Digestive health issues can be a major disruption to daily life. According to a survey by the American Gastroenterological Association, 40% of Americans have stopped routine activities in the past year due to uncomfortable bowel symptoms, including exercising (19%), running errands (17%), and spending time with family and friends (16%).

“From our perspective, the largest contributor to gut problems is the excessive amount of significantly processed foods we consume,” said Paul Altaffer, chief innovation officer at RFI Ingredients. “This, in addition to severe anxiety and other emotional disorders, contributes to a bad recipe for gut health.” 

A 2022 review of National Health and Nutrition Examination Survey (NHANES) data concluded that consumption of ultra-processed foods increased among all U.S. adults. Ultra-processed foods have increased from 53.5% to 57% of all calories consumed by the U.S. population between 2001 and 2018.¹

“Digestive concerns are an early warning sign for a series of health issues; it all starts in the gut and consumers are increasingly aware of this,” said Len Monheit, executive director of the Global Prebiotic Association (GPA). He noted that a part of the rise in reported digestive health issues may be due to better diagnostics in general.

Monheit pointed to a 2022 Ingredient Transparency Center survey that identified the top reasons consumers choose to use probiotics and prebiotics. Alongside digestive health, regularity, and bloating, many consumers were interested in using prebiotics for bone health, brain health and mental acuity, weight management, and athletic performance. Meanwhile, aside from digestive health, probiotics were commonly cited by users for immune support, inflammation, autoimmune conditions, cardiovascular health, and blood sugar management.

Young people, and especially young women, are using digestive support products like probiotics, prebiotics, and digestive enzymes at record rates, said Nena Dockery, scientific affairs manager at Stratum Nutrition. “Interest in the gut-brain axis and the overall gut-body connection has been a strong influence.” 

COVID-19 exacerbated gut issues, leading to a heightened awareness, she added. “Compounding this effect were changes in eating habits, increased alcohol consumption, disrupted sleep, and weight gain, all of which are major factors contributing to digestive disorders,” Dockery said.

The digestive health segment is broad and attracts a wide range of people with diverse health goals, noted Melanie Bush, vice president of science and research for Artemis International. “Products ranging from yogurt and prebiotics for the maintenance of overall gut wellness fill a different need than products that repopulate healthy probiotic bacteria after a course of antibiotics, or products that help combat chronic issues with diarrhea or constipation or other complaints.”

Immune-Inflammatory Interplay

There are complex interactions at play in both directions between the gut and both immune and inflammatory systems. The Gut Associated Lymphoid Tissue (GALT) is the largest immune tissue in the body.

Jordi Riera, chief business development manager at Kaneka Probiotics, referenced the “Old Friends Hypothesis,” which suggests that exposure to more diverse microbes and allergens helped to shape immune regulatory systems over the course of humanity’s evolution.² “There are scientific studies that suggest an association between non-westernized lifestyles and a lower prevalence of inflammatory bowel disease,” Riera said.

Gut barrier integrity can be negatively impacted by unfavorable immune and inflammatory factors. Alina Slotnik, vice president of bioactives at Brightseed, said the company is particularly excited about the emerging focus on this area, especially for its role in downstream immune functions.

Brightseed intends to continue building upon its foundational research for NCT and NFT, two compounds discovered in hemp fibers, to demonstrate more about their role in intestinal permeability following work with the RepliGut model and human colon cells. 

On the Axis

“Understanding the gut-brain connection, as well as the complexity of the gut microbiome are the two greatest challenges, as well as areas for innovation. We are literally only scratching the surface,” said Altaffer.

The gut microbiome can promote inflammation in the central nervous system, leading to a number of cognitive health issues and increased risk of depression, Alzheimer’s disease, stroke, and more. It also has a role in blood-brain barrier function. The 100 million nerve cells lining the gut are the largest collection of neurons outside of the brain, and by far the largest department of the peripheral nervous system.^3,4

ADM has been addressing gut-brain axis challenges both with small and large combinations of probiotic strains. The 14-strain BioKult was tested last year in a study population of 71 volunteers with moderate depression over 4 weeks, where researchers “examined changes in psychological processing and measurements of low mood,” said Vaughn DuBow, director of marketing for microbiome solutions at ADM.⁵

Meanwhile, in a preclinical zebrafish model, ADM’s ES1 strain and Lactobacillus rhamnosus CECT8361 demonstrated altered swimming patterns and average swimming speed, as well as a reduction in bottom-dwelling behavior, all of which are positive mood-related endpoints.

