Bioactive compounds, antibiotics and heavy metals: Effects on the intestinal structure and microbiome of monogastric animals – a non-systematic review

Anna Winiarska-Mieczan; Małgorzata Kwiecień; Karolina Jachimowicz-Rogowska; Siemowit Muszyński; Ewa Tomaszewska

doi:10.2478/aoas-2022-0057

Winiarska-Mieczan, Anna; Kwiecień, Małgorzata; Jachimowicz-Rogowska, Karolina; Muszyński, Siemowit; Tomaszewska, Ewa

2023-04-01 00:00:00

Ann. Anim. Sci., Vol. 23, No. 2 (2023) 289–313 DOI: 10.2478/aoas-2022-0057 Bioactive compounds, antiBiotics and heavy metals: effects on the intestinal structure and microBiome of monogastric animals – a non-systematic review* 1♦ 1 1 2 3♦ Anna Winiarska-Mieczan , Małgorzata Kwiecień , Karolina Jachimowicz-Rogowska , Siemowit Muszyński , Ewa Tomaszewska Institute of Animal Nutrition and Bromatology, University of Life Sciences in Lublin, Akademicka 13, 20-950 Lublin, Poland Department of Animal Physiology, University of Life Sciences in Lublin, Akademicka 12, 20-950 Lublin, Poland Department of Biophysics, University of Life Sciences in Lublin, Akademicka 13, 20-950 Lublin, Poland Corresponding authors: anna.mieczan@up.lublin.pl; ewarst@interia.pl abstract the intestinal structure and gut microbiota are essential for the animals’ health. chemical components taken with food provide the right environment for a specific microbiome which, together with its metabolites and the products of digestion, create an environment, which in turn affects the population size of specific bacteria. Disturbances in the composition of the gut microbiota can be a reason for the malformation of guts, which has a decisive impact on the animal’s health. This review aimed to analyse scientific literature, published over the past 20 years, concerning the effect of nutritional factors on gut health, determined by the intestinal structure and microbiota of monogastric animals. several topics have been investigated: bioactive compounds (probiotics, prebiotics, organic acids, and herbal active substances), antibiotics and heavy metals (essential minerals and toxic heavy metals). Key words: bioactive compounds, heavy metals, intestine structure, microbiome, monogastric animals The optimum health status of an animal is largely of probiotic properties in a complex intestinal ecosystem determined by the proper function of its gastrointestinal makes it difficult to identify the relationship between tract, that is, morphological integrity of guts and the cor- specific functions of various bacterial strains and the ani- rect population size and composition of the gut micro- mal’s health status, but studies corroborate the potential biota (Diaz Carrasco et al., 2019). Intestinal epithelium of Lactobacillus to regulate the function of the immune serves as a place where digestive enzymes are produced system, improve the digestive capacity of intestines and and nutritional components are absorbed. In addition, it to maintain balance in the pigs’ gut microbiota (Vale- forms a physical barrier against many dietary antigens riano et al., 2017). It results from the action of Lacto- (Tomaszewska et al., 2012). Intestinal villi are covered bacillus sp. which positively influences the population with enterocytes, which originate from the crypts. The size of probiotic bacteria by the production of lactic mucus produced by crypt cells separates the gut epithe- acid, which reduces the pH of the chyme (Yang et al., lium from microbiota and protects the intestinal mucosa 2018). The animals’ diet has also an essential influence against gastrointestinal juices, pathogens and physico- on the composition of the gut microbiome. Certain di- chemical damage (Bansil and Turner, 2018). The mucus etary components stimulate the development of lactic contains mucins, antibacterial enzymes and antibodies acid bacteria and inhibit the growth of pathogenic bac- forming the gut’s first protective barrier (Melhem et al., teria, notably Escherichia coli (e.g., probiotics, prebi- 2021). Maintaining the proper morphology and struc- otics, phytobiotics, organic acids, and minerals); other tural integrity of the intestines is necessary to prevent (e.g., xenobiotics) can disturb the proper proportions the translocation of gastrointestinal bacteria (Wu et al., in the microbiome’s composition. The gut microbiota 2016). is essential for the health, and thus has an influence on The microbiome consists of all types of bacteria performance. This review aimed to analyse information (commensal, symbiotic and pathogenic) forming the mi- available in scientific literature, published over the past croecosystem of the gastrointestinal tract. Microbiome 20 years, concerning the effect of nutritional factors modulation is one of the most prospective new strate- in the diet of monogastric animals on their gut health, gies aimed at improving the health status and animals’ determined by the intestinal structure and microbiota. performance (Rebersek, 2021). However, the diversity Contrary to similar reviews, the presented review is not __________ *This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 290 A. Winiarska-Mieczan et al. limited only to livestock animals, but also presents the et al., 2018). At the same time, commensal bacteria com- results obtained in experimental works carried out on pete with the host for nutrients, produce toxic metabo- monogastric laboratory animals (rat, mouse), which can lites, affect the guts’ morphology and trigger a continual be considered as preliminary studies for products that immune response in the gastrointestinal tract, which un- can be introduced as feed additives in livestock animal doubtedly has a negative impact on the animal health and nutrition. performance. The pH in the stomach serves as an eco- logical filter playing a crucial role in limiting bacteria, information search strategy so it is essential to shaping the composition of the whole The review and analysis of information available in intestinal microflora (Beasley et al., 2015). The most the world scientific literature were conducted in Febru- common factor leading to dysbiosis and disturbances in ary and March 2022 using the PubMed, Scopus, Web of the immune homeostasis is gut infections caused by para- Science and Google Scholar databases. The databases sites, viruses and bacteria. were searched according to keywords: “animal”, “diet”, Disturbances in the composition of the gut microbiota “gastrointestinal tract”, “gut structure”, “microbiome”, can be a reason for the malformation of guts, which has and “supplements”. The search resulted in 5689 records, a critical impact on the animal health. An excessive pop- so – following an analysis of the titles and abstracts of ulation size of Clostridium perfringens of A/G type in the scientific publications – the time frame was narrowed to small intestine causes necrotic enteritis in poultry aged the years 2002–2022, and the terms “antibiotics”, “heavy 2–6 weeks (Lee and Lillehoj, 2022). Toxins produced by metals”, “herbs”, “organic acids”, “phytobiotics”, “prebi- these bacteria damage the intestinal wall; in a sub-clini- otics”, and “probiotics” were used as the keywords. The cal form they lead to decreased feed intake and digestive result was 798 hits. After the abstracts had been read, the disorder, and in a clinical form they cause up to 50% of publications were initially verified and, following analy- birds’ mortality in 24 hours (Uzal et al., 2014; Caly et al., sis of the whole works, the most relevant were selected, 2015; Tsiouris, 2016; Broom, 2017). It is assumed that and ultimately 237 were used, including 182 original re- the main virulent factor is NetB toxin, heptameric protein search and 55 review articles. encoded by plasmid, although some scientific evidence implies that other toxins take part in the pathogenesis of Significance of the proper intestinal structure and necrotic enteritis (Lee and Lillehoj, 2022). Ulcerative co- microbiome for the organism function litis is a disease caused by Clostridium colinum, with a The mucus barrier of the gastrointestinal tract en- mortality rate reaching up to 100% in several days (Radi, sures the physiological stability and protects against ex- 2004). A characteristic feature is ulceration along the gas- ogenous factors modulating the activity of the immune trointestinal tract: the duodenum, the jejunum, the ileum system and controlling the transit of beneficial and toxic and the cecum; it often concurs with peritonitis and mul- substances through the epithelial barrier (Corfield et al., tifocal necrotic hepatitis. The imbalance of the intestinal 2000; Herath et al., 2020). In response to antigens pre- microflora due to the abuse of antibiotics, a deficiency of sent in the chyme, the immune system secretes immuno- nutrients and/or an infection with the protozoans Eimeria globulins, as well as triggers specific responses of mac- spp. is associated with the growth of and colonisation by rophages, lymphocytes and cytokines, then inflammation Salmonella and Clostridium strains in the gastrointestinal occurs which disturbs absorptive and secretive functions tract, which increases the susceptibility to various types (Corfield et al., 2000; Herath et al., 2020; Wiertsema et of diseases (Madlala et al., 2021; Wickramasuriya et al., al., 2021). 2022). The infection with Eimeria destroys the cells of The microbiota of the gastrointestinal tract, dynam- the epithelial barrier, which increases intercellular per- ic community composed of several hundred species of meability and the outflow of nutrients and impairs the bacteria, mainly anaerobic having a beneficial effect on digestion and absorption of proteins (Leung et al., 2018; the host organism and inhibits the development of patho- Nabian et al., 2018). Gut damage due to colonisation genic bacteria, is not fully defined (Chen et al., 2022). by Eimeria is also associated with multiple disorders in The species and amount of bacteria differ depending on the composition of intestinal micro-organisms, which the animal’s species, age, section and pH of the gastro- fosters the colonisation and growth of other pathogens intestinal tract and on the nutritional and environmental (e.g., Clostridium perfringens), making the infected factors (Luise et al., 2020). The microbiota is important chicks susceptible to secondary diseases that increase the since it affects the animal’s immunity, which has an in- mortality rate (Madlala et al., 2021). In addition, such fluence on its health, as demonstrated by comparative conditions give rise to inflammatory cytokines such as studies involving animals kept in a conventional and in IL-1β, IL-10, IL-17A, and IFN-γ promoting proliferation a sterile environment (Luczynski et al., 2016; Gabay et and survival of pathogens (