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Digesting the Evidence – Latest Research and Commercial Implications for Oral Enzyme Supplements (2024)

Published on 20 March 2024
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As relative newcomers to the dietary supplements market, digestive enzymes are still finding their footing. Formulated to mimic the enzymes naturally produced by the pancreas to absorb nutrients, the theoretical health benefits of digestive enzymes cover an extensive range of digestion-related symptoms and disorders. The wellness and self-care movements, as well as an aging population with increased prevalence of digestive disorders, have resulted in above-market growth in demand for enzyme supplements1. As a consequence of this increased interest, major media platforms published pieces questioning the benefits of wide-scale enzyme supplementation, particularly for generally healthy individuals. In response, enzyme manufacturers are diversifying their formulations and investing more into clinical research. The result will be a more fragmented market, with various condition-specific enzymes designed to meet the needs of specific consumers segments.

In this paper, we discuss some of the latest research conducted on enzyme supplementation and the commercial implications for different health indications. Although consumers understand much more about the causes of their digestive problems than ever before, the success of enzyme supplements will still depend on how well the industry players can communicate the results of this research to consumers.

Boosting absorption of vital nutrients from foods

Amino acids, the building blocks of proteins, are crucial at every stage of life but their importance becomes particularly critical in older ages to avoid falls or fractures and sarcopenia. Maintaining a healthy and balanced diet is essential for healthy aging and yet a 2021 research indicated that up to 46% of the 71+ year old population in the USA are not meeting the recommended protein intake levels.2 Moreover, macronutrient deficiency is a shared global concern, with less economically developed countries exhibiting deficiencies across all age groups due to socio-economic factors. So, if increasing protein consumption is a challenge, could enzyme supplements provide a solution by enhancing the absorption of vital nutrients from foods without increasing quantity of intake?

Plant-based proteins have a sub-optimal digestion when compared to animal proteins. In a randomised, double-blind, cross-over study published in September 2023 (1) supplementation with a 3-protease enzyme blend in healthy adults resulted in earlier release of amino acids into blood circulation. Outcomes show that co-ingestion of a microbial protease blend with a single 25g pea protein allowed for an elevated exposure to postprandial plasma total of amino acids over the 5-hour period after pea protein consumption. The plasma amino acid concentrations were measured using liquid chromatography/mass spectrometry over the 5-hour period with P-3 enzyme blend versus placebo.

This trial suggests that taking enzyme supplements may be effective in increasing the amount of amino acids absorbed from a meal, essentially providing a greater health benefit without increasing the amount of food consumed (note that subjects only consumed a single dose of pea protein, making the effectiveness of the P-3 enzyme blend unclear for different dosages).

Approximately 75% of the world’s population lose their ability to digest lactose as they get older, due to  a gradual decrease in the production of lactase enzymes.3 Cow’s milk, and dairy products that contain lactose, are also considered FODMAP4 foods, which are often avoided by people with digestive issues. At the same time, dairy products also contain proteins which are essential for healthy aging. Those who are lactose intolerant or suffer from gradual lactase deficiency generally choose to avoid consuming cow’s milk or similar dairy products to prevent abdominal pain and indigestion. But what if getting old didn’t mean cutting down dairy or FODMAPs?

In a randomised, controlled, double-blind trial that was completed in September 2023 (2) participants experiencing functional dyspepsia took either 2 capsules a day of a 200 mg. multi-enzyme blend (protease, amylase, lipase, cellulase and lactase), or a placebo, along with their normal diet. The subjects filled in the Nepean Dyspepsia Index-SF (NDI-SF) Questionnaire, the Pittsburgh Sleep Quality Index Questionnaire, and Visual Analog Scale (VAS). Results showed an improvement in NDI-SF1, a decrease in NDI-SF2-5 scores, and a decrease in VAS scores, indicating a positive effect on quality of life and severity of pain experienced. It is important to note that, although participants were instructed not to change their regular “normal” diet, no details were provided on their dietary habits, which could influence results.

