Engineered probiotics address several critical shortcomings of the current industry. For example, many existing products lack differentiation and fail to provide targeted and consistent benefits to the consumer. Currently, some variation on a composition of Bifidobacterium,Lactobacillus, Saccharomyces, Enterococcus,Bacillus, etc. is found in nearly every product, where the main differentiator is often the advertised colony forming units (CFU) per dose, despite lack of scientific evidence that “more is better” for that particular population. In contrast, genetically engineered microorganisms (GEMs) can be tailored to a specific use-case more simply and safely than hunting down novel isolates with the desired function, and a single strain can be optimized to provide a benefit at much lower CFUs.

To expand the current repertoire of probiotics, companies have resorted to scouring nature in an attempt to find strains with uniquely beneficial properties. This approach requires a large investment of time and money to not only identify said strain, but also prove its efficacy, safety, and feasibility as a consumer product. Once discovered, the strain is not patentable and will eventually be added to the list of off-the-shelf products. With a much quicker turnaround time, we have the option to build strains with the benefits we desire while not limiting ourselves to, for example, bacterial pathways found in pre-established probiotics, or enzymes that are stable enough to be purified and delivered orally. We can expand the use-case of probiotics and rapidly respond to significant global challenges, such as emerging health threats and extreme climate change. We envision a future with GEMs that can mitigate our exposure to microplastics, highly processed foods, and air pollution, which are increasingly prevalent in our environment and new to our biology.

The development of GEMs to tackle unique challenges, and the speed with which we can develop new strains for testing, highlights not only the immense potential of genetic engineering but also an opportunity to reduce costs and make products with genuine functions more accessible. The technology to build and test GEMs has evolved immensely, streamlining the process of getting the next generation of probiotics into the hands of the everyday user. And while many companies fear consumer rejection of GMOs, the market for genetically engineered probiotics is growing. Contrary to widespread belief, most people (in the US at least) are not specifically opposed to all GMOs outright, and they are more than happy to purchase products that provide them with the benefits they want, provided there is transparency and clear communication about their safety and efficacy. By being open about the genetic modifications, educating the populus on how the technology works, and clearly describing the benefits they offer, companies can foster consumer trust and acceptance. This approach not only builds confidence in the technology but also encourages informed decision-making among consumers, and there are now companies who have demonstrated success in the consumer space with transparently labeled GMO probiotics. When companies transparently and responsibly use genetic engineering to develop new products with targeted benefits for the end user, people will appreciate the improvement and make the conscious decision about which GEMs they want to include in their daily lives.

The emerging field of genetically engineered probiotics necessitates robust safety considerations and meaningful regulations to ensure its success. Safety is paramount, as it not only protects consumers but also paves the way for the industry's growth and acceptance. Innovators in the biotechnology space generally want to do the right thing, and by having accessible and clear guidelines, we can make it easier for future companies to contribute to the success of the industry. As scientists who are encouraging the use of GEMs, we want to ensure that there aren’t well intentioned but ill-informed innovators releasing potentially hazardous products that could lead to reactionary regulations and stifle innovation.

We, along with other academics, industry representatives, and regulatory officials, believe a voluntary framework for regulation is an essential first step towards properly regulating genetically engineered probiotics. Such a framework would allow the industry to establish best practices and standards, providing a playbook for safe and effective development. This approach also encourages transparency and accountability, building trust within the community and creating space for continued innovation. As we set new standards, we can iterate on the framework as the technology grows, such that inevitable government regulations reflect the learnings of scientists in both industry and academia.

We envision, as part of the voluntary framework, tools to provide guidance to those who want to use GEMs in product development. Akin to decision trees for the history of safe use in the food ingredient space, we believe a safety assessment during the design phase can reduce risks by limiting the potential unknowns of a GEM. And at least in the nascent stages of this category, we advocate for a conservative and risk-minimizing approach. For example, if a probiotic is intended for release, a series of questions can help to calculate the likelihood of causing ecological disruption, the potential to break evolutionary bottlenecks, and the risk of introducing untested functions into an ecosystem. We are currently working with the American Society for Testing Materials (ASTM) on that exact guideline (WK84273). And as we develop this, we have been and continue to solicit feedback and input from experts in academia, government, and industry to reflect the current state of the field as much as possible. Collaborative efforts are going to be instrumental in setting these standards.

