Evidences suggest that the homeostasis of gut microbiota is among the most important factors for maintaining the physical and mental health of the host. Among the multiple factors affecting the homeostasis of gut microbiota, diet is one of the decisive factors. Bioactive peptides derived from protein hydrolyzed by protease or fermented by microorganism have many physiological activities that their parent proteins do not have. Currently, bioactive peptides attract more and more attention due to their bidirectional interaction with gut microbes. It has been reported that some bioactive peptides could alter the composition of gut microbiota by influencing the intestinal microenvironment. Meanwhile, quite a few bioactive peptides that are released by gut microbes or intestinal cells could resist the pathogenic bacteria to sustain the homeostasis of gut microbiota. In this review, some exogenous bioactive peptides derived from food and some endogenous bioactive peptides released from intestinal cells or microbes were discussed to summary their effects on the modulation of gut microbiota. This review is expected to provide new ideas for related research, and as well to promote the application of bioactive peptides in the fields of food and medicine.
The total number of bacteria that colonize in the adult intestinal is about 1014, which is outnumbers the human cells in the body by tenfold [1, 2]. All kinds of microorganisms living in the intestine constitute gut microbiota with a complex structure and in dynamic balance. In recent years, many studies have revealed that the homeostasis of gut microbiota plays an important role in the occurrence and development of a variety of human non-communicable diseases (NCDs) including diabetes, hypertension, Alzheimer’s disease, and so on . The homeostasis of gut microbiota could be affected by many factors such as diet, lifestyle, aging, and environmental pollutants (Fig. 1) [4,5,6,7]. Many researchers recommend increasing prebiotics in the diet to regulate the structure of gut microbiota. With the deepening of understanding about intestinal microorganisms, the concept of prebiotics has been updated many times since it was first proposed in 1995 . The latest definition of prebiotics is that “a non-digestible compound that, through its metabolization by microorganisms in the gut, modulates composition and/or activity of the gut microbiota, thus conferring a beneficial physiological effect on the host”, which was proposed in 2015 . Currently, the non-digestible oligosaccharides are the main research object in the field of prebiotics because it could successfully reach the colon without being digested by enzymes and selectively promote the growth of probiotics. However, some protein hydrolysates can also resist the digestion of protease in the gastrointestinal tract to modulate the composition of gut microbiota. For example, it has been reported that the peptides whose molecular weight was below 1 kDa in the whey hydrolysates could markable increase the relative abundance of Lactobacillus spp., Bifidobacterium spp. and Bacteroidetes in the intestinal of the standard-diet-fed Wistar rats . Moreover, supplementation with casein hydrolysates could increase the number of lactobacilli and reduce the abundance of Bacteroides spp. in the rat fecal samples . Therefore, these protein hydrolysates fulfil the definition of prebiotics.
In recent years, protein hydrolysates have attracted many researchers’ interests due to their multiple functions. It has been more than 100 years since the peptide was first found by Bayliss and Starling, two physiologists at the London Medical College, who found secretin in animal gastrointestinal . Based on the difference in function, these peptides can be roughly divided into two categories, one is nutritive peptides, and the other is bioactive peptides (BAP). Nutritional peptides perform protein nutrition functions like amino acids and proteins. In addition to providing protein nutrition for the host, BAP can also participate in the regulation of the host’s physiological metabolic activities and improve or enhance the host’s physical health. The definition of BAP is that “Some low-molecular-weight polymers between protein and amino acids produced during the enzymatic hydrolysis of proteins, which have special physiological regulation functions. They are composed of 20 natural amino acids with different compositions and arrangements from dipeptides. The general term of peptides is a complex linear and circular structure” . BAP is a type of peptide with a relative molecular mass of less than 6000 Da, and its molecular structure varies in complexity. The smallest BAP can be composed of two amino acids, while the larger one can be composed of dozens of amino acids (usually less than 20) connected by peptide bonds. Moreover, BAP can be modified by phosphorylation, glycosylation, or acylation. The physiological functions of biologically active peptides are diverse, including antibacterial, antioxidant, anti-inflammatory, anti-hypertensive, immune regulation, lipid-lowering, and weight-loss, etc. . BAP has attracted increasing attention, especially in the fields of food, feed production, and biomedicine due to its easy absorption and digestion, as well as its functions of physiological regulation and biological metabolism.
Considering the important effect of diet on the homeostasis of gut microbiota and the vital role of gut microbiota on the host health, it is necessary to investigate the effects of new products on the composition of gut microbiota when developing functional foods, dietary supplements, feed additives, and drugs. In this review, we divided BAP into exogenous BAP and endogenous BAP based on their sources from in vitro or in vivo of the host. To better understand the relationship between BAP and gut microbiota, we first summarized the exogenous BAP that derived from food which could change the structure of gut microbiota. According to the literature review, microorganisms in the intestine can produce BAP to maintain their ecological niche in the intestinal micro-ecosystem. Moreover, gut peptides released by intestinal cells could affect the metabolic activity of the host by altering the structure of gut microbiota. Thus, the endogenous BAP that released by intestinal cell or gut microbes were summarized in the second part.