In a smaller clinical trial that was completed in January 2023 (3), twenty healthy adults with self-reported bloating or abdominal distension co-digested an enzyme blend of 18 digestive enzymes or a placebo pill along with a test-meal (two slices of pizza), with a washout period of 1 week between the observations. Participants’ waists were measured for visible changes in stomach distension and questionnaires were administered both prior and after consuming the test meal to assess the perceived changes in bloating and stomach distention. Overall, 80% of participants had less waist distension (as measured by waist circumference) after consuming the enzyme and 65% reported less stomach discomfort. The findings suggest that the enzyme supplement was effective and well-tolerated in addressing abdominal distension and bloating related symptoms. That said, the enzyme supplement tested in this trial also included herbs such as fennel seed, ginger root and pepper mint leaf, which may have contributed to the beneficial effects observed.

Besides lactose, there are also fructan-type FODMAPs that are found in vegetables and fruits which can cause digestive discomfort or gut inflammation in some individuals. A common strategy is to avoid the foods which cause discomfort; however, enzyme supplements could also play a role in breaking down FODMAP fructans. In an in vitro experiment published in May 2023 (4) it was found that even a small quantity of inulinase enzyme could effectively break down fructans. The experiment was carried out using the INFOGEST protocol to simulate the conditions present in the human digestive system. It was demonstrated that exogenously supplied inulinase enzyme remained active and stable in the acidic conditions of the stomach, and it suggested that inulinase-mediated fructan hydrolysis in the stomach with inulinase supplementation could also promote growth of beneficial gut microbes. The paper acknowledges the downside of inulinase supplementation, namely that inulinase would hike up the availability of fructose from fructans. Excess fructose consumption has been linked to health issues such as obesity, diabetes, and hypertension. Researchers must take this into account when designing a follow-up study on human subjects.

Apart from being considered a FODMAP, cow’s milk contains whey protein, which is a high-quality protein which includes leucine – one of the essential amino acids in muscle building and recovery. In contrast to plant-based proteins, whey-protein – especially whey-protein isolate- is easily digested by most people. An in vitro INFOGEST5 protocol compliant experiment published in September 2023 (5), showed that oral microbial protease enzyme supplementation (3-protease) can also enhance the total amino acids (TAA), essential amino acids (EAA), branched-chain amino acids (BCAA), and leucine release from whey protein. The results demonstrated a dose-response relationship, whereby higher doses of P3 enzyme led to greater increase in TAA, BCAA and EAA concentrations. This was a “simulated” gastric digestion according to the INFOGEST protocol and the paper acknowledges that digestion is a complex process and that results might differ in human trials. Further, the experiment only covered the 2 minute “oral salivary phase” and 2 hour “gastric phase” of digestion,  meaning it excluded the “intestinal phase” of the protocol. Complete postprandial results, which take a longer duration, have therefore not been observed.

These findings suggest that enzymes are effective in addressing indigestion and abdominal pain. In context of healthy aging, accommodating dairy and FODMAPs consumption could also be crucial in addressing macronutrient deficiencies and increasing protein intake.

Aging is associated with systemic low-grade inflammation. A gradual increase in inflammatory markers in the body – even without an infection or an injury- is thought to result from senescence of immune cells and alterations in the gut microbiota.6 This “inflammaging” process is thought to contribute to age-related diseases from cardiovascular diseases to cancer. Recent research on enzyme supplements also focused on the anti-inflammatory and pain-relieving effects. Could emphasizing the anti-inflammatory effects of enzymes allow them to break into the anti-aging market?

In a prospective, randomised, double-blind, placebo-controlled trial whose results were published in July 2023 (6), the effect of pre- and post- operative use of an oral enzyme blend supplementation (90 mg. bromelain, 48 mg trypsin, 100 mg rutoside) on inflammation and pain in patients receiving an elective total hip replacement surgery was studied. Over the course of 8 weeks spanning both before, during, and after the operation, 33 subjects digested an enzyme blend or a placebo without a meal. Changes in systemic inflammation (CRP), self-reported hip pain at rest, analgesic use, oedema (thigh and calf circumference), cumulative Redon drain discharge volume, temperature, Harris Hip Score (HHS), patient-rated Patient Global Impression of Change (PGIC), and the Clinical Global Impression-Improvement Scale (CGI-I) were recorded. Results indicated a reduced level of systemic inflammation (CRP) and less self-reported pain during the early phase (days 1-7). Reduced inflammation is related to better outcomes and the enzyme group also demonstrated 32% lower CRP levels.