Kaneka’s Floradapt Intensive GI (a combination of P. acidilactici KABP 021, L. plantarum KABP 022, and L. plantarum KABP 023) was linked to improvements in inflammatory bowel symptoms and stress-associated diarrhea through a mechanism of action involving the gut-brain axis in a group of 50 healthy adult volunteers, noted Riera.⁶

“Sabinsa’s LactoSpore spore-forming probiotic, has been shown to alleviate major depressive disorder (MDD) associated with Irritable Bowel Syndrome,” said N. Kalyanam, PhD, president of R&D, Sabinsa Corporation. “A human clinical study afforded evidence of LactoSpore being effective not only in MDD related symptoms but also lowering the inflammatory biomarker myeloperoxidase associated with MDD.”⁷

“The gut-brain interaction is less like an axis with two endpoints communicating back and forth and more like an ecosystem in which an imbalance in one part has consequences across the entire system,” noted Eric Withee, director of ingredient innovation at Freemen Nutra Group.

Research has suggested the gut microbiome plays a role in nutrient absorption, intestinal permeability, and may be implicated in obesity.⁸

Both ADM’s BPL1 probiotic and the heat-treated version have shown positive results in supporting visceral fat reduction, a healthy waist circumference, and other factors associated with metabolic health, noted DuBow.⁹

Given the effects gut function has on metabolism, changes can be made for downstream liver health benefits, said Riera. “Back in 2010, we introduced the world’s first probiotic to act on the gut-liver axis to lower cholesterol,” he said.

Cutting-Edge Biotics

Synbiotics, which involve a combination of a microbe and a substrate which confer health benefits when combined, are set to explode as a novel category, according to Monheit.

Seed Health, Inc. recently launched PDS-08, a complementary synbiotic with nine probiotic strains and mixed-chain oligosaccharides, which is supported by 18 strain-specific clinical studies on gut barrier integrity, gut-immune function, dermatological health, and respiratory health. In a clinical study evaluating the combination formula versus a placebo, researchers administered either the synbiotic or a placebo to 64 children between the ages of 3 and 17 for 12 weeks. The number of spontaneous bowel movements increased in the treatment group without any adverse effects or GI distress.¹⁰

The potential that working with proprietary postbiotic ingredients will have for the category can’t be overstated and is not yet realized, said Dockery. “Since they are not live organisms, they have excellent shelf stability and their efficacy is unaffected by passage through the acidic gastric environment. They are also more versatile for placement in multiple types of formats, including beverages and conventional foods. Though postbiotics are relatively new to the market […] Lactobacillus LB (LBiome) has been utilized for a century in its inanimate form. Its use is supported by a multitude of published research studies, including over 12 clinical trials.”

Delivery and Dosage

Resilient probiotics, such as spore-forming bacteria or bacteriophages, along with pre- and postbiotics, are being used more widely thanks to their versatility.

Deerland Probiotics and Enzymes and ADM showcased unique delivery platforms for their prebiotic, probiotic, and postbiotic ingredients at Natural Products Expo West in Anaheim, CA, in March. Concepts included DE111, heat-treated BPL1, and Fibersol with formats including a lime-mint tri-biotic gummy, a women’s health chocolate square that included isoflavones and vitamins D and E, a dissolving mint probiotic strip, a prebiotic lollipop, and more.

“Our heat-treated BPL1 (Bifidobacterium animalis subsp. lactis CECT8145) postbiotic of non-viable microorganisms and can withstand harsh processing environments like high heat to create a range of formats from snack clusters to bars and beverages,” said DuBow. “Formulators don’t have to make adaptations for live colony-forming units.”

On the prebiotics front, newly-discovered fibers that are efficacious at a low dose are changing the game with format flexibility, Monheit said. “In order to supply a good inulin dose, for example, multi-gram formulations are required, which is problematic in format and can lead to gastric challenges.”

A wave of prebiotic and probiotic soda brands are staking claims in a space that’s blurring the lines between soda and kombucha. Over the past few years, Olipop, Poppi, Culture Pop, Vina, Turveda, and other brands have debuted new lines of better-for-you beverages with prebiotics, probiotics, and other fermented ingredients targeting the microbiome.

For a more portable option, stick packs containing pre- and probiotics are also stirring interest. For instance, MegaFood’s Digestive Health Water Enhancers are beverage powders containing Deerland’s DE111 probiotic in addition to kombucha powder, apple cider vinegar, green tea extract, and prebiotic fiber from Jerusalem artichoke.