Exogenous BAP derived from food
The foremost factor that can influence the composition of gut microbiota is diet. It has been reported that approximately 12–18 g of protein and 40 g of carbohydrate reach the colon every day while most of the fats are absorbed in the small intestinal . At present, the effects of diet on intestinal flora mostly are focused on carbohydrates, especially polysaccharides. The study of dietary proteins effect on gut microbiota is still relatively less. This might be explained by two reasons. On the one hand, compared with polysaccharide, the food-derived protein would be digested by enzymes in the gastrointestinal and the produced peptides and amino acids could be adsorbed by intestinal epithelial cells. It is difficult to analyze the components in the whole process of digestion due to the dynamic changes. On the other hand, the undigested protein could reach the colon and would be fermented by some gut microbes to produce phenols, ammonia, and amines. These products could induce gastrointestinal cancers once their concentration exceed the threshold . However, the source, concentration and amino acid composition of protein are important factors affecting the physiological activity of protein. Choosing high-quality protein as dietary supplement could bring health effects to the host. Recent studies have indicated that amino acids and peptides from the protein that are produced by proteases and peptidases in the digestive tract could optimize the structure of gut microbiota, improve the barrier function of the intestinal, and regulate metabolic activities of the host. The regulation of amino acids on the intestinal microbial composition could refer to a recently published review . Herein, we focused on the summary of BAP derived from food that could affect the structure of gut microbiota (Table 1).
Milk, soybean, eggs, and many kinds of meat derived from terrestrial and marine animals are composed of the protein sources for human beings. Previous studies have focused on the effects and mechanisms of these foods on human nutrition. With the rapid development of biological separation technology, BAP from these foods have been continuously isolated and identified.
Milk normally contains about 3.5% protein, of which casein accounts for 80% and whey protein accounts for about 20%. The casein is rich in amino acids, calcium, phosphorus, and a variety of trace elements, which have high nutritional value. According to literature review, some casein components have biological activity and could be an excellent source of BAP . The casein contains a variety of active peptide sequences that will be released when casein is hydrolyzed with appropriate protease.
At present, a variety of BAP could be isolated from casein, including immunomodulatory peptides, antithrombotic peptides, mineral element-binding peptide (e.g., casein phosphopeptide, CPP) and casein glycomacropeptide (CGMP). Among these BAP, CGMP was identified with the ability to modulate the composition of gut microbiota. CGMP is an active glycosyl phosphopeptide containing sialic acid (SA) which is found to be released from κ-casein when it is treated with chymosin . To investigate the effects of CGMP on the growth of Bifidobacterium lactis in milk, two different sources of CGMP (one from bovine milk and another from combined (50:50) ovine and caprine milk) were supplemented at 2% in the growth medium . After incubated 24 h at 37 °C, the counts of Bifidobacterium lactis was significantly increased by 1.5 log cycles than that of the medium was not supplemented with CGMP. Moreover, there was no difference in the counts of Bifidobacterium lactis between the two kinds of CGMP. In addition, the researchers also investigated the prebiotic potential of CGMP in the simulated intestinal model in vitro. The effects of two CGMP products, a commercially available product (70.22 ± 4.7% CGMP) and a semi-purified preparation (51.39 ± 7.1% CGMP), on the structure of elderly fecal microbiota were explored in an artificial colon model over 24 h. The results indicated that CMGP had a positive relationship with the relative abundance of two health-promoted gut microbes (Coprococcus spp. and Dorea) in the healthy elderly subjects. Moreover, the species diversity of fecal microbiota in the healthy elderly subjects was even higher than that in the lactose supplemented group .
CGMP could also improve the host’s ability to cope with diseases by changing the composition of gut microbiota. It has been suggested that CGMP could be developed as a potential prophylactic agent for the control of allergic diseases [22, 23]. To better understand the mechanism of its effects, the ovalbumin sensitized rat model was constructed by gavage with CGMP. The allergy-protective microbes, including Bacteroides, Lactobacillus, and Bifidobacterium in the fecal microbiota of rats, were monitored during the intervention. Interesting findings showed that the amounts of Lactobacillus and Bifidobacterium were markable increased in the feces of allergen-sensitized rats just after 3 days of treatment. Instead, the increase of Bacteroides was not observed as fast as the other two, while a significant improve was identified after 17 days of CGMP administration. In addition, the alteration effects of CGMP on intestinal microbes could continue even after the supplement was ceased. The counts of Lactobacillus and Bacteroides still increased for ten days after the gavage halted . From the above reports, it is apparent to reveal the ability of CGMP on the modulation of gut microbiota.