We fundamentally believe that regulation should focus on assessing each GEM product individually. For example, GEMs that are constructed of sequences reasonably likely to have previously existed in nature in the intended ecosystem result in final products with lower risk. Additionally, final strains should adhere to traditional safety considerations including being stable to mutation and free from risky components, such as transposable elements, antibiotic resistance, and pathogenicity. These, among other careful approaches to genetic engineering, ensure that the resulting probiotics are both effective and safe for long-term use. These evaluations are best made at the design stage to streamline safe product development and limit large resource investments into potentially hazardous GEMs.

Results of a human pilot study indicated that participants who consumed a natural pomegranate extract standardized to 30% punicalagins daily for three weeks felt less hungry and more replete after a meal compared to a placebo group. (4) In fact, polyphenols may influence satiety signalling via hormones that affect hunger and fullness, and increase adiponectin levels, which may impact fat metabolism and positively influence the microbiome and gut-brain axis through the modulation of satiety-related gut peptides. (5) They may also improve metabolic health by modulating blood pressure and stress hormone levels, as shown in a clinical trial which revealed that the intake of pomegranate extract led to significant increases in urinary phenolics excretion and antioxidant capacity, along with reductions in salivary cortisol levels, blood pressure, body fat and fat mass, while lean body mass increased. (6) These results confirm previous data, with the pomegranate extract linked to a reduction in insulin resistance and salivary cortisol levels and cortisol/cortisone ratios. (7)

Stress hormone cortisol can promote fat storage, increase muscle breakdown and disrupt sleep, which also affects appetite regulation. Therefore, managing stress levels is important for maintaining a healthy weight. When stress is lower, people typically experience more control over their eating habits and eat more intuitively. Similar to stress, sleep also plays a crucial role in regulating metabolism and weight management. Lack of sleep or poor quality sleep can affect impulse control and lead to hormonal imbalances that affect hunger and satiety hormones. When we are well rested, our energy levels rise and we are more likely to move and exercise.

In a recently published pre-clinical study, pomegranate extract was also shown to reduce the adverse effects of high fructose consumption, such as weight gain, hepatic steatosis, dyslipidaemia, inflammatory and immunological responses. In addition, it was reported to have a beneficial effect on metabolic profiles and microbiota composition, thus potentially preventing fructose-induced metabolic damage. (8) Another recent pre-clinical study revealed that the same extract reduced the age-related involuntary weight loss, providing a potential approach to an important aspect of frailty in the elderly, and highlighting its holistic properties in overall weight management strategies. (9)

An ABA-standardized fig extract has been shown to regulate blood glucose and insulin levels, and lower the glycaemic and insulinemic index of high glycaemic foods. (10) These effects can promote satiety, reduce cravings for high-sugar foods and support weight management. ABA can increase insulin sensitivity and glycaemic control by modulating metabolic activity in skeletal muscle, which may have implications for weight management too. (11) Furthermore, ABA triggers cellular signalling that enhances glucose uptake and increases the expression and membrane translocation of a glucose transporter protein, thus improving glucose homeostasis. In addition, the phytohormone is able to promote the browning of visceral fat, converting white adipose tissue (WAT) into brown adipose tissue (BAT), which plays a crucial role in generating heat through thermogenesis. Notably, studies have identified brown, fat-like cells, referred to as beige cells, within WAT. Increasing the presence of beige adipocytes in WAT has been shown to enhance overall energy expenditure and reduce the risk of obesity, and metabolic diseases resulting from a high-calorie diet. (12)

Genetically engineered probiotics hold immense potential to improve our lives and through this create a burgeoning industry offering tailored solutions to modern health and environmental challenges. However, this potential can only be realized through a commitment to safety, transparency, and scientifically motivated regulation. By building trust with the community and establishing clear standards, we can create a sustainable future for genetically engineered probiotics, benefiting both the consumer and the biotech industry.

We will stay in the Mediterranean again with the ingredient Morosil (red moro orange). Red Moro oranges are high in anthocyanins (polyphenols), and research completed with Morosil shows it impacts body weight, waist circumference, and hip circumference. (21)

We will see amla listed if we refer to the list of ingredients with specific effects on gut health. Amla is also high in polyphenols, and research shows it is an excellent skin health, primarily in control of collagen metabolism. (22)

The growing body of evidence showing that botanicals play an important role directly on gut health and the microbiome is promising. With new research stating the impact of botanicals high in polyphenols on gut health and the microbiome leads us to ask the question, why not combine botanicals with probiotics to achieve a better outcome for the gut, and gut-blank-axis health concerns? Based on the growing body of evidence, botanicals should be considered a primary way to support both gut and gut-blank-axis health concerns.