Effect on post-surgical recovery

The typical daily protein intake requirement of an adult is 70 g/d, but this is increased considerably in post-surgical patients who require a protein intake of up to 300–400 g/d⁽Reference Levenson and Lund¹⁶⁾. Surgical trauma leads to an increase in whole-body protein degradation⁽Reference Clague, Keir and Wright¹⁷⁾, with the extent depending on the severity of the insult⁽Reference Tashiro, Yamamori and Takagi^18–Reference Yamamori, Tashiro and Mashima²⁰⁾. These changes in whole-body protein turnover result in a period of negative N balance. Due to the importance of protein nutrition in tissue repair, high-protein diets have been shown to accelerate the rate of tissue regeneration and increase tensile strength of the wound⁽Reference Harvey and Howes³⁾. Protein hydrolysates have also been investigated and a study by Ziegler et al. ⁽Reference Ziegler, Ollivier and Cynober²¹⁾ followed twelve intensive care patients after abdominal surgery and compared the effect of two enteral diets with identical N and energy supply – a lactoserum protein hydrolysate diet and a non-degraded protein diet (control). Compared with the control diet, the protein hydrolysate diet was more effective at restoring plasma amino acid and protein levels; in particular it significantly increased plasma concentrations of thirteen amino acids (including all essential amino acids and BCAA) compared with only two in the non-degraded protein diet⁽Reference Ziegler, Ollivier and Cynober²¹⁾. There was also a significantly greater increase in plasma insulin concentrations 1 h after consumption with the protein hydrolysate diet⁽Reference Ziegler, Ollivier and Cynober²¹⁾. Thus, compared with consuming native protein, the consumption of hydrolysed protein post-surgery may promote greater increases is plasma concentrations of essential amino acids, resulting in an environment that is more conducive to tissue repair, and thus result in a more rapid repair of damaged tissue. However, additional well-controlled human trials are required to confirm this finding.

Effect on severe burn recovery

The stress response to severe burn injury initiates a catabolic cascade that rapidly decreases lean body mass⁽Reference Bessey, Jiang and Johnson^22, Reference Jahoor, Desai and Herndon²³⁾ and the associated depletion of protein stores leads to altered immune function and impaired wound healing⁽Reference Bessey, Jiang and Johnson^22, Reference Jahoor, Desai and Herndon²³⁾. Considerable attention has focused on attenuating this response with early nutritional support, with one study involving the administration of a protein hydrolysate. Demling & DeSanti⁽Reference Demling and DeSanti²⁴⁾ compared the effect of two diets – a standard nutrient supplement (protein intake 1·3–1·5 g/kg per d) and a high-protein diet plus protein hydrolysate (70 g/d; protein intake 1·7–2 g/kg per d) on the recovery of fifteen patients with severe burns. While both groups gained weight and improved muscle strength and endurance, the increase in protein intake with the high-protein/hydrolysate diet increased the rate of restoration of body weight and muscle function⁽Reference Demling and DeSanti²⁴⁾. However, the design of this study did not allow for determination of whether the more rapid recovery was due to either the high protein content of the diet or to the inclusion of the hydrolysate into the diet.

Effect on gastric repair

The benefits of providing hydrolysed protein preparations has been studied in patients with peptic ulcers or gastric haemorrhages who require additional protein intake without adding dietary bulk⁽Reference Levy²⁾. In a group of patients with hypoproteinaemia following gastrointestinal haemorrhage, compared with a standard diet, patients who consumed the standard diet and an additional 150–200 g of protein hydrolysate returned to normal circulating protein levels in 10·2 d, where as those on the standard diet only returned to normal protein levels in 19·5 d⁽Reference Levy²⁾. The patients consuming hydrolysed protein also reported feeling better and stronger, and experienced an improved sense of well-being compared with controls⁽Reference Levy²⁾. Tui⁽Reference Tui¹⁵⁾ also observed improved symptoms and ulcer healing in 164 patients with previously intractable peptic ulcers who were given very high-protein diets in the form of partially hydrolysed protein (0·6 g N/kg/d) in an uncontrolled study.

There are several suggestions regarding how protein hydrolysates might promote the healing of peptic ulcers. The prompt recovery response is thought to be due to a combination of the neutralisation of the acidity of the gastric juice by the strong buffer action of protein hydrolysates, reduced work of digestion due to the protein already being partially digested, and the rapid provision of essential protein components and amino acids for tissue repair⁽Reference Tui¹⁵⁾. Hence the action of neutralisation of the gastric acid in addition to a rich nutrient supply is believed to promote a more rapid tissue repair⁽Reference Tui¹⁾.

