Research & Education

Do Proteolytic Enzymes Help Resolve Inflammation?

Inflammation has been getting a bad rap the last several years. Name a chronic non-communicable disease and chances are a mountain of scientific evidence shows it’s associated with inflammation. But as one paper describes it, “Inflammation is a normal response to protect the tissues from various noxious stimuli and is one of the most normal clinical conditions.” Without the inflammatory cascade, serious consequences could come from minor injuries, such as paper cuts or bruised knees. Nevertheless, even this type of acute inflammation must be resolved properly, or long-term adverse effects may develop. The human body obviously has ways of resolving inflammation, but can supplemental proteolytic enzymes help boost this critical process? 

Proteolytic enzymes are often used in orthopedic clinics and in recovery from trauma, typically co-administered with pharmaceutical drugs such as NSAIDs. It is proposed that the activity of proteolytic enzymes is “vital for the control of inflammation by clearing inflammatory debris.” If administration of exogenous proteolytic enzymes can help reduce the doses of NSAIDs needed, this may help decrease risk for some of the adverse side-effects of NSAIDs, such as peptic ulcer, gastrointestinal bleeding and increased risk for heart attack or stroke

A study looking at proteolytic enzymes for resolution of acute inflammation in rats showed that this indeed may be the case. The proteolytic enzymes chymotrypsin, trypsin, and serratiopeptidase were all shown to exert dose-dependent anti-inflammatory activity in the context of carrageenan-induced paw edema and experimentally induced granuloma formation. At the highest doses tested, results with each individual compound were similar to those seen with aspirin given at 200mg/kg (56% reduction in edema). At the lowest doses tested, none of the enzymes showed a significant beneficial effect, but when the lowest doses were combined with lower-dose aspirin (54mg/kg), edema was reduced more than with the higher dose of aspirin in the cases of chymotrypsin and serratiopeptidase, but slightly less for trypsin (43.5% reduction in edema versus 56%). 

Of note, the rats treated with lower dose aspirin and the lowest dose of enzymes showed significantly decreased ulcer index compared to rats treated with the high dose of aspirin. The study authors wrote, “The combination of low doses of these enzymes with sub antiinflammatory dose of aspirin resulted in synergistic antiinflammatory activity without ulcerogenic potential appears to be clinically a beneficial interaction [sic]. If the present findings could be extrapolated to human beings, such combination therapies may reduce the adverse effects of NSAID’s like aspirin.” Turning to research in humans, oral supplementation with proteolytic enzymes may be an alternative for patients with rheumatic diseases who cannot tolerate NSAIDs.

You are likely familiar with trypsin and chymotrypsin as digestive enzymes instrumental in the breakdown of dietary protein. You may be less familiar with serratiopeptidase, a.k.a. serrapeptase or serrapeptidase. This is a proteolytic enzyme produced by native Serratia bacteria in the digestive system of silkworms (it dissolves the worm’s cocoon). Compounds that mimic its effects are commercially available and may be helpful for respiratory conditions, partly by disrupting the formation of bacterial biofilms. Four weeks of oral supplementation with serratiopeptidase reduced the viscosity of mucus in patients with chronic sinusitis. A double-blind RCT showed that, compared to placebo, serratiopeptidase supplementation resulted in reductions in symptoms of acute or chronic ear, nose and throat disorders in as little as four days. Researchers concluded that serratiopeptidase is anti-inflammatory, reduces edema, and acts rapidly on localized inflammation. According to a paper exploring the role of serratiopeptidase in resolving inflammation, “The exact molecular mechanism of serratiopeptidase is not known completely but research findings have demonstrated that enzyme [sic] possesses the unique ability to dissolve the dead and damaged tissue that is a by-product of the healing response without harming living tissues.”

Bromelain, a phytochemical found in pineapple, is a proteolytic enzyme regarded for its beneficial effects on respiratory conditions. It appears to have adaptogenic-like effects with regard to inflammation, helping to reduce inflammation when it is overactivated, and to stimulate it when needed acutely. In vitro data show that bromelain “potentially activates the healthy immune system in association with the rapid response to cellular stress.” (It downregulates COX-2 and PGE-2 expression and activates the inflammatory mediators IL-1β, IL-6, INF-γ and TNF-α.) Conversely, when the immune response is already stimulated and there’s an over-production of inflammatory cytokines, bromelain reduces these factors. 

Nattokinase is an additional compound with proteolytic enzyme activity. Nattokinase is isolated from natto, a traditional Japanese fermented soy product time-honored for its therapeutic benefits. Cardiovascular disease is believed to be driven in part by inflammation, and the Japanese diet has long been recognized for supporting healthy cardiovascular function. This is often attributed to a high intake of omega-3 fatty acids from seafood, but natto may be another contributing factor, as it has been shown to be fibrinolytic and antithrombotic. It inhibits platelet aggregation in animal models and has a modest blood pressure lowering effect in humans with hypertension, with a strong safety profile and an absence of adverse side-effects.  

Supplemental proteolytic enzymes may hold promise for helping those with inflammatory conditions, particularly those associated with edema or buildup of scar tissue. When used in combination with conventional pharmaceutical treatments, proteolytic enzymes may allow for lower doses of the drugs, potentially reducing risk for undesirable effects.