The effects of CGMP on gut microbiota are mainly attributed to its structure. The structure of N–acetylglucosamine or oligosaccharide with N–acetylglucosamine in the CGMP could promote the growth of Bifidobacterium. Gyorgy et al.  found that the secondary terminal N–acetylglucosamine was exposed after hydrolysis of CGMP by sialidase, thus promoting the growth of Bifidobacterium. Moreover, there are many prebiotics in the structure of CGMP, such as galactose, mannose, fucose, and N–acetylgalactosamine [26, 27]. Besides, the different sources derived CGMP have different carbohydrate composition. Compared with bovine CGMP, the human CGMP possess a wider spectrum of carbohydrate. The role of carbohydrate within CGMP is suggested to be essential for promoting the successful utilization of polypeptide by bifidobacterial, since carbohydrate-free CGMP was even found to inhibit the growth of Bifidobacterium .
Whey is the main by-product in the production of cheese and casein, accounting for 85%-95% of the total volume of milk . It is also rich in other nutrients, such as whey protein, lactose, vitamins, and minerals, accounting for about 55% of the milk. Among these nutrients, the whey protein, which accounts for about 20% of total milk protein and is rich in essential amino acids, should receive reasonable treatment during the processing of whey . The whey protein contains a variety of proteins, such as α-lactoalbumin (α-LA), β-lactoglobulin (β-LG), immunoglobulin (Ig), lactoferrin (LF), lactoperoxidase (LPO), and other bioactive proteins. These proteins have various physiological functions including antibacterial, antiviral, antioxidant, immunity regulation, and metabolism of trace elements [30,31,32,33]. In addition, these proteins could be used as precursors to produce BAP. Till now, many kinds of BAP have been isolated and identified from their enzymatic hydrolysates [34,35,36,37]. Among these BAP, the most studied one and could modulate the structure of gut microbiota is lactoferricin (Lfcin) .
Lfcin has a wide range of biological activities, including broad-spectrum antibacterial effect, participating in inflammatory reactions, and regulating the immune system. It is also one of the important components for the immune defense system . Currently, two kinds of Lfcin have been isolated from human LF and bovine LF, which were separately termed as Lfcin H and Lfcin B. It has been reported that Lfcin possessed stronger antibacterial effects than their parental LF. This might be due to both Lfcin H and Lfcin B are positively charged, and contain amphiphilic structure and clear hydrophobic surface . They can bind to specific sites on the cell wall of bacteria. The initial binding site on Gram-negative bacteria is lipopolysaccharide, and that with Gram-positive bacteria is teichoic-acid . Unlike other antimicrobial peptides which form pores on the cell membrane and decompose the cytoplasmic membrane, Lfcin do not significantly damage the integrity of the cytoplasmic membrane, but change membrane permeability [40, 41]. This will lead to the outflow of small ions, resulting in the loss of transmembrane electrochemistry and pH gradient [42, 43]. Lfcin can interact with polyanionic molecules once entering the cytoplasm. The bactericidal mechanism of Lfcin B has been most-studied while that of Lfcin H is not yet clearly illustrated . For Gram-positive bacteria, Lfcin B could inhibit the synthesis of DNA, RNA, and protein to disinfect bacteria after entering the cytoplasm, and the morphological of bacteria will be significantly altered . In addition, it should be noticed that the bactericidal activity of Lfcin B is stronger than that of Lfcin H. This might be caused by the presence of β-sheet structure in the secondary structure of Lfcin B, which has been reported to across the cytoplasmic membrane better than the α-helical translocate .
In addition, some prebiotic peptides that derived from LF have been confirmed to overlap or belong to Lfcins’ sequences. Two stimulating bifidobacterial growth peptides for the first time were isolated from the pepsin-treated human LF at 2002. One of them has been verified by mass spectrometry and indicated that from Lfcin H sequence, while the other one was derived from residues 341–352 (353) and 361–364 of human LF. In addition, these peptides have been suggested that could resist the digestion of pepsin, trypsin, and chymotrypsin. Hence, it is proved that they have potential ability to pass through the gastrointestinal tract and stimulate bifidobacterial growth in vivo. Besides, a new small peptide (PRELP-I) was designed and synthesized according to the motif which was obtained by using sequence alignment, and its performance was verified to be as effective as the native peptide at stimulating the growth of Bifidobacterium [46, 47].