Effect on pressure ulcer recovery

Nutritional supplements, specifically high-protein diets, are often used for the treatment and/or prevention of pressure ulcers (bed sores), although the research supporting this use is limited. An association between protein nutrition status and the maintenance of tissue integrity was observed by Mulholland et al. ⁽Reference Mulholland, Tui and Wright²⁵⁾ as long ago as 1943 when they found that low plasma protein levels were associated with the occurrence of bed sores and that the ulcers healed promptly when N balance was restored. This finding was interpreted as suggesting that protein-deficient tissues undergo pressure necrosis more readily than normal tissue⁽Reference Mulholland, Tui and Wright²⁵⁾.

More recently, a study which examined the effect of a collagen protein hydrolysate supplement on pressure ulcer healing demonstrated more rapid healing compared with standard treatment⁽Reference Lee, Posthauer and Dorner²⁶⁾. Seventy-one long-term care residents with pressure ulcers were given standard care plus either a concentrated fortified collagen protein hydrolysate supplement or placebo. Residents who received the supplement and standard care had significantly better healing (combined score for parameters of exudate, wound surface area and tissue type) compared with standard care with the placebo after 8 weeks of treatment⁽Reference Lee, Posthauer and Dorner²⁶⁾. While both groups had decreased scores, indicating healing, the protein hydrolysate group had approximately twice the rate of healing compared with the standard care-only group, indicating that the collagen hydrolysate enhanced the recovery process. However, the mechanism by which the more rapid tissue repair occurred was not identified in this study.

Effect on preventing the development of atopic dermatitis-like skin lesions

Whey protein hydrolysates have also been investigated for their effect on the development of atopic dermatitis-like skin lesions. Shimizu et al. ⁽Reference Shimizu, Dairiki and Ogawa²⁷⁾ compared the effect of a whey protein hydrolysate, casein and a casein protein hydrolysate diet on the development of atopic dermatitis-like skin lesions induced by mite antigen in NC/Nga mice. Thirty-five mice were fed one of the diets for 2 weeks before and during 4 weeks of mite antigen application. Whey protein hydrolysate-fed mice showed significantly less atopic dermatitis-like skin lesions at 2 and 4 weeks, whereas both casein protein hydrolysate- and casein-fed mice manifested in a similar manner, with no inhibitory effect⁽Reference Shimizu, Dairiki and Ogawa²⁷⁾. Serum soluble E-selectin was significantly lower with the whey protein hydrolysate diet and correlated with skin scores (the degree of erythema/haemorrhage, oedema, excoriation/erosion and dryness)⁽Reference Shimizu, Dairiki and Ogawa²⁷⁾. The pathologic tissue of the whey protein hydrolysate-fed mice had less infiltration of inflammatory cells, such as neutrophils than the casein protein hydrolysate-fed mice⁽Reference Shimizu, Dairiki and Ogawa²⁷⁾. IgE levels were similarly elevated in all groups, suggesting that the mechanism for the suppressive effect of whey protein hydrolysate on atopic dermatitis-like skin lesions is independent of IgE production⁽Reference Shimizu, Dairiki and Ogawa²⁷⁾. There was also no difference in cell proliferation or cytokine production from cervical lymph nodes, suggesting that the suppressive effect of whey protein hydrolysate on atopic dermatitis-like skin lesions did not involve T cells⁽Reference Shimizu, Dairiki and Ogawa²⁷⁾. The authors proposed that it was probably due to different effects on macrophages at the inflammation site through the different peptides resulting from whey and casein protein digestion⁽Reference Shimizu, Dairiki and Ogawa²⁷⁾; however, further research is needed to investigate these mechanisms.

Effect on recovery from muscle damage

Muscle protein synthesis is depressed for several hours following tissue injury⁽Reference Lowe, Warren and Ingalls²⁸⁾ and exercise⁽Reference Rennie and Tipton²⁹⁾ while the rate of protein degradation is increased for days. This results in a net loss of total protein and limits the rate of restoration of function⁽Reference Lowe, Warren and Ingalls²⁸⁾. By counteracting the negative N balance that occurs after muscle injury, supplementation that can attenuate functional losses or accelerate recovery may be useful. It is possible that protein hydrolysates may be useful for enhancing the recovery from exercise, specifically recovery of muscle damage induced by exhaustive exercise⁽Reference Saunders, Moore and Kies^30–Reference Cooke, Rybalka and Stathis³²⁾.