Specialty Ingredients

There are many ingredients outside of established digestive health staples that may be beneficial to the gut, said Dockery. Additionally, essential nutrients like omega-3s, which influence systemic inflammatory activity, have been associated with positive changes in the gut, including increased gut microbial diversity.

It’s important not to discount essential nutrition in the gut-health puzzle, noted Kalyanam. For example, selenium deficiency is associated with Crohn’s disease. “Plasma and erythrocyte selenium levels as well as the selenium transporter protein, Selenoprotein P, are lower in Crohn’s subjects than in healthy subjects. Consumption of food with adequate nutrients lowers chances of gut issues,” he said. Sabinsa’s Selenium SeLECT ingredient has been shown to significantly increase selenoprotein P levels in selenium-deficient participants.¹¹

Bioactive-rich plant proteins, as a replacement for excess animal proteins, may also be suitable for gut-health positioning, Dockery noted. “As more people are consuming high-protein diets, particularly in wealthier countries, there has also been an increase in chronic health diseases such as cardiovascular disease and colon cancer.… This might be due to high consumption of animal protein. Plant protein is not likely to contribute to this negative effect, as it also contains prebiotic compounds and a variety of micronutrients.”

Riera noted the growing interest in human milk oligosaccharides as a synbiotic component with more to offer than its standalone prebiotic activity. “We’ve recently published research on one of our strains, Bifidobacterium longum KABP-042. This strain can utilize HMOs to produce a postbiotic called polyphosphate that can highly improve the gut-barrier function, acting as a biologic glue for the intestine’s tight junctions.”

Botanical bioactives are also making a case for themselves in this category. For example, at this year’s Integrative Healthcare Symposium in New York City, Biocidin Botanicals debuted GI InnerCalm, a clinician-crafted gut powder containing multiple nutrients, the amino acid glycine, GutGard deglycyrrhizinated licorice (DGL), chamomile, lemon balm, aloe, and ginger.

The formula, designed to soothe acute symptoms and remove harmful biofilms in the gut, joins the company’s healthcare practitioner line of digestive health products, which includes its 30-day Microbiome Detox Program.

Artemis International recently launched a European black elderberry ingredient, ElderGut, which contains both antioxidants for immune support with an added concentration of polyphenols linked to prebiotic activity.

“Historically, prebiotic activity has been limited to fiber materials like inulin, but researchers found that polyphenols from ElderCraft, a European black elderberry extract, demonstrated prebiotic activity and elevated Akkermansia muciniphila levels with a lasting effect. [Akkermansia muciniphila] has been tied to gut-brain axis discoveries as well as overall improved wellness,” said Bush.¹²

Sabinsa’s C3 Complex was the first curcuminoids ingredient to be studied for its prebiotic-like effects, according to Kalyanam. “Incidentally, curcumin is known for its restoration of intestinal barrier function and increased expression of tight junction proteins.”¹³

In partnership with NXT USA, Freemen Nutra Group recently introduced Digexin, a proprietary herbal formula designed to stimulate peristalsis and soothe the gut tract. It can also improve the body’s ability to respond to stress, improve sleep quality, and boost levels of serotonin through metabolic pathways typical of herbal formulas, according to the companies.

“When managing gut disorders, it is important to also address the issue of stress,” Withee noted. “We’re seeing research on how non-physical factors have widespread physiological implications for largely, but not exclusively, gut and brain health.”

Enzymes are becoming popularized for post-meal applications. “With an estimated 90% of nutrient absorption occurring in the small intestine, certain enzyme supplements have potential to support the breakdown of nutrients to aid in the digestion process in the stomach, allowing for more efficient nutrient absorption and helping to lessen ‘contact time’ in the gut,” said DuBow. “We purposefully designed solutions like ProHydrolase and Glutalytic for consumer’s needs in this space.”

Suboptimal levels of digestive enzymes in the gut result in discomfort and digestion problems, said Kalyanam. “Sabinsa has successfully developed a blend of enzymes, Digezyme, consisting of amylase, protease, lipase, cellulase, and lactase, which successfully addresses these concerns.” Kalyanam noted that research has supported the use of Digezyme in cases of functional dyspepsia, and for reducing serum total cholesterol and LDL cholesterol blood levels.

Precision R&D

Artificial intelligence (AI) platforms akin to those used by the pharmaceutical industry are now being used in nutrition to discover novel compounds and microbes, and their potential mechanisms of action, at a very rapid pace.

“In prebiotics specifically, we’re seeing precision prebiotics where linkages or types of carbohydrates are adjusted to allow for much more selectivity, in turn driving activity with specific probiotic strains. It is these types of advancements that allow us to better manage the issue of our unique microbiomes. Some strains are broadly deficient; others need to be optimized to increase diversity,” said Monheit.