The similar work was also conducted to identify bifidogenic peptides derived from bovine LF (bLF). Oda et al.  firstly compared the activity of bLF and its pepsin hydrolysates (bLFH) on the growth of infant-representative species such as Bifidobacterium breve ATCC 15700 T and Bifidobacterium longum subsp infantis ATCC 15697 T. The results indicated that bLFH showed higher bifidogenic activity than bLF. After that, the bifidogenic peptide with heterodimer of A1–W16 and L43–A48 linked by a disulfide bond (named BLP) was finally isolated from the bLFH by multistep activity analysis and HPLC separation. The sequence of bLFH has been certificated to overlap with that of Lfcin B. Furthermore, a total number of 42 bifidobacterial strains that came from nine species were employed to investigate the bifidogenic spectra of bLF, bLFH, and BLP. It has demonstrated that both bLFH and BLP could exhibit bifidogenic activity, especially for infant-representative species (Bifidobacterium breve ATCC 15700T and Bifidobacterium longum subsp infantis ATCC 15697T). The bifidogenic activity of these BAP isolated from LF might be attributed to their disulfide bridges which had been reported to act as nutrient carriers for bifidobacterial .
Eggs contain about 12–16% protein, which is also a common protein food in daily diet. Shell (including shell membrane), albumen and yolk are the main components of eggs. Among these three components, albumen and yolk have been reported to contain peptides that can regulate the structure of gut microbiota.
Egg white accounts for 63% of the total weight of the egg and involves a variety of proteins with bioactivity . Ovomucin is a kind of protein in egg white, which is rich in sialic acid (2.6–7.4%, w/w). It could be supplied as the source of sialic acid for human because the sialic acid in ovomucin is same as that in humans. Moreover, sialic acid-containing substances have been reported to possess bifidogenic activity. In addition to the sialic acid, the ovomucin hydrolysates could also serve as active substance. To further investigate the activity of ovomucin hydrolysates, Sun et al. determined the effects of proteolysis on the sialic acid content and the bifidogenic activity of ovomucin hydrolysates. The growth and metabolism of six bifidobacterial were explored in this study, the results indicated that pepsin–pancreatin ovomucin hydrolysate could promote the growth of Bifidobacterium infantis .
Gut microbiota has been closely implicated in the energy intake from diet. Optimization of gut microbiota composition has become an important target in many anti-obesity studies . However, there are few studies about the relationship between BAP intake, obesity-associated metabolic dysfunctions, and gut microbiota. In a previous work, potential hypocholesterolemia properties of egg white hydrolysate (EWH) produced with pepsin was reported. Moreover, EWH was also observed to show the capability to alleviate obesity-associated markers in obese Zucker rats [53, 54]. To further confirm the beneficial effects of the EWH on the alteration of gut microbiota, the microbial composition and metabolite in feces of obese Zucker rats were investigated after receiving daily 750 mg kg−1 EWH in drinking water for 12 weeks. The results indicated that the composition of gut microbiota in obese Zucker rats fed with EWH was similar with that in the lean control. Moreover, the concentration of lactic acid in the feces was significantly declined and there was a tendency to decrease the production of total SCFA and obesity-associated complications .
In the aspect of immune regulation, peptides derived from egg white were suggested to play a functional role. Ankylosing spondylitis (AS) is a kind of chronic inflammatory autoimmune disease, and various studies have pointed out that the gut microbiota was involved in the development of AS. It has been revealed that a tripeptide Ile–Gln–Trp (IQW) derived from egg white could effectively downregulate cytokine-induced inflammatory protein expression. To access the protective effects of IQW on the AS mouse model, the inflammatory indicators, gut microbiota, and oxidative stress of the mouse model were investigated. Based on the results, the species diversity of gut microbiota in IQW treated mice increased more significantly than that of control group. Meanwhile, the indicators of inflammation and antioxidant were separately reduced and increased, indicating a beneficial influence on AS .
Egg yolk accounts for about 27.5% of the total egg mass. The main components are protein and lipid, mainly in the form of lipoprotein which can be divided into granule part and serous part . The components within egg yolk were believed to be effective for improving the immunity. It has been reported that egg yolk contains antiadhesive compounds and its effects has been confirmed in vivo and in vitro experiments. To identify the effective components, various granule and plasma fractions were extracted from egg yolk to investigate their capability to resist foodborne pathogens (including Salmonella enteritidis, Salmonella typhimurium, and Escherichia coli O157:H7) . The study finally revealed that the high-density lipoprotein (HDL) was the effective compound to prevent pathogens through antiadhesion. In addition, the HDL hydrolysate obtained from the enzymatic digestion of pepsin and trypsin has been confirmed with the antiadhesion effects. These results indicated that there were peptides derived from HDL with the function to inhibit the adhesive of foodborne pathogens to the host cell.
