**6. Safety of probiotics**

Probiotics are often perceived as "natural" and safe alternatives to pharmaceuticals. They are routinely marketed as something which restores or aligns the patient back into a state of health rather than treating a specific disease state. In general, probiotics are considered safe provided the user has a competent immune system.

### *Translation of Immunomodulatory Effects of Probiotics into Clinical Practice DOI: http://dx.doi.org/10.5772/intechopen.109864*

A review by the Agency for Healthcare Research and Quality (AHRQ ) looked at 387 studies of which there were 24,615 users and there was no statistically significant increase in the number of adverse events in the probiotic group compared to the control group [125].

Although there have been great strides to incorporate probiotic therapy into modern medicine, researchers have presented concerns about the potential negative effects of probiotic supplementation. Numerous virulent pathways can be expressed and carried out by probiotics that can put the human host at risk as there is a possibility of resistance transfer from the probiotic to pathogenic bacteria. Horizontal gene transfer (HGT) is the movement of genetic code between organisms mediated by transformation, transduction, conjugal transfer, or with specialized gene transfer vehicles such as viruses or other bacteria [126]. Recent literature has suggested the human gut rich in HGT activity and the transfer of genetic code from successfully adapted organisms to recipients provides useful properties resulting in increased fitness and competitiveness in the microbial ecosystem. Examples of HGT among probiotic strains have been documented for *Lactobacillus rhamnosus*, *Lactobacillus gasseri*, *Lactobacillus paracasei, Lactobacillus reuteri*, and *Lactobacillus plantarum*. Some literature suggests there has been a gene flux from Gram-positive cocci for genes encoding for streptogramin resistance [127]. Tetracycline resistance gene transfer has been reported from *L. reuteri* to other bacteria native to the human gut microbiota [128].

The use of probiotics in the processed food industry has increased over the years as some byproducts of these organisms are used as additives. One of the most popular microbial-derived additives is transglutaminase. Interestingly, this catalytic enzyme has been implicated in intestinal tight junction permeability and the increasing incidence of autoimmune diseases [129]. This molecule can be detrimental when crosslinked with gliadin as this complex mimics tissue transglutaminase and is immunogenic in patients with celiac disease [130]. In addition to the potential for immunogenicity, numerous case reports have described systemic infections caused by probiotic strains. Fungemia caused by *Saccharomyces cerevisiae* and *Saccharomyces boulardii* is by the far the most reported single event associated with the consumption of *S. boulardii* [131]. Other complications reported include overt sepsis and endocarditis associated with *S. bouldarii*, *Lactobacillus* GG, *Bacillus subtilis*, *Bifidobacterium* breve, *Lactobacillus*, and *Streptococcus* species [132–137].

The PROPATRIA trial highlighted a concern surrounding probiotic safety in critically ill patients. Researchers explored the ability of multi-strain probiotics to help prevent infectious complications in patients with severe acute pancreatitis. Patients in the experimental arm that received the probiotic were shown to have a much higher mortality rate. The authors of the study suggested that the increase in mortality was associated with bowel ischemia caused by either increased mucosal oxygen demand by the exogenous bacterial metabolic demand in the setting of decreased blood flow or an inflammatory cascade triggered by the probiotic in the setting of decreased capillary blood flow [138]. Other metabolic derangements such as D-lactic acidemia and acidosis in humans have been associated with *Lactobacillus* and *Bifidobacterium* species. Interestingly, these species of bacteria are among the most used in probiotic formulations. D-lactic acidosis has been associated with abdominal bloating, chronic fatigue syndrome, and neurocognitive symptoms such as brain fogginess [139–142]. These findings have also been implicated in the literature surrounding small bowel intestinal overgrowth (SIBO). The resolution of symptoms after antibiotic therapy, in this population, reinforces the proposed causative association [143]. In general, the

current medical literature cautions against the use of probiotic supplementation in patients with immunocompromised states such as those undergoing chemotherapy or immunosuppressive therapy, HIV/AIDS, post-organ transplant, pregnancy, neutropenia, antibiotic-induced diarrhea, and inflammatory bowel disease [144–146].

To date, there is no data on long-term safety of probiotic usage. This makes meaningful safety recommendations on such a diverse array of bacterial strains and dosages within probiotic formulations a nearly impossible task. For this reason, probiotics tend to fall under the unregulated form of other supplements.
