The relationship between the microbial community in the gut and overall wellbeing is intricate, complex, and personal down to the genomic level. Though mechanisms of action remain uncertain, several emerging health conditions are garnering interest in the probiotics field.

“The local and intestinal benefits of probiotics are well-established,” said Mark Haupt, MD, chief medical officer at IFF Health. “If we consider the microbiota as an organ, like the pancreas or liver, greater evidence is required to understand what role it may have in systemic processes [beyond the gut].”

“Currently, 76% of global consumers recognize a link between their digestive and overall health,” said Vaughn DuBow, global director of marketing, microbiome solutions, ADM. “These include elements of physical, mental, and emotional wellbeing, from immune function and weight management to sleep support, reduced stress, balanced mood, and cognitive focus.”

According to a survey conducted by B2B nutrition brand Nutiani, a growing number of consumers are seeking out probiotics for novel benefits, including immunity (35%), weight management (20%), better skin (19%), mood/stress (18%), and feminine needs (12%). However, “very few brands market products for these benefits,” noted Peyton Rudy, global marketing manager at Nutiani’s parent company, Fonterra.

Still, digestive health is the leading growth driver for probiotics. A 2021 study found that 40% of adults worldwide are experiencing “functional gastrointestinal disorders.”¹ Meanwhile, a 2022 study concluded that 29% of people who were infected with COVID-19 developed at least one new symptom related to “disorders of the gut-brain interaction” (DGBI), noted Rudy.²

“Although we are seeing probiotics being studied for very complex pathologies like autism, it is important to also note that there is still a lot of evidence needed in other well-known indications like digestive health or immunity,” said Sergi Audivert, co-founder and executive director of AB-Biotics, an affiliate of Kaneka Probiotics.

Camille Binachon, product manager at Lallemand Health Solutions, acknowledged the sea change in topics of clinical trials registered with the World Health Organization (WHO). Across 335 clinical trials on probiotics registered with WHO in 2022, gut health (28%) still led by a significant margin, followed by metabolism (20%), women’s health (12%), immune function (11%), oral health (11%), mental health (10%), skin health (5%), and sports nutrition (2%).

“Everything connects to the gut, from gut-associated lymphoid tissue, which is the largest immune network in the body, to the 500 million neurons constituting the enteric nervous system, which take part in the gut-brain axis connection,” Binachon said.

Metabolic Health

Recent studies have evaluated the role probiotics play in reducing metabolic disease risk, by reducing lipid peroxidation, producing short-chain fatty acids like butyrate, or through other lesser-known means.

“The growth of this field of research is due to the few available therapeutic options there are in the market today, most of them being drugs,” said Audivert.

Though perhaps less effective than drugs or lifestyle changes, probiotics have been linked to improvements in weight, body mass index, blood pressure, glucose metabolism, and blood lipids, all clinical components of metabolic syndrome, as noted in a 2020 systematic review.³ A 2023 systematic review published in Cureus highlighted significant effects on cholesterol levels from certain probiotic strains, such as Bifidobacterium, L. acidophilus, L. plantarum, and more.⁴

In July, a study published in Clinical Nutrition found that supplementing with a strain patented by Probi called L. paracasei 8700:2 was linked to significant improvements in metabolic syndrome factors in a population of 130 people. After three months, the treatment group experienced a significant reduction in remnant cholesterol made of very low-density lipoprotein, which is a heart attack and stroke predictor. Subjects also saw improved endothelial function, lowered triglycerides, alleviated total metabolic syndrome severity scores, and more.⁵

ADM’s proprietary BPL1 strain has been the lead ingredient in a number of metabolism and weight management formulations, since research first linked supplementation to reductions in fat and waist circumference, increased satiety, and antioxidant and inflammatory-modulating effects. The strain produces lipoteichoic acid, which can affect insulin signaling pathways and other metabolic-related mechanisms, according to the company.⁶

Women’s Health

Menopause symptoms have become another target of intrigue in recent years, with studies confirming a bidirectional link between the microbiome and estrogen production. Researchers suspect dysbiosis may play a role in menopause-related symptoms and even diseases like osteoporosis, breast cancer, and more, according to a 2023 review published in Current Nutrition Reports.⁷

“Women’s health is a great example in which understanding the health journey is critical to developing impactful products,” Haupt said. “Menopause isn’t just about hot flashes; the wide array and severity of symptoms experienced goes well beyond hot flashes, which can be highly disruptive on their own.”