As an important source of high-quality protein, meat is also an important donor of BAP . According to nutrition, meat can be divided into “red meat” and “white meat”. Red meat is dark in color and generally contains high fat. The common red meat is pork, cattle, sheep and other meat, while poultry and seafood are white meat which have low fat content and light meat color. Moreover, the content of unsaturated fatty acids in white meat is high, which is not easy to cause metabolic disease such as hypertensive, diabetes and hyperlipidemia and has higher nutritional value . Due to its special growth environment, aquatic products show unique advantages and characteristics compared with proteins from terrestrial animals and plants. Recently, there was a report about supplementation with tuna meat protein hydrolysates could alleviate the hyperuricemia and associated renal inflammation of ICR mice . The α and β diversity of treated groups were shifted from model to control group. A taxonomic analysis indicated that there were more than 60 OTUs of the gut microbiota in mice were restored corresponding to dietary treatments. Among them, 13 OTUs were found significantly negatively with hyperuricemia phenotypes, and five out of 13 negatively correlated OTUs were also negatively correlated with renal inflammation phenotypes. Moreover, the fecal microbiota transplantation experiment was conducted to verify whether the gut microbes play an important role in the alleviation of hyperuricemia. The results showed that the mice received fecal microbiota transplantation share the similar gut microbiota structure and phenotypes with the fecal-donor mice. The data from this study could explain the beneficial effects of tuna meat protein hydrolysates on hyperuricemia were partially mediated by the gut microbiota.
Plant-derived protein is an important part of human diet. From the view of health, compared with plant protein, red meat and processed meat contain higher content of saturated fatty acids, which will increase the cardiovascular burden; From the view of nutritional, plant protein usually contains more nutrients, intaking these proteins could fulfil the human’s demand of essential amino acids. In recent years, with the popularity of plant protein-based products, plant-derived BAP has also received extensive attention. It has been widely reported to obtain antioxidant peptides, antihypertensive peptides and antithrombotic peptides from plant-derived foods .
Walnut is considered to be able to improve the cognitive level in traditional Chinese culture because its appearance looks like the human brain. In fact, scientific research has shown that walnuts do improve brain function, especially learning and memory in the hippocampus . Walnut protein contains eight essential amino acids, which are similar to animal protein. Compared with walnut protein, there are many outstanding properties of walnut protein hydrolysate (WPH), which makes it could be used as an effective ingredient in the development of functional food and dietary supplements. WPH have been demonstrated to improve cognitive impairment in mice. Via cell experiment in vitro and animal experiment in vivo, a pentapeptide (PPKNW) isolated from WPH has been confirmed with similar function to WPH on the anises of cognitive impairments. To illustrate the mechanism, correlation analysis was conducted by detecting the composition of fecal microbiota and sixteen targeted metabolites in the serum of mice. It has been suggested that there was a close relationship between the alteration of targeted metabolites and the change of gut microbiota. The pentapeptide could effectively reduce the Aβ plaques in the brain of APP/PS1 mice, and alter both the abundance of gut microbes and the concentration of serum metabolites, which is associated with cognitive improvement .
Sesame is one of the important oil crops in the world. Modern pharmacological studies have found that sesame could protect cardiovascular system, lower blood pressure, regulate lipid metabolism, antioxidation and enhance immunity. Sesame is rich in plant protein, unsaturated fatty acids, vitamin E, minerals and so on. The content of sulfur-containing amino acids in sesame protein is high, which is not only easy to be digested and absorbed by human body, but also has high nutritional value. Therefore, sesame protein is a good resource of BAP. Sesame meal, which is obtained after oil extraction, contain 35–60% protein [65, 66]. The sesame meal-derived BAP was selected as a prebiotic supplementation and antibiotic for broiler chickens, its effects on the growth and intestinal health in broiler chickens were compared with mannose–oligosaccharides and avilamycin. The study had verified that supplementation with 100 mg/kg sesame meal-derived BAP could increase the relative abundance of Lactobacilli in caecum of broiler chickens. Besides, the inhibition effect on the Escherichia coli in caecum was also found in all graded levels of BAP treatment groups, and the villus length of the intestinal in the BAP-treated group was also enhanced. These results showed the sesame meal-derived BAP exhibited beneficial effects on the gut microbiota and intestinal morphology of broiler chickens 
Wheat is a widely cultivated crop in the world, and its total yield ranks the second in the world (whole wheat bread: effect of bran fractions on dough and end-product quality). Wheat gluten is a by-product of wheat starch production. It contains more than 75% protein and possess a wide range of amino acids. There were many reports indicated that the wheat gluten hydrolysates exhibited beneficial effects on rat and human hepatitis. A peptide (pyroGlu–Leu) was purified from the wheat gluten hydrolysates and identified as one of hepatoprotective peptides. Moreover, the peptide was also certified could alleviate the inflammatory bowel diseases in mice at a dose of 0.1 mg/kg body weight and indirectly increase the ratio of Bacteroidetes to Firmicutes via increasing the concentration of antibacterial peptides (rattusin) in the host [68, 69].
