**7. Future research and directions**

As mentioned earlier, probiotics are living nonpathogenic bacteria or yeast that can potentially be beneficial by restoring the microbial balance in the gut; however, only some probiotic products are backed by evidence-based trials [147–150]. Probiotics have been extensively utilized in numerous disease states, including gastrointestinal diseases, metabolic syndrome, cardiovascular disease, periodontal disease, and osteoporosis [49]. The hallmark of maintaining a healthy intestinal ecosystem is the integrity of the interstitial barrier [151], and probiotics employ their beneficial effects by modulating immunologic response, strengthening gut barrier function and competing with pathogenic bacteria [152]. Numerous *in vitro* and animal studies have implied the significance of improving the mucosal barrier function by probiotic treatment [153]; however, extrapolating these studies to humans is challenging. For example, some probiotic species, such as *Akkermansia muciniphila*, VSL#3 encompassing *Lactobacillus* and *Bifidobacteria* strains, and *L*. *plantarum* Dad-13, have proven benefits of protecting against obesity, dyslipidemia, insulin resistance, and fat mass development in mice [46, 48, 52, 154]; however, this has not been significantly reproduced in human studies. While multiple clinical trials have attempted to evaluate the prophylactic and therapeutic effect of probiotics in different disease states, the quality of evidence to support clinical use of probiotics is poor. In addition, it is unclear which species and their respective optimal quantity and duration are beneficial for specific disease states. Hence, there is no consensus recommendation for its use. More research is warranted exploring the overall safety of probiotic supplementation. In addition, given the laxity in oversight by the Food and Drug Administration (FDA), allergic reactions and anaphylaxis should be a focus of safety as some probiotic blends can include allergens such as cow milk and chicken egg protein [146]. Systematic reviews published within the last 5 years have highlighted concern about the broad generalization of conclusions, lack of structural classification, variations in bacterial strains and dosages, and incomplete reporting of probiotic supplementation regimens and subject population identification [53, 144, 155]. Moving forward, more randomized controlled trials with larger sample sizes would help strengthen current data surrounding the utility of probiotics and aid in identifying any serious deleterious effects on patients' health.