A 2021 review published in BMJ Open, which included 497 participants, concluded that probiotic supplementation was linked to significantly higher bone mineral density in the lumbar spine, compared to controls in populations of postmenopausal women. Probiotic treatment may represent “a new concept that could lead to a paradigm shift in osteoporosis prevention,” the authors said. Though studies have been observational, probiotics are linked to changes in inflammatory mediators and cytokines in bone marrow, which might have changed bone cell signals affecting bone homeostasis, the authors noted.⁸

The potential benefit of probiotics in vaginal health, including maintenance of a healthy pH and localized microbiome, has led to a proliferation of products marketed for women. This is based on several studies linking diverse vaginal microbiota to better overall health, and associations with both local immunity and alleviation of gynecological diseases, as described in a review published in Frontiers in Cellular and Infection Microbiology last year.⁹  

Designs for Health recently launched a highly-concentrated probiotic formulation branded as ProbioMed Women featuring 10 clinically-studied strains, including Astarte, a complex of four bacterial strains native in typical healthy vaginal microbiota.

Developmental Nutrition

While prebiotics like human milk oligosaccharides have been popular in infant products, the inclusion of probiotics is drawing interest.

A review published in Nutrients this year discussed many leading bacterial strains in infant health research. Healthy infants treated with certain strains have experienced significantly improved GI conditions, along with beneficial immune responses to infectious events, dermatitis, and allergies in studies to date.¹⁰

Some of the most promising strains, as mentioned in the review, include: B. animalis sp. Lactis Bb-12; B. lactis CNCM I-3446; L. casei CRL431; B. lactis Bb-12; L. paracasei sp. Paracasei strain F19; L. reuteri DSM 17938; L. rhamnosus GG; L. fermentum CECT5716; B. breve CECT7263; and more. 

According to a 2021 review of studies involving probiotic interventions on infants, some benefits have been found for a number of conditions, including diarrhea, colic, regurgitation, IBS/IBD, constipation, ulcerative colitis, Crohn’s, and allergies—though further research is needed.¹¹

This summer, AB-Biotics launched a new supplement for infants, Vitamin D + Probiotic Drops, which contains Bifidobacterium longum CECT 7894 and Pediococcus pentosaceus CECT 8330, a combination shown to balance the gut flora and decrease crying time in infants with colic.

Skin Health

Most probiotic skin benefits are achieved through gut-skin communications along immune pathways, according to Rudy, as is the case with the strain Nutiani HN301, which diminishes inflammation and redness through multiple immune pathways.

“ADM has created two probiotic blends that leverage the skin microbiome and target different aspects of skin health,” said DuBow. “Our AD blend may provide support for skin vitality and clear skin and help improve skin health. Our Smooth Skin blend also has potential to support overall skin health and clear skin. These science-backed probiotic blends are exciting additions to the expanding beauty-from-within segment of the dietary supplements space.”