Soybean, which contains 36–56% protein, is one of the most abundant sources of plant protein and a good source of BAP. The protein hydrolysates and peptides of soybean have high nutritional value and excellent functional properties such as antihypertensive, cholesterol-lowering, antioxidant, and anticancer activities. The soybean-derived BAP has not been reported comprehensively on the modulation of gut microbiota until a recent published review, which summarized well the effects of soybean BAP on the gut microbiota .Thus, no further discussion will be provided herein.
Protein in food will be hydrolyzed and denatured due to the effects of physical (temperature and pH, etc.) and/or microorganisms during food processing. This process not only reduces the allergenicity of protein, but also provides BAP and amino acids to meet the demands of human physiological activities. At present, the food processing-derived BAP, which had been reported to modulate the composition of gut microbiota, were mainly obtained during fermentation and Maillard reaction.
Microbial fermentation is one of the most important approaches to produce BAP. The fermented foods are widely and popularly adapted in the world for a long term, and with regional characteristics. It has been reported that the peptide fraction from digested Parmigiano Reggiano cheese could promote the growth of lactobacilli and bifidobacteria . There were 71 new peptides were identified after simulated oral, gastric, and duodenal transit. These peptides could promote the growth of lactobacilli and bifidobacteria in pure culture conditions, and there were species-specific peptide preferences might be due to their specific protease and and/or peptide transporters’ recognition system.
Fermented alcoholic beverages are the typical fermented food in the world, and currently there is ongoing debate about the health-promoting benefit of drinking these beverages. However, it was revealed that some un-alcohol substances in the beverages could bring beneficial effects to human, such as BAP . It has been reported that two pyroglutamyl peptides (pyroGlu–Tyr and pyroGlu–Asn–Ile) with anti-colitic activity had been identified from the traditional Japanese alcoholic beverage, sake. In vivo experimental proved that supplementation with pyroGlu–Asn–Ile could decrease the ratio of Firmicutes to Bacteroidetes in dextran sulphate sodium (DSS)-induced colitis mouse model while pyroGlu–Tyr has no effects. These results indicated that modulation of gut microbiota might be one of the mechanisms of pyroglutamyl peptides to exhibit anti-colitis .
Maillard reaction refers to the polymerization and condensation of free amino compounds and reducing sugar or carbonyl compounds at room temperature or heating. After a complex process, melanin like substance, food color and flavor substances, including melanin like substances, reducing ketones, aldehydes and heterocyclic compounds, were finally produced. It has been reported that consumption of the Maillard reaction products (MRP) could modulate the composition of gut microbiota. Supplementation with galactooligosaccharide (GOS) glycated with fish peptides diet to mice could increase the relative abundance of Anaerovibrio and Prevotella-9 and decrease the relative abundance of Alloprevotella and Holdemanella. The prebiotic activities of GOS were improved . Moreover, the soy peptide and rapeseed peptide MPRs had been revealed could improve the relative abundance of beneficial bacteria (Lactobacillus and Bifidobacterium) and inhibit the level of pathogenic bacteria in D-galactose induced aging mice, demonstrating the potential prebiotic activities of peptide-MPRs on attenuating aging [75, 76].
Endogenous BAP released from intestinal cells and gut microbes
Intestinal cells released BAP
Defensins are a large family of antimicrobial peptides. At present, defensins have been found in animals and plants, which are essential components of host innate immunity . Unlike other antimicrobial peptides that act on pathogens’ enzymes, defensins act directly on the cell membrane of pathogens, thus avoiding the resistance of target cells (Fig. 2). The structure of mammalian derived defensins is characterized by three pairs of intramolecular disulfide bonds. According to the different connection modes of disulfide bonds, defensins in mammals can be divided into three categories: α-defensins, β-defensins, and θ-defensins .
The α-defensin is secreted by leukocytes (mainly neutrophils) and mammalian intestinal Paneth cell with the disulfide bonds of cys1–cys6, cys2–cys4, and cys3–cys5 . At present, six kinds of α-defensins have been found in the human body, which can be divided into human neutrophil polypeptides (HNP) and intestinal α-defensins (HD) according to different secretory cells. There are four kinds of HNPs, which are mainly secreted by neutrophils, also known as myeloid defensins. HD5 and HD6 are two kinds of HDs that are mainly secreted into the mucous by the Paneth cell . Different from myeloid defensin, HDs are stored as a pre-peptide in human and is matured by serine and trypsin during secretion or after secretion into the intestinal cavity . The regulation of α-defensins on gut microbiota is mainly by resisting pathogenic microorganisms and adjusting the structure of intestinal flora. HD5 could disinfect both Gram-positive and Gram-negative bacteria directly, inhibit the toxicity of Clostridium exotoxin B and restrain the spore germination of microsporidium [81,82,83]. In addition, compared with normal mice, the abundance of Firmicutes in the terminal ileum of HD5 transgenic mice was decreased by about 50% and that of Bacteroides was increased by twice . Unlike HD5 and other α-defensins, HD6 has little antibacterial activity in vitro. While in vivo, it was found that HD6 and its polypeptides could form nanonets to surround bacteria, bring indirect effect on microbial infectivity and prevent bacterial translocation from penetrating the intestinal wall. Overall, HD6 plays an important role in maintaining the integrity of the human intestinal barrier [85, 86].