Eccentric exercise is associated with skeletal muscle damage and the more rapid repair of this damage would facilitate a more rapid recovery of contractile function and may be accelerated by protein hydrolysates. Buckley et al. ⁽Reference Buckley, Thomson and Coates³¹⁾ observed that a single dose of a whey protein isolate hydrolysate (25 g) resulted in a more rapid recovery of muscle force-generating capacity following eccentric exercise compared with flavoured water or a non-hydrolysed whey protein isolate. Participants consuming the whey protein hydrolysate had complete muscle strength recovery by 6 h post-exercise while muscle strength in the other groups was still suppressed at 24 h. The mechanism underlying the enhanced recovery was not apparent but was thought to be due to the supplement accelerating tissue repair. Despite the more rapid recovery of muscle strength the whey protein hydrolysate had no effect on muscle soreness or blood markers of muscle damage and inflammation⁽Reference Buckley, Thomson and Coates³¹⁾, although the authors argued that the relatively short time period (i.e. 24 h) over which the assessments were conducted may have been too short for changes in blood markers to manifest.

Similarly, Cooke et al. ⁽Reference Cooke, Rybalka and Stathis³²⁾ compared a carbohydrate supplement with a hydrolysed whey protein isolate (about 120 g/d) following muscle-damaging exercise. The hydrolysed whey protein isolate resulted in an attenuation of the exercise-induced force reduction during the recovery period⁽Reference Cooke, Rybalka and Stathis³²⁾. It was suggested this was due to an increase in protein synthesis from the essential amino acids contained in the whey protein hydrolysate supplement and also attributed to a reduction in the extent of muscle damage as suggested by a trend for lower plasma lactate dehydrogenase⁽Reference Cooke, Rybalka and Stathis³²⁾.

Intense and prolonged exercise causes a decrease in glutamine levels, which may lead to immunosuppression and consequently a higher incidence of infection and illness and delayed wound healing⁽Reference Parry-Billings, Budgett and Koutedakis³³⁾. Thus, an increase in glutamine status is required for muscle restoration. Protein hydrolysates, specifically hydrolysed whey protein isolate, contain high concentrations of essential amino acids, including BCAA which are the major precursors for glutamine synthesis. The consumption of whey protein hydrolysates has been shown to increase plasma and muscle glutamine stores⁽Reference Castell and Newsholme³⁴⁾ and, thus, supplementation with a rich source of BCAA, such as whey protein hydrolysates, may attenuate the decline in plasma glutamine levels seen after intense endurance exercise⁽Reference Bassit, Sawada and Bacurau³⁵⁾ and thus contribute to the maintenance of tissue integrity or promote tissue repair.

Enhanced availability

The absorption of amino acids by the intestine can have a critical influence on their availability to peripheral tissues and therefore the kinetics of amino acid absorption can largely mediate their subsequent effects on wound healing and muscle protein anabolism⁽Reference Manninen⁷⁾. It has been suggested that the ingestion of a fast-acting protein hydrolysate (i.e. one which is rapidly broken down and absorbed) results in a less efficient uptake by the splanchnic bed, resulting in a more rapid increase in circulating amino acid concentrations⁽Reference Manninen⁷⁾ and thus maximises tissue amino acid delivery.

