Safety
Probiotics have generally been associated with a long history of safe use54,1,27; in fact, many probiotic species are integral to the production of fermented foods and have been consumed safely as part of these foods for millennia.56 Furthermore, many bifidobacteria and lactobacilli species are normal, nonpathogenic inhabitants of the human gastrointestinal tract, oral cavity, skin, and the vagina.51, 46, 1, 56 While, theoretically, probiotic bacterial species may act as opportunistic pathogens, epidemiological surveillance data indicate that the risk of infection from consumption of lactobacilli is negligible.58, 59, 53, 54 In the available literature, documented cases of infection attributable to probiotic treatment are extremely rare and limited to a few individual case reports.47, 37, 50, 24, 42
Theoretically, there are 2 patient populations that may exhibit unfavorable, adverse effects to probiotic treatment: patients with pre-existing digestive lesions/syndromes and immunocompromised individuals. Individuals with pre-existing digestive lesions may, in theory, be more vulnerable to the translocation of bacteria from the gut lumen. Clinical studies, however, have indicated that a wide spectrum of probiotics can be consumed safely in patients with various gastrointestinal diseases28, 53, 12, 34, 38, 55, 65, 30, 42, 16, 62 or in immunocompromised conditions.67, 6, 7
In the United States, harmless lactic acid producing bacteria, including L. acidophilus, may be used as optional ingredients in cultured milk (including buttermilk), sour cream, and cottage cheese (21 C.F.R. §§ 131.112, 131.128, 131.160; FDA 2001) 17. Yogurt may also contain these bacteria, provided the mandatory cultures of L. bulgaricus and S. thermophillus are also used (21 C.F.R. § 131.200; FDA 2001). FDA has affirmed Streptococcus lactis, S. cremoris, and S.lactis subsp. diacetylactis and 2 Leuconostoc species as GRAS for use in the production of butter starter distillate (21 C.F.R. §§ 184.1848). In addition, FDA raised no questions in response to Nestlé USA’s GRAS notice (GRN 49) for use of Bifidobacterium lactis strain Bb12 and Streptococcus thermophilus strain Th4 in milk-based infant formula (FDA 2002).18 Lactobacilli and bifidobacteria species are accepted as safe food ingredients in Japan and Europe.57 It is estimated that the daily consumption of ~20 g cheese and ~400 g yogurt would correspond to a lactic acid bacteria intake of approximately 10 viable bacteria or 0.5 to 2.0 g freeze-dried bacteria.11 In comparison, the intake of specific formulated lactic acid bacteria through the intended use of VSL#3® as a medical food ranges from 4.5 x 1011 to 1.8 x 1012 bacteria/day in adults.
Since lactic acid bacteria are ubiquitous in the diet and in various compartments of the human body soon after birth, a classical risk assessment approach, similar to that used for chemicals, is neither possible nor warranted for probiotic microorganisms.1 Donohue and Salminen10 (1996) proposed a list of suggestions and recommendations in order to test the safety of novel probiotic bacteria. These guidelines included intrinsic properties of the bacteria (e.g., adhesion, antibiotic resistance, plasmid transfer, enzyme profile), metabolic products, acute toxicity, infective properties, efficacy, clinical side effects, and epidemiological surveillance. The probiotics formulated into VSL#3® would not be considered novel strains based on their substantive history of use in foods and safe strain lineage48; however, these lactic acid bacteria would satisfy the general guidelines of safety proposed by Donohue and Salminen (1996). All of the bacterial strains contained within VSL#3® are anaerobes, which are generally considered to have no infectivity.29 In addition, the species contained within VSL#3® are generally accepted as safe, as evidenced by their history of safe use as food ingredients.45 The International Dairy Federation (IDF) and the European Food and Feed Cultures Association (EFFCA) recognize all 8 species in VSL#3® as having a history of safe use in foods.45
Studies of VSL#3® formulations (reported as VSL#3®) containing a different number of probiotic microorganisms per unit amount than does VSL#3®, have been conducted in several animal models of colitis and inflammatory liver disease. 61, 60, 9, 13, 36, 31 Since all of the bacterial species contained in VSL#3® have a history of safe use as food ingredients, these animal studies have been designed specifically to evaluate endpoints of efficacy, rather than to assess safety, as would be required for food ingredients with no history of safe use. In experimental animal models of colitis, there are serious derangements in epithelial permeability and barrier function, causing the animals to be particularly vulnerable to bacterial translocation and inflammatory immune responses. Collectively, these studies demonstrate that VSL#3® normalizes gut permeability and barrier function and that it is associated with beneficial anti-inflammatory and immunomodulatory properties. Thus, despite an increased gut permeability and inadequate barrier function, the probiotics contained within VSL#3® do not translocate from the gut lumen and act opportunistically when ingested by animals suffering from colitis.
