The formal concept of prebiotics was first introduced in 1995 (1) and has since been redefined as research has expanded our understanding of how prebiotics in foods and supplements contribute to health. The current scientific consensus led by the International Scientific Association for Probiotics and Prebiotics (ISAPP) defines prebiotics as "a substrate that is selectively utilized by host microorganisms conferring a health benefit" (2). However, EFSA considers ‘prebiotic’ as an implied health claim and there is no guidance in order to obtain a prebiotic health claim in Europe.

A significant challenge for European health claims in general is establishing a direct cause-and-effect relationship between the ingredient and the health benefit, a key requirement set by EFSA for health claim substantiation. A prebiotic health claim would require a further relationship established between the prebiotic-induced microbiota changes and the health benefit.

The European branch of the International Life Science Institute (ILSI) has taskforces comprised of academic and industry scientists which are active in the science of prebiotics and non-digestible carbohydrates. Activities included a monograph explaining prebiotics as well as reviews advancing their scientific knowledge (3-6) . In addition, ILSI Europe led a workshop highlighting research gaps and documentation challenges while proposing steps toward obtaining authorization for the use of "prebiotic" in future EU health claims (7).

This article discusses the current regulatory status for potential prebiotic health claims in Europe as well as the status of science knowledge that would be required to support such physiological health benefits.

The EFSA evaluates health claims according to the EU Nutrition and Health Claims Regulation 1924/2006 (8), based on: (a) clear characterization of the food or constituent, (b) defined physiological benefits, and (c) evidence of a cause-and-effect relationship. In general, EFSA has a high standard for assessing the clinical and mechanistic evidence for an ingredient health claim. To substantiate specifically a ‘prebiotic’ health claim, EFSA would require that a causal relationship between an increase in certain bacteria and a physiological benefit be established. EFSA has issued guidances for studies and clinical trials that provide the necessary documentation for health claim applications such as gut health and immunity, however, there is an absence of EFSA guidance on documenting prebiotic mechanisms and benefits. Consequently, EU member states have issued varying regulatory guidance on the use of ‘prebiotic’ and similar terms like "probiotic" in food and supplement labelling. Most member states align with the European Commission’s stance that ‘prebiotic’ is considered an implied general health claim, and thereby, may only be considered for an established prebiotic provided accompanied by an authorized health claim under Articles 13 or 14.

Although a prebiotic health claim and the prebiotic term has no guidance nor is included in the EU register of health claims, certain food ingredients recognized as prebiotic have received EFSA-approved health claims. For example, chicory inulin, well-established prebiotic, has an EC authorised health claim for improving stool frequency or digestive health (9).

Recently ISAPP have published an expert recommendation or scientific framework for the classification of compounds as prebiotics, including useful methodologies, and statistical approaches to establish causal links between selective microbiome and health effects (10). The minimum criteria needed to classify compounds as prebiotics was also addressed, such as besides clinicals performed in the host, also both the selective microbiome and physiological health effects should be demonstrated in the same trial. They also addressed topline the regulation of prebiotics and communication to consumers globally.

Furthermore, in order to facilitate the development of an EFSA scientific guidance for ‘prebiotic’ health claims, ILSI Europe hosted a workshop in 2023 with academic and industry scientists and regulatory experts who came to the following proposal for a roadmap for an EU health claim for ‘prebiotic’ (Figure 1) (7).

Figure 1. A roadmap for an EU health claim on 'prebiotic'. Adapted from Tuohy et al., 2024 (7).

Altogether, these initiatives are essential to develop both strong scientific criteria and eventually support European regulation to give credibility to prebiotic health benefits.

Initially, research on prebiotics focused on their ability to selectively stimulate the growth of gut microbes bifidobacteria and lactobacilli, and this has been documented over the decades for inulin and GOS (11). Advances in high-throughput sequencing and molecular analysis have since revealed that prebiotics can selectively enhance a broader range of beneficial microorganisms beyond these two groups (10). It is noteworthy that the ISAPP definition extends beyond oligosaccharides or fibers to include non-carbohydrate compounds like polyunsaturated fatty acids and polyphenols (2). Studies have demonstrated that certain oligosaccharides such as acacia fiber, inulin, and fructooligosaccharides stimulate beneficial microbes, including bifidobacteria and via cross feeding butyrate producers (11-13). Novel techniques such as multiplex community sequencing are being employed to gain a deeper understanding of how prebiotics influence the gut microbiota (14). Another challenge is establishing definitive links between microbiome modulation and specific health benefits, which recent recommendations can support (10).

However, another key aspect to advance regulatory approval, is well-designed clinical trials with outcomes assessed by validated and robust methodologies and plausible mechanisms for such benefit. Some promising benefit fields are discussed below.

Digestive Health: EFSA has outlined scientific requirements for substantiating digestive health claims, including those related to bowel function, gastrointestinal comfort, and nutrient digestion. Acceptable measures include validated symptom questionnaires and biomarkers (15). Numerous studies have shown that inulin-type fructans can stimulate bifidobacteria growth and bacterial biomass, enhance short chin fatty acid (SCFA) butyrate levels, due to gut bacterial cross-feeding by butyrate producing microbes such as Faecalibacterium prausnitzii (3, 11). Chicory inulin has an authorised health claim for increasing stool frequency, and EFSA made the mechanistic link that it was caused by enhancing bacterial fermentation and fecal bulk (9).

Some other dietary fibers have EC health claims for improving bowel habit, for example, sugar beet fiber (16), as well as the disaccharide lactulose, which accelerates intestinal transit by increasing osmotic pressure and acidifying the colon (17). While there is evidence for various dietary fibers/ingredients for improving digestive health, they may lack documented selective effects on the gut microbiota or may improve digestion by alternative noon-microbiota mechanisms and thus may not comply with the prebiotic definition.