The Smooth Skin blend was tested in a 12-week randomized, double-blind, placebo-controlled study involving 90 adults with plaque psoriasis. Treatment, in conjunction with corticosteroids, led to greater reductions in psoriasis area, reduced severity, and a lower risk of relapse, compared to corticosteroids alone.¹²

The AD blend was tested in a 12-week placebo-controlled study involving 50 children with atopic dermatitis. It was found that, compared to placebo, the blend of Bifidobacterium lactis CECT 8145, B longum CECT 7347, and Lactobacillus casei CECT 9104 was associated with improved SCORAD (Scoring Atopic Dermatitis) scores.¹³

A recent review published this year highlighted how strains of Nitrobacter, Lactobacillus, and Bifidobacterium can help to reduce the severity of atopic dermatitis, acne, wound healing, and more by regulating skin physiology, noted Nena Dockery, scientific affairs manager at Stratum Nutrition.¹⁴

Gut-Brain Axis

Microbial composition has links to a person’s affect, motivation, and cognitive function, according to a review published in Annals of Gastroenterology. The primary mechanisms of action appear mostly to do with brain chemistry and neuro-endocrine systems associated with stress response, memory function, and anxiety. In clinical practice, evidence is now sufficient to consider functional gastrointestinal disorders like irritable bowel syndrome (IBS) to be gut-brain axis disorders, researchers concluded.¹⁵

DuBow cited a study published last year by a team of researchers at Oxford University in collaboration with ADM Protexin which found that administration of a 14-strain probiotic blend called Bio-Kult in a group of 71 adults for four weeks, resulted in several improvements in emotional processing and cognitive function.

This population, which had mild-to-moderate depression, saw greater accuracy (12%) at identifying and classifying facial expressions (a marker of improved low mood), improved scores for concentration and tiredness, and increased perceptiveness and attention toward non-emotional cues.¹⁶

Another study conducted by King’s College London in conjunction with ADM Protexin found that a probiotic blend was linked to significantly greater improvements in depression and anxiety scores when used alongside standard antidepressant medication, compared to antidepressants alone. The results tracked over eight weeks suggested the potential that probiotics have as an adjuvant therapy alongside standard antidepressants, authors said.¹⁷

Beyond mood parameters, early-stage research is now uncovering potential benefits on cognitive performance level, Dockery said, such as memory improvements in cognitive disorders, as noted in a 2021 review published in Pharmacology Research.¹⁸

Relatively short-term supplementation can achieve lasting effects on the gut-brain connection. In a study published in September, a proprietary combination of L. fermentum LF16, L. rhamnosus LR06, L. plantarum LP01, and B. longum 04 marketed as Bifizen by Probiotical was linked to significant improvements in research-validated questionnaires on sub-clinical depression and anxiety in a population of 70 adults.

These significant differences were maintained three weeks after the nine-week treatment period, suggesting lasting effects even after the washout period. Blood concentrations of serotonin were significantly higher after treatment, and serotonin levels remained elevated even after the three-week washout period. While circulating serotonin can’t cross the blood-brain barrier, the researchers hypothesized that it may serve as a surrogate signal of other metabolites which mediated the positive mood changes.¹⁹

The inclusion of prebiotic fibers in clinical studies on the gut-brain axis has also been notable, according to Dockery. Bimuno, a branded galactooligosaccharide (GOS), has been linked to improved gastrointestinal health issues and reductions in antisocial behavior in a study population of 30 autistic children, as well as improvements in cognitive parameters in a group of psychosis patients.^20-21

Stability and Survivability

Functional foods with spore-forming probiotics are making microbiome solutions more recognized and accessible to consumers, said Dockery. In certain applications, like shelf-stable foods for instance, spore-forming probiotics like Bacillus coagulans offer clear inherent survivability advantages, Dockery noted.²²

Microencapsulation is the leading technology used to preserve live bacteria in supplements, but the key challenge is that a balance must be struck between protection and CFU count, noted Dockery.

“Spray-drying and freeze-drying techniques as well as extrusion technologies have been used for years to protect probiotics in encapsulated formulations. These technologies have improved over the years to increase viability all the way from the production line to their destination in the lower GI tract. And, in recent years, more technologies have been developed including vacuum drying, microwave drying, emulsification, and electro-spraying, among others. They all have advantages and disadvantages,” she said.

Lallemand has been responding to demand for functional food and beverage formats for probiotics through its internal bioprocess and galenic forms platform, and has added lozenges and orally-dispersible stick powders to its list of gut health applications compatible with probiotics, noted Binachon.

