. DOI: 10.1371/journal.pone.0113456.

Interpretive Summary: Probiotics are live microorganisms which confer a health benefit on the host when administered in adequate amounts. Until recently, probiotics were mostly found in yogurts and fermented milks, but probiotics are increasingly being found in a wide range of non-dairy foods with an increasing use due to beneficial health claims associated with its consumption. Lactobacillus rhamnosus GG ATCC 53103 (LGG) is one of the most studied probiotics. Its precise pharmacologic effects and mechanisms of action are not known but include colonization resistance in the gastrointestinal and respiratory tracts, immune modulation, and direct antimicrobial effects. The FDA Center for Biological Evaluation and Research [FDA/CBER] asked us to complete a Phase I Open Label study under IND to evaluate the safety and tolerability of the use of LGG in 15 healthy elderly volunteers. Thus the primary aim of this Phase I open label study was to provide information on adverse events that may occur in healthy elderly volunteers receiving LGG administered twice a day for 28 days. The secondary aims were to evaluate potential mechanisms of action of LGG in the healthy elderly by studying their gastrointestinal microbiome (C Fraser, manuscript in preparation) as well as immunologic responses to consumption of LGG for 28 days (G Solano-Aguilar, manuscript in preparation). This paper describes the detailed adverse event profile of the elderly volunteers and their serum cytokine profiles, particularly changes in pro and anti-inflammatory cytokines.

Technical Abstract: Although Lactobacillus rhamnosus GG ATCC 53103 (LGG) has been consumed since the mid 1990s by between 2 and 5 million people daily, the scientific literature lacks rigorous clinical trials that describe the potential harms of LGG, particularly in the elderly. The primary objective of this open label clinical trial is to assess the safety and tolerability of 1 x 1010 CFU LGG administered orally twice daily to elderly volunteers for 28 days. The secondary objectives were to evaluate the effects of LGG on the gastrointestinal microbiome, host immune response and plasma cytokines. Fifteen elderly volunteers, aged 66-80 years received Lactobacillus rhamnosus GG ATCC 53103 (LGG) capsules containing 1 x 1010 CFU, twice daily for 28 days and were then followed through day 56. Volunteers completed a diary every day, a telephone call on study days 3, 7 and 14 and study visits in the Clinical Research Centers at baseline, day 28 and day 56 to determine whether adverse events had occurred. Assessments included prompted and open-ended questions. There were no serious adverse events. The 15 volunteers had a total of 47 events (range 1-7 per volunteer), 39 (83%) of which were rated as mild and 40% of which were considered related to consuming LGG. Thirty-one (70%) of the events were expected, prompted symptoms while 16 were unexpected events. The most common adverse events were gastrointestinal (bloating, gas, and nausea), 27 rated as mild and 3 rated as moderate. In the exploratory analysis, the proinflammatory cytokine interleukin 8 decreased during LGG consumption, returning towards baseline one month after discontinuing LGG (p=0.038) while there was no difference in other pro or anti-inflammatory plasma cytokines. Lactobacillus rhamnosus GG ATCC 53103 (LGG) is safe and well tolerated in healthy adults aged 65 years and older.