Metabolic Health: The potential metabolic benefits of (candidate) prebiotics have been explored in animal and human studies. Research is intensifying in this field currently due to the use of medications such as GLP-1 receptor agonists for diabetes and obesity. It is noteworthy that non-digestible carbohydrates like FOS and galactooligosaccharides (GOS) have approved EC claims related to lowering blood glucose (18). Human studies have shown that diets high in inulin-type-fructan (ITF)-rich vegetables increase satiety and reduce cravings, contributing to reduced nutrient intake and weight loss in people with obesity (19, 20). Recently a systematic review and meta-analysis supported improved weight management outcomes for chicory ITFs (21). Various mechanisms are implicated such as the SCFA production site in the body, i.e. the proximal versus the distal colon, but also the impact of SCFA or the altered gut microbiome on the hormones in the body, such as GLP-1, PYY, ghrelin amongst others, which may influence metabolic outcomes (22). Despite promising results, a direct causal link between prebiotic or dietary fiber-induced microbiome changes and improved metabolic markers remains unproven, necessitating further research.

Immune Health: Dietary fibers and prebiotics may influence immune function both directly but also indirectly through microbiota-mediated mechanisms. In vitro and animal studies suggest that certain dietary fibers and prebiotics enhance immune responses by at least the following mechanisms: (a) increasing SCFA production during fermentation and SCFA are implicated in stimulating immunity (23); (b) modulating Toll-like receptor (TLR) signalling e.g., pectin inhibiting TLR-2 (24); and (c) demonstrating immune-modulating effects influenced by chain length, e.g., for inulin-type fructans in human vaccination trials (25, 26). However, challenges in human studies persist due to interindividual variability in immune responses due to ingredients, and perhaps more so for prebiotic-modulated microbiota effects. EFSA has guidance for defence against pathogens as well as beneficial change in response to allergens, though there are no validated biomarkers of the immune effect of dietary interventions except for vaccination trials (15).

Cognitive and Mental Health: Research on the gut-brain axis has spurred interest in prebiotics for cognitive function. There has recently been a thorough review on the evidence of prebiotics to promote cognitive functioning, as well as highlighting the knowledge gaps and proposing recommendations to progress this field (4). Most findings so far arise from animal models and or in vitro studies, while the number of human studies to date remains limited. Nevertheless, there is some evidence to give just two examples. A recent study demonstrated that the 12-week intake of prebiotic ITFs in healthy twins aged 60 years or above resulted in improved cognitive function, particularly in relation to associative learning and memory (27). Another human study showed that GOS consumption produced cognitive benefits in medicated psychosis patients (28). Much evidence has shown that organic acids and other microbial metabolites produced by intestinal bacteria, can cross the blood-brain barrier and may exert neuroprotective and anti-inflammatory effects important for brain health (29). There is a risk that human cognitive tests used in prebiotic research may lack sensitivity to nutritional effects, however technologies such as functional Magnetic Resonance Imaging (fMRI) with mental assessments can support trials in this field.

There will undoubtedly be significant fundamental developments in emerging prebiotic benefit areas, particularly with the rapidly evolving fields of gut-lung, gut-liver, gut-immune-brain and skin health axes (10, 30, 31). To ultimately establish prebiotic health claims in Europe, high-quality randomized controlled trials (RCTs) are essential for demonstrating clear cause-and-effect relationships. These trials should be supported by robust statistical analyses, and artificial intelligence and machine learning technologies applied to in vitro models or trial data can help confirm, for example, that microbiome modulation is causally linked to specific health benefits. A current challenge in achieving prebiotic health claims is the lack of universally accepted biomarkers, particularly in areas like immunity and intestinal health. Additionally, individual variability in microbiota responses to dietary interventions can confound outcomes, making it difficult to generalize results. Strategic cross-disciplinary collaboration and partnerships, in academic fields and with the industry, is vital to address these challenges. Approaches involving machine learning, metagenomics, and metabolomics to analyze complex datasets from microbiota and human samples, may facilitate identification of biomarkers, and the prediction of individual microbiota responses and thus potential outcomes of human interventions. This could also facilitate the development of personalized nutrition strategies based on an individual’s gut microbiota composition or blood markers, which would be essential for optimizing prebiotic interventions and securing health claims (10, 30).

Navigating the regulatory landscape to achieve authorization for prebiotic health claims is essential for the industry as solid scientific evidence and substantiated claims in Europe will give consumer trust for foods and beverages with these claims. It is important that the academic community are in accordance with the science. In addition, educating consumers about the regulatory approved benefits of prebiotics through marketing and informational campaigns can build trust for prebiotic products. Ultimately, these strategies along with innovations in research and technologies, will be critical in advancing prebiotic health claims for better health.

In the scientific community, ‘prebiotic’ is well defined and accepted, and certain ingredients comply to the prebiotic criteria of selective microbiota effects with a health benefit. Despite the clear scientific support, the EU regulatory framework doesn’t have guidance for prebiotic claims as in other regions of the world. The EU regulatory framework for health claims is challenging due to the high standards in proving direct cause-and-effect relationships for food ingredients in general to show health effects. Advancing research methodologies, harmonizing regulatory approaches, and industry investment in high-quality clinical trials to substantiate health claims are crucial for obtaining European authorized health claims for prebiotics. The scientific criteria for ‘prebiotic’ and the proposed roadmap toward the development of prebiotic-specific health claims can stimulate further discussions and activities eventually for innovative food products with scientifically proven prebiotics with health claims substantiated for the European consumers.