In combination with Aventus, the owner of Nutrajit technology, the company has developed the patent-pending GUARD technology, which forms a gel in acidic conditions to protect active ingredients like probiotics in the stomach. The gel eventually dissolves in higher pH conditions found in the large intestine. To minimize risk for bacteria in processing conditions, the ingredient is added during powder blending, so no additional step is needed in production of blends in capsules.

Srikanth Ineedi, senior marketing manager of dietary supplements and gut health at dsm-firmenich, said that relying on the strength of strains with an inherent resistance to gastric conditions is a more reliable move than the “mostly unsuccessful” microencapsulation, enteric coating, or delayed release technologies.

“Synthetic enteric tablet coatings are the most commonly used method for protecting bacteria strains inside and outside the body … but with demand for clean label products heating up, supplement brands are searching for new, natural protective solutions,” said Carin Siow, senior pharmaceutical application scientist at Roquette.

Roquette recently launched a new grade of its excipient Pearlitol, called Pearlitol ProTec, which is a co-processed mannitol-starch especially suitable for probiotic-containing formulas due to having a water activity value of less than 0.2, moisture content below 1%, and good “ compactability performance.”

The More the Merrier?

Leading developers in the probiotics market are creating products with longer lists of strains, prebiotics, postbiotics, enzymes, bacteriophages, and more. Whether longer ingredient lists are a good thing depends on a lot of factors, including what a brand’s goals are, or who you ask.

“Multifunctional products that provide a suite of benefits are of great interest, but a ‘Swiss-Army Knife’ probiotic doesn’t exist, nor should we expect it to,” said Haupt. “We need to think carefully about complementary mechanisms and health areas that can be addressed with multiple solutions in a single product, including pre- and postbiotics, and other microbiome modulators.”

“Probiotic supplements should be formulated to contain strains that complement each other regardless of whether they are transient or native-derived strains, but often formulators aren’t aware of potential interactions between strains,” Dockery said. “In most cases, more strains are not better. A few good strains that have known functions in the gut and ‘play well together’ can usually provide the best outcome for the consumer.”

In multi-strain probiotic formulas, there can be up to 50 billion CFUs per serving, noted Binachon. It’s important to note “what the promised concentration at the end of the shelf-life is versus concentration at the time of manufacturing,” she said. “A greater number of probiotic strains does not always translate to increased health benefits. The best dose is the one tested in human clinical trials showing significant results.”

Postbiotics are a relatively new category in the ‘biotics’ space, but will likely be featured more as a primary or standalone ingredient as clinical research establishes such use cases, said Ineedi.

“Some of the more exciting research is on postbiotics, such as LBiome … Since postbiotics are non-viable and are usually heat-treated microorganisms, they are considerably more shelf-stable and versatile in their use in all populations, even children and persons who are immune-compromised,” said Dockery, noting that the fermentate of these inactivated bacteria is usually the source of benefits.

ADM has been responding to increased demand for the heat-killed version of one of its flagship probiotics. “Earlier this year, we opened the world’s first production facility with both probiotics and postbiotics produced at the same time,” said DuBow. “The Valencia, Spain facility supports global supply of our award-winning probiotic BPL1 [Bifidobacterium animalis subsp. lactis CECT8145] and heat-treated BPL1 postbiotic, which are noteworthy for targeting aspects of metabolic health.”

Preclincial and early clinical studies suggest that ADM’s Active Lifestyle Blend, which consists of ES1 (Bacterium longum CECT7347), BPL4 (Lactobacillus casei CECT9104), and BPL15 (Lactobacillus rhamnosus CECT8361), has been linked to positive changes in biomarkers related to post-exercise oxidative stress, a component of exercise recovery. ²³

While multi-strain formulas can offer a wider net of health benefits or synergy, interactions across various microbial environments aren’t well-understood, Rudy noted, and it can be challenging to avoid antagonistic effects or reduced efficiencies.