It is generally accepted that protein hydrolysates are absorbed faster and utilised more effectively than intact proteins⁽Reference Bucci, Unlu, Wolinsky and Driskell^6, Reference Manninen^7, Reference Di Pasquale^9, Reference Poullain, Cezard and Roger^10, Reference Koopman, Crombach and Gijsen^36–Reference Manninen³⁸⁾. A number of studies have shown that the same N load is absorbed faster when delivered as hydrolysed protein, or di- and tri-peptides rather than as whole protein or free amino acids⁽Reference Silk, Chung and Berger^37–Reference Morifuji, Ishizaka and Baba³⁹⁾ and this results in significantly greater increases in plasma concentrations of amino acids and dipeptides⁽Reference Morifuji, Ishizaka and Baba³⁹⁾. These greater increases in absorption and appearance of amino acids in plasma have also been associated with greater incorporation of N into protein, with a number of studies demonstrating greater N incorporation into tissue protein in animals fed hydrolysed whey peptides compared with intact protein⁽Reference Poullain, Cezard and Roger^10, Reference Boza, Moënnoz and Vuichoud⁴⁰⁾. However, some studies have failed to demonstrate a greater increase in circulating amino acid concentrations following consumption of hydrolysed protein. Farnfield et al. ⁽Reference Farnfield, Trenerry and Carey⁴¹⁾ reported that compared with consuming 25 g of whey protein isolate, the consumption of 25 g hydrolysed whey protein isolate led to a slower rate of increase in plasma amino acid concentrations over the 2 h period immediately post-consumption. Power et al. ⁽Reference Power, Hallihan and Jakeman¹¹⁾ also found no difference in the rate of increase of BCAA in the circulation and no difference in the estimated rate of gastric emptying over 3 h following the ingestion of 45 g of intact whey protein or whey protein hydrolysate. The rate of increase in plasma amino acid concentration also appears to be related to the type of protein consumed, as plasma amino acid concentrations have been shown to increase more when a whey protein hydrolysate was consumed compared with a soya protein hydrolysate⁽Reference Morifuji, Ishizaka and Baba³⁹⁾. The effects on circulating amino acid concentrations, and the mechanisms regulating the magnitude of increase in concentration, might be specific to the particular protein or protein hydrolysate consumed, which in turn might be related to the manufacturing processes to which the protein has been subjected. Hydrolysates can be produced by fermentation or by enzymic hydrolysis. The endproduct depends to a great extent on the duration of hydrolysis and, for enzymic methods, on the pH and enzymes used, which can alter the composition of different proteins in protein isolates and the level of hydrolysis in protein hydrolysates⁽Reference Manninen^7, Reference Clemente^8, Reference Neklyudov, Ivankin and Berdutina⁴²⁾. Additional research is required to allow us to better understand the factors that influence amino acid bioavailability as this can make an impact substantially on protein synthesis rates, and therefore potentially influence tissue repair. In particular, effects on the bioavailability of the BCAA leucine, as well as valine and isoleucine, are important to study given the important role of these amino acids in stimulating protein synthesis⁽Reference Buse and Reid⁴³⁾.

Studies have investigated the acute response of muscle protein synthesis to the ingestion of protein hydrolysates. One study compared the effects of rapidly digested (whey hydrolysate and soya protein) and slowly digested protein (casein) on muscle protein synthesis at rest and after resistance exercise and found that the consumption of whey protein hydrolysates stimulated the greatest degree of muscle protein synthesis⁽Reference Tang, Moore and Kujbida⁴⁴⁾. Another study compared carbohydrate with and without a casein protein hydrolysate during a 2 h resistance exercise session⁽Reference Beelen, Koopman and Gijsen⁴⁵⁾. Protein co-ingestion led to higher plasma amino acid concentrations, higher protein oxidation and synthesis rates, and lower whole-body protein breakdown, which promoted a positive whole-body net protein balance⁽Reference Beelen, Koopman and Gijsen⁴⁵⁾.

Another study found that a whey protein hydrolysate, compared with a free amino acid formula, led to higher N retention and glutamine stores (plasma and muscle concentrations), despite higher glutamine intake with the amino acid formula⁽Reference Boza, Moënnoz and Vuichoud⁴⁰⁾. The whey protein hydrolysate formula also showed significantly higher energy conversion efficiency, protein efficiency ratio, N protein utilisation (retention) and biological value than the amino acid formula⁽Reference Boza, Moënnoz and Vuichoud⁴⁰⁾. These effects might have been due, at least in part, to the amino acid composition and higher digestibility of the hydrolysate formula (i.e. absorbed N/ingested N) promoting higher plasma essential amino acid concentrations and essential/non-essential amino acid ratios than those fed with the amino acid formula, despite the amino acid formula providing a higher intake of essential amino acids⁽Reference Boza, Moënnoz and Vuichoud⁴⁰⁾. The greater increase in glutamine stores with the whey protein hydrolysate diet may have important implications for tissue recovery. Glutamine, an important fuel for some cells of the immune system, may have specific immunostimulatory effects⁽Reference Castell and Newsholme³⁴⁾ and is known to be depleted after severe tissue injury. Rats that were fed the whey protein hydrolysate diet restored their plasma and muscle glutamine pools whereas the rats fed with the amino acid formula, which was richer in glutamine, did not⁽Reference Boza, Moënnoz and Vuichoud⁴⁰⁾. During tissue injury and inflammation immune cells increase their glutamine consumption⁽Reference Wilmore and Shabert⁴⁶⁾. If tissue glutamine requirements are not met by dietary intake or endogenous production, this leads to a state of glutamine deficiency. During glutamine deficiency, tissue stores become depleted and plasma and whole blood glutamine concentrations decrease, which limits the ability to achieve optimal responses to catabolism, inflammation and infection⁽Reference Wilmore and Shabert^46, Reference Lacey and Wilmore⁴⁷⁾ and can lead to a negative protein balance⁽Reference Hall, Heel and McCauley⁴⁸⁾.