The binding modes of six cysteine residues of β-defensins were cys1–cys5, cys2–cys4, and cys3–cys6 . β-defensins are mainly expressed in epithelial tissues of mammals, such as the gastrointestinal tract, respiratory tract, tongue, gingiva, kidney, and skin . Unlike α-defensins, β-defensins have antiviral activity [89,90,91]. It has been reported that β-defensins, which were found to have broad-spectrum antibacterial activity, could affect the composition of gut microbiota mainly by inhibiting pathogenic microorganisms that from in vivo and in vitro [92, 93].
θ-defensins were first reported in 1999 by isolating from rhesus macaque leukocytes [90% polymorphonuclear (PMN)] and was termed as rhesus theta defensin-1 (RTD-1). It is an 18-residue macrocyclic antibacterial peptide with the binding model of six cysteine residues, which are cys1–cys4, cys2–cys5, and cys3–cys6 . Two truncated α-defensins head–tail connections are included within the biosynthesis of θ-defensin, which requires the formation of two new peptide bonds. Similar with β-defensins, θ-defensins could affect the structure of gut microbiota by acting as microbicidal. The θ-defensins has strong antibacterial activity and could inactivate bacteria and fungi at the concentration of low micromolar. The antibacterial activity of θ-defensins was suggested to rely on its ring structure, based on the observation that there was no antibacterial effect of the analogs with opening structure .Gut microbes released BAP.
Similar with defensins, bacteriocins are also a kind of antimicrobial peptides, which are encoded by bacteria or archaea genes and synthesized by the ribosome in the process of metabolism . Through the production of bacteriocins, the producer can obtain sufficient nutrients and living space, which is conducive to improve or maintain the environmental niche. Bacteriocin synthesis generally starts at the late logarithmic growth stage and continues to the plateau stage . The bacteriocins are released mainly through the ABC transport system, Sec pathway, cell lysis pathway, and other exclusive pathways [98,99,100]. These processes can not only make the bacteriocin secrete rapidly but also is an autoimmune mechanism of the producing bacteria to prevent themselves from inactivating [101, 102]. The structure of bacteriocin determines its antibacterial mechanism. At present, most bacteriocins have 20–60 amino acid residues with at least one positive charge and amphiphilic structure. This structure enables the bacteriocin to adhere to the surface of bacteria by electrostatic force as well as allows the insertion into the target cells or penetration through the cell membrane, leading the inhibition of peptidoglycan synthesis and inducing cell death. Moreover, some bacteriocins could even degrade the target cell DNA directly via interacting with ribosomes or tRNA to inhibit the protein synthesis [102,103,104,105].
The discovery of bacteriocin was almost at the same time with antibiotics. However, due to the excellent antibacterial performance of antibiotics, bacteriocin was only used in the field of bacterial typing. The overuse of antibiotics urges the demand of alternatives to antibiotics. Bacteriocin, which has broad-spectrum antibacterial properties, is a promising candidate to replace antibiotics. Studies have shown that 99% of natural bacteria can produce at least one kind of bacteriocin . Currently, the most studied bacteriocins are produced by lactic acid bacteria (Table 2). This kind of bacteria has been extensively applied in the food industry as a kind of probiotics due to its safety and benefits to the intestinal environment. Therefore, the bacteriocins produced from lactic acid bacteria are also characterized by low toxicity, environmental friendliness, no side effects, no drug dependence and favorable stability. Hence, its application in aquaculture, food, and medicine is increasing.
Nisin is an antibacterial peptide composed of 34 amino acid residues. It has been approved as a food preservative by many countries in the world , and widely used in dairy products, meat products, and alcoholic beverages. Currently, many different types of Nisin (such as J, F, Q and U, etc.) had been isolated from different species of lactic acid bacteria. Compared with the amino acid sequence of Nisin A, there are differences or deletions of 1–10 amino acids [107,108,109,110,111,112]. Nisin usually has an intramolecular ring formed by thioether bond. This ring structure is an important property for Nisin to destroy the integrity of cell membrane, maintain the rigidity of peptide and protect it from protease and thermal degradation [113, 114]. Nisin interacts with the anionic lipids on the bacterial cell membrane, thus causing the disturbance of the cell membrane and inhibiting the bacteria. The pore formed by Nisin–anionic lipid interaction can lead to the collapse of ATP, amino acids or important ions gradient, leading to cell death [115, 116]. It has been reported that Nisin has strong inhibitory effect on some gram-positive bacteria, such as Listeria monocytogenes, Staphylococcus aureus, Bacillus cereus, Lactobacillus plantarum and Micrococcus luteus [117,118,119,120].