An article from January 2023 (7) highlighted the anti-inflammatory or pain-relieving effect of enzyme supplementation (bromelain, trypsin and flavonoid rutin). It showcased 3 case studies of patients with different inflammatory conditions: persisting asthenia and polyarthalgia (Patient 1), psoriatic lesions and polyarthalgia (Patient 2); knee osteoarthiritis and obesity (Patient 3). In all three cases, patients were treated with a lifestyle change intervention consisting of diet, exercise, and enzyme supplementation. The levels of inflammation were tracked with reference to CRP. In all three cases, CRP levels decreased considerably (to normal levels) once enzyme supplements were initiated. A key limitation of these cases was their reliance on CRP as the only measurement of inflammation.

The landscape of oral enzyme supplements in 2024 presents both opportunities and challenges in meeting consumer needs. As highlighted by recent research, enzyme supplementation shows promise in addressing a variety of digestion-related health concerns, However, the commercial viability of enzyme supplements hinges not only on evidence but also on effective communication and product differentiation in a rapidly evolving market rife with scepticism. A nuanced understanding of both the data available and consumer preferences will be crucial to meet the demands of an increasingly health-conscious population. By embracing these insights and fostering collaborations between industry stakeholders, the growth potential for oral enzymes remains significant.

Sector & Segment has extensive experience supporting companies through every stage of launching a new product or campaign. Some of our areas of expertise include:

  • Translating scientific research into compelling consumer marketing;
  • Sizing market demand and identifying key client segments;
  • Developing a tailored go-to-market strategy;
  • Concept testing new products or campaigns with consumers and healthcare professionals.

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  • Deutz MT, Kevin JM Paulussen, McKenna CF, Askow AT, Barnes TM, Garvey SM, Guice JL, Tinker KM, Paluska SA, Ulanov AV, et al. 2023. Microbial Protease Supplementation Potentiated The Early Net Exposure To Postprandial Amino Acids In Healthy Adults. Medicine and Science in Sports and Exercise. 55(9S):920–920. doi: 10.1249/01.mss.0000988400.30134.b1

  • Ullah H, Di Minno A, Piccinocchi R, Buccato DG, De Lellis LF, Baldi A, El-Seedi HR, Khalifa SAM, Piccinocchi G, Xiao X, et al. 2023. Efficacy of digestive enzyme supplementation in functional dyspepsia: A monocentric, randomized, double-blind, placebo-controlled, clinical trial. Biomedicine & Pharmacotherapy. 169:115858. doi: 10.1016/j.biopha.2023.115858

  • Martin-Biggers J. 2023 Oct 13. A digestive enzyme and herbal dietary supplement reduces bloating in a single use in healthy adults: A randomized, placebo-controlled, cross over study. Research Square (Research Square) (Preprint). doi:
  • Guice JL, Hollins MD, Farmar JG, Tinker KM, Garvey SM. 2023. Microbial inulinase promotes fructan hydrolysis under simulated gastric conditions. Frontiers in Nutrition. 10. doi:
  • Sidney Abou Sawan, Garvey SM, Tinker KM, Guice JL, Bashir R. 2023. Microbial Proteases Enhance Amino Acid Release From Whey Protein Under Simulated Salivary-gastric Conditions. Medicine and Science in Sports and Exercise. 55(9S):921–921. doi:
  • Jiří Vosáhlo, Salus A, Smolko M, Barbora Němcová, Nordmeyer V, Mikles M, Rau SM, Odd Erik Johansen. 2023. Oral enzyme combination with bromelain, trypsin and the flavonoid rutoside reduces systemic inflammation and pain when used pre- and post-operatively in elective total hip replacement: a randomized exploratory placebo-controlled trial. Therapeutic Advances in Musculoskeletal Disease. 15. doi:
  • Pelosi E. 2023. Effect of oral enzyme combination, diet and exercise on chronic low-grade inflammatory conditions—a report of three cases. AME Case Reports. 7:7–7. doi:

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