On the other hand, one or just a few strains can offer more targeted benefits, with fewer strain-strain interactions and lower risk of adverse effects, but benefits might be more limited.

While formulations containing a high number of strains may seem appealing to consumers, it’s important to remember that these combinations often have never been tested in finished form, and synergistic activities tend to occur in smaller combinations of three or four strains, said Audivert. “It’s essential to emphasize that the true measure of efficacy lies in the clinical evidence supporting the blend’s health benefits.”

A Deep Knowledge Gap

Despite advancements, the field of probiotics research is still defined by many fundamental, unanswered questions and inconsistencies.  

“In some instances, the degree of granularity we’re able to uncover opens the door to novel research mechanisms and opportunities, while in others, we find ourselves encountering new questions, which is a good thing,” said Haupt.

Ineedi noted that while effects like inhibiting pathogenic bacteria, supporting growth of other good bacteria, producing metabolites, and maintaining low pH are well-understood, the mechanisms behind the majority of systemic benefits aren’t.

Even separation of causality from correlation is often lacking, Rudy said. “There’s still much to learn about the vast array of metabolic activities the microbiome performs. This includes its role in nutrient synthesis, drug metabolism, and impact on host metabolism.”

There are many reasons that research on probiotics is inconsistent, Dockery noted, such as the fact that many endpoints rely on multiple bodily processes or other environmental factors, inadequate study designs, and genetic variability across individuals which affects the microbiome.

“One of the biggest knowledge gaps continues to be in the understanding of how strong and influential, yet delicate our microbiomes are, and how easily they can be compromised by dietary habits, lifestyle choices, and medications,” Dockery said. “Pathogenic and opportunistic microbes are often much more resilient and will sneak back in if there isn’t an effort to restore healthy, beneficial microorganisms.”

Most probiotics sold today are studied in a very narrow group of people, often with one ethnicity and located in one region. Outside of small homogenous or condition-specific groups, it’s hard to predict the usefulness of a probiotic, Dockery added.

“There are several times more genes within the gut microbiome than there are within a human’s own genome, and these genes are extremely diverse,” Dockery said. And statistical and computational models are just beginning to effectively predict how successful an intervention might be. Mechanistic models like a metagenome-scale model called MICOM, which can provide better data across diverse populations and simulate certain population groups, are still highly limited by their reliance on existing knowledge bases.

While it can be easy to gather individuals’ details, creating dynamic product combinations at scale is a daunting task, and predictive technology is still creating more questions than answers.

The first steps will be allowing individuals to track their responses to products, and know when benefits might be waning, Haupt said. “Precision nutrition incorporates multifactorial components including age, sex, ancestry, epigenetics, specific polymorphisms in genes related to your metabolite or physiologic process of choice. Additionally, consumers are increasingly taking data into their own hands via non-invasive sleep monitoring tools, as well as continuous glucose monitoring.”

“Lallemand Health Solutions is involved in one of the most ambitious data collection projects going on now called the French Gut, which is part of a vast international project, the “Million Microbiome of Humans Project (MMHP), bringing together several research institutes around the world to constitute the largest global database of human microbiota with a million samples,” Binachon said.

The French Gut project seeks to collect intestinal metagenomes from 100,000 French people along with nutritional and clinical data for analysis. It’s supported by INRAE, the French National Research Institute for Agriculture, Food, and the Environment, in close association with the Assistance Publique – Hôpitaux de Paris (AP-HP), a university hospital center which receives 8.3 million patients yearly in its 38 hospitals. The project is part of INRAE’s MEtaGenoPolis unit which seeks to create an encyclopedic amount of metagenomic data on 100,000 stool samples by 2027.

Probiotic-specific regulations throughout the world are slow in coming, despite the explosion of interest in the human microbiome. In the EU, for instance, lack of harmonization is causing labeling issues and consumer confusion, Dockery said. Even with organizations such as the International Scientific Association for Prebiotics and Probiotics (ISAPP) establishing consensus definitions, terms are still used inconsistently.

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