Native (undenatured) type II collagen maintains intact the triple helix structure and enhances joint health by means of a specific immune mediated mechanism of action known as oral tolerance (9). Oral tolerance has been defined as the active suppression of specific immune responses to antigens first encountered in the gastrointestinal tract and represents a mechanism to protect from inappropriate immune responses to harmless antigens (10). In summary, antigens are recognized by antigen-presenting cells in the gut-associated lymphoid tissue (GALT) and favour the differentiation of T cells (Tregs) which in turn, modulate the immune response inducing immune tolerance (9). The oral tolerance to type II collagen seems to result in cartilage protection in models of arthritis through the control of the articular inflammation (11, 12). Interestingly, it was demonstrated that when the triple-helix is denatured, this specific mechanism is lost (11). The mechanism of oral tolerance was initially evaluated for autoimmune conditions which is not the case of OA. However, there is evidence suggesting that deregulations of the immune response have an impact on disease pathogenesis (13). In OA, structural changes of joint tissues are driven by mechanical factors and also by inflammation (14). It has been suggested that cartilage fragments could have a role as autoantigens responsible to trigger inflammation (15). In fact, human intervention studies have confirmed the potential of the oral tolerance mechanism to support joint health in different conditions including OA (Figure 2).

Clinical research on supplementation of native (undenatured) type II collagen has mainly focused on its potential therapeutic benefits for joint health. Many randomized, double-blind, placebo-controlled studies showed the improvement on joint mobility and the reduction of joint pain in healthy athletes and runners with knee pain (16-18) and in adults with osteoarthritis (19), compared to placebo. Moreover, a clinical trial compared native type II collagen versus placebo versus the standard clinical treatment of chondroitin sulphate and glucosamine chloride, obtaining remarkable differences compared to placebo and the highest significant improvements in relevant measures of pain (WOMAC score) (20). On the contrary, another study carried out during only 3 months could not see these superior effects (21). Nonetheless, more clinical studies should take place to guarantee the efficacy and safety of native type II collagen and to have more valuable data to ensure it is a valuable treatment to reduce joint discomfort. The most common and accepted parameters to assess the effectiveness are the WOMAC and VAS score, which give a punctuation based on the level of pain of the participants along the clinical study (22).

Interestingly, most of the studies, the tested dose is 40mg/d during a period of 3 to 6 months. This daily dose is low as compared to the dose recommended for hydrolysed collagen (up to 10g/d) (6). For this reason, besides its common use as an ingredient for food supplements, native (undenatured) type II collagen has also been positioned as a potential ingredient for functional foods.

In addition, consumers are looking for alternative formats apart from pills, capsules, and soft gels. The preferred alternatives are gummies, which have grown a 75% in 2021 representing a 21,3% of the non-pill market share (4). Nonetheless, the development of functional foods entails some challenges, such as modifications of the bioactive ingredient due to the conditions encountered during the food manufacturing and extrusion processes, and the development of specific methods of analysis to detect the ingredient in food matrices (23).

Native (undenatured) type II collagen could be especially sensitive to the technological challenges of the food manufacturing processes, because to maintain the biological effects, it is required to preserve the triple helical structure intact. These affecting conditions encompass temperature, humidity, and low pH (24, 25). For instance, during the processing, protein is especially prone to changes in its digestibility and bioavailability (26) and in the extrusion processing, thermal degradation can lead to the denaturation of collagen (27).

In summary, there is a clear opportunity for the development of functional foods containing native type-II collagen, but the nature of the ingredient would require the development of specific production methods to ensure that the ingredient is successfully incorporated into each food matrix preserving its specific biologic activity.

Joint health has become an important public health concern globally. Among joint health ingredients, collagen has emerged as a focus of particular interest. Even though, there are different collagen ingredients with different structures, compositions, and biological effects, native (undenatured) type II collagen is an ingredient characterized by the preservation of triple helix structure. This ingredient has a specific immune-mediated mechanism known as oral tolerance, that inhibits inflammation and tissue catabolism at articular level. Native type II collagen has been shown to be effective in population with joint discomfort at a dose of 40mg/d. The reduced daily dose allows the possibility to include the ingredient in functional foods, besides food supplements.