AI allows for predictive and extrapolative strategies that fully account for modulations which impact thousands of individual gut microbe strains, he noted.

Another way to position a personalized product for a given demographic is by showcasing clinical research directly involving that target population.

For instance, “Emerging data suggests that ES1 [Bifidobacterium lomgum CECT7347] has the potential to help support digestive and GI health as well as gut function in gluten-sensitive individuals,” DuBow said.¹⁴

Brightseed’s Bio 01 ingredient, a hemp-derived dietary fiber containing two novel bioactives, NCT and NFT, was discovered by the company’s AI platform, known as Forager. The two compounds are each linked in vitro and in vivo to improved gut barrier integrity, and improved absorption of nutrients. “Bioactives are health-benefiting compounds found in plants and fungi that can be powerful drivers to maintain health and fight disease, but less than 1% of them are understood today,” said Slotnik.

Every human being has a unique microbiome, Riera noted. “Personalized gut health should target biomarkers of issues and associations that are sustained in science more than trying to mimic a standardized composition of our microbiome,” said Riera.

References

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2. Rook, GA. et al. (2013). Microbial ‘Old Friends’, immunoregulation and stress resilience. Evol Med Public Health. Jan; 2013 (1):46-64. Doi: 10.1093/emph/eot004

3. Zhu, S. et al. (2020). The progress of gut microbiome research related to brain disorders. J Neuroinflammation. https://doi.org/10.1186/s12974-020-1705-z

4. Kulkarni, S. et al. (2018). Advances in Enteric Neurobiology: The ‘Brain’ in the Gut in Health and Disease. Journal of Neuroscience 31 October 2018, 38 (44) 9346-9354. https://doi.org/10.1523/JNEUROSCI

5. Baiao, R. et al. (2022). Multispecies probiotic administration reduces emotional salience and improves mood in subjects with moderate depression: a randomised, double-blind, placebo-controlled study. Psychological Medicine. https://doi.org/10.1017/S003329172100550X

6. Sato, T. et al. (2022). A probiotic blend improves defecation, mental health, and productivity in healthy Japanese volunteers under stressful situations. Heliyon. (8) 9; e10614. https://doi.org/10.1016/j.heliyon.2022.e10614

7. Majeed, M. et al. (2018). Bacillus coagulans MTCC 5856 for the management of major depression with irritable bowel syndrome: a randomised, doubleblind, placebo controlled, multi-centre, pilot clinical study. Food & Nutrition Research. https://doi.org/10.29219/fnr.v62.1218

8. Duranti, S. et al. (2017). Obesity and microbiota: an example of an intricate relationship. Genes and Nutrition. Published online 2017 Jun 15. Doi: 10.1186/s12263-017-0566-2

9. Pedret, A. et al. (2019). Effects of daily consumption of the probiotic Bifidobacterium animalis subsp. lactis CECT 8145 on anthropometric adiposity biomarkers in abdominally obese subjects: a randomized controlled trial. International Journal of Obesity (2019) 43:1863–1868. doi.org/10.1038/s41366-018-0220-0

10. Tierney, BT. et al. (2022). Functional response to a microbial synbiotic in the gastrointestinal system of children: a randomized clinical trial. Pediatr Res. https://doi.org/10.1038/s41390-022-02289-0

11. Burk, R. et al. (2006). Effects of Chemical Form of Selenium on Plasma Biomarkers in a High-Dose Human Supplementation Trial. Cancer Epidemiology, Biomarkers, & Prevention. https://doi.org/10.1158/1055-9965.EPI-05-0950

12. Reider, S. et al. (2022). Short- and Long-Term Effects of a Prebiotic Intervention with Polyphenols Extracted From European Black Elderberry – Sustained Expansion of Akkermansia spp. Journal of Personalized Medicine. 12(9):1479. https://doi.org/10.3390/jpm12091479

13. Peterson, C. et al. (2018). Effects of Turmeric and Curcumin Dietary Supplementation on Human Gut Microbiota: A Double-Blind, Randomized, Placebo-Controlled Pilot Study. Journal of Evidence-Based Integrative Medicine. https://doi.org/10.1177/2515690X18790725

14. Olivares, M. et al. (2014). Double-blind, randomised, placebo-controlled intervention trial to evaluate the effects of Bifidobacterium longum CECT 7347 in children with newly diagnosed coeliac disease. Br J Nutr. 2014 Jul 14;112(1):30-40. doi: 10.1017/S0007114514000609