Pediocin PA-1, as a kind of antibacterial peptide, has been widely studied and applied in the field of food preservation . It has been reported that pediocin PA-1 from Pediococcus acidilactici UL5 showed strong inhibition effects on various Listeria monocytogenes strains [122, 123]. To investigate the anti-Listeria effect of pediocin PA-1 in vivo, an ICR model mice was employed . After supplementation with 250 μg/day pediocin PA-1 for three days, the Listeria counts in fecal was received 2-log reductions compared with the infected control group. There was no Listeria translocation into the liver and spleen within six days. Moreover, the food intake, body weight, and gut microbiota structure of the mice was affected during the intra-gastric administration of pediocin PA-1. These results demonstrated the potential ability of pediocin PA-1 against L. monocytogenes in vivo. Clostridium difficile is a Gram-positive bacterium that grows anaerobically. It is a normal flora in the human intestine. The application of antibiotics can lead to the overgrowth of this bacteria, which is believed to be associated with antibiotic-related diarrhea [125, 126]. Among the strains that belong to Clostridium difficile, the BI/NAP1/027 strain type is very difficult to be eradicated from the health care facilities due to its abundant shedding of spores [127, 128]. To effectively sterilize the BI/NAP1/027 strain, a contractile R-type bacteriocin (“diffocin”) from C. difficile strain CD4 was genetically modified . Results indicated that the modified diffocin were stable to pass through the gastrointestinal tract and did not alter the composition of gut microbiota in mice. Moreover, the antibiotic-induced inoculation of the BI/NAP1/027-type strain spores in the colon was inhibited after feeding with the modified diffocin containing water. These results suggested that the modified bacteriocin could prevent or potentially treat Clostridium difficile infections without affecting the homeostasis of gut microbiota.
The production of bacteriocin by lactic acid bacteria that colonized within the human intestine could prevent the invasion of pathogens. However, there was limit knowledge about these bacteriocin-producing bacteria’s influences on the structure of gut microbiota. To further understand these bacteria, mice supplemented with drinking water containing five kinds of bacteriocin-producing bacteria was applied to investigate their effects on the gut microbiota composition of mice. The overall structure of gut microbiota in all mice was not largely altered. However, some transient but advantage changes were observed in the presence of sakacin-, plantaricins- and garvicin-producing bacteria, in which case some pathogenic bacteria could be inhibited .
Taken together, the bacteriocin-producing bacteria that colonized in the intestine normally not dramatically alter the structure of gut microbiota in vivo. However, their existence is still considered to be important for maintaining the intestinal homeostasis because bacteriocins could be released if they are attacked by pathogenic bacteria.
With the continuous iterative update of sequencing technology and the rapid development of bioinformatics, the vital role of gut microbes plays in the occurrence and development of many diseases have been reported. The structure of gut microbiota could be affected by many factors (diet, genes, age, etc.), among which diet is one of the decisive factors. During the literature review, we could find that researches about the modulation of gut microbiota are mainly focused on the polysaccharides or polyphenol from diets. There are less reports about the effects of polypeptides on the gut microbiota. Considering the important role of gut microbiota for health and the recently increasing attention on the development of BAP, the food-derived exogenous BAP and intestinal cells and gut microbes released endogenous BAP were reviewed.
At present, the research about the function of food-derived BAPs mainly focuses on anti-inflammatory, antihypertension, anti-oxidation and immune regulation, etc. However, these functions normally were verified in vitro and there are still lack of definite experiments to illustrate their effects and mechanisms in vivo. Although the molecular weight of BAP is relatively small and it is easy to be absorbed by intestinal epithelial cells, considering the transport efficiency and complex physiological conditions in vivo, it is certain that a portion of BAP could reach the colon and affect the structure of gut microbiota. In terms of the important role of gut microbiota in the development of many diseases, it is necessary to investigate the effects of BAP on the gut microbiota when evaluate their functions in vivo. This may provide a new perspective for elucidating these BAP functions in vivo.
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This present work was funded by the National First-Class Discipline Program of Light Industry Technology and Engineering (LITE2018-22) and the National Key Research & Developmental Program of China (2018YFA0900304).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Guo, Z., Yi, D., Hu, B. et al. The alteration of gut microbiota by bioactive peptides: a review. Syst Microbiol and Biomanuf (2021). https://doi.org/10.1007/s43393-021-00035-x
- Bioactive peptides
- Gut microbiota