Increase in levels of insulin

Protein hydrolysates have been shown to produce greater insulinotropic effects compared with intact proteins⁽Reference Power, Hallihan and Jakeman^11, Reference Calbet and MacLean⁴⁹⁾ and it has been suggested that this enhanced insulin response contributes to protein anabolism⁽Reference Calbet and MacLean⁴⁹⁾. Increasing plasma insulin levels stimulate muscle protein synthesis and attenuate protein catabolism after injury⁽Reference Woolfson, Heatley and Allison^13, Reference Odessey and Parr¹⁴⁾ and enhance muscle and tissue uptake of BCAA. It has been suggested that the extent of the insulinotropic response is dependent on both the source and degree of hydrolysis of the protein⁽Reference Claessens, Saris and van Baak⁵⁰⁾ and different amino acids/peptides have been shown to have varying insulinotropic responses. A recent study found that whey protein hydrolysates caused significantly greater increases in insulin compared with whey protein, soya protein and soya protein hydrolysates⁽Reference Morifuji, Ishizaka and Baba³⁹⁾. Another study found that peak plasma insulin concentrations were 28 % higher following the ingestion of hydrolysed whey protein compared with intact whey protein isolate⁽Reference Power, Hallihan and Jakeman¹¹⁾ and this was independent of blood glucose concentrations. Both pea and whey protein hydrolysates have also elicited a peak insulin response two to four times greater than cows' milk (control) and this was closely related to a greater increase in plasma amino acid levels, especially leucine, isoleucine, valine, phenylalanine and arginine⁽Reference Calbet and MacLean⁴⁹⁾. On the other hand, it has been shown that despite no differences in gastric emptying rates and amino acid absorption, peptide hydrolysates (casein and whey) elicited about 50 % more gastric secretion than their corresponding whole proteins⁽Reference Calbet and Holst⁵¹⁾. This consequently led to higher plasma levels of glucose-dependent insulinotropic polypeptide, an incretin hormone during the first 20 min of the gastric-emptying process⁽Reference Calbet and Holst⁵¹⁾. However, some studies have shown no difference in insulin and glucagon concentrations after the ingestion of intact whey protein and its hydrolysate⁽Reference Claessens, Saris and van Baak⁵⁰⁾. Differences in insulinotropic potential between various protein hydrolysates are probably associated with amino acid composition and/or the average amino acid chain length of the protein hydrolysate.

The mechanism by which the ingestion of protein increases circulating insulin is still uncertain. Several postulated mechanisms include a change in gastric emptying⁽Reference Calbet and MacLean⁴⁹⁾, the magnitude of change in circulating essential amino acids and the secretion of incretin hormones from the gut⁽Reference Holst and Gromada⁵²⁾. However, Power et al. ⁽Reference Power, Hallihan and Jakeman¹¹⁾ found no significant difference in gastric emptying time and rate of appearance of BCAA over a 3 h period following the ingestion of hydrolysed whey protein and whey protein isolate. Postprandial increases in circulating essential amino acids stimulate a marked rise in protein synthesis⁽Reference Tipton, Ferrando and Phillips^53, Reference Fujita, Dreyer and Drummond⁵⁴⁾, and this effect appears to be due to amino acids themselves acting as the stimulus and not an effect due to the modest increases in insulin that result from amino acid ingestion⁽Reference Greenhaff, Karagounis and Peirce⁵⁵⁾.

Bioactive properties

It has also been proposed that protein hydrolysates may have impacts beyond the simple supply of nutritional requirements for amino acids⁽Reference Crittenden, Buckley and Cameron-Smith⁵⁶⁾. The physiological effects of protein hydrolysates, in particular the ability to speed recovery from exercise, may be due to the presence of particular peptide(s) that are produced during the hydrolysis process. This suggestion is supported by that fact that several peptides with known biological activity that are not possessed by the native protein can be produced by the hydrolysis of that protein⁽Reference Korhonen and Pihlanto^57, Reference Meisel⁵⁸⁾. An example is the production of angiotensin I-converting enzyme-inhibitory peptides from milk protein following enzymic hydrolysis or food processing⁽Reference Pihlanto-Leppälä⁵⁹⁾. Further research is needed to identify other bioactive properties of protein hydrolysates that may assist in various types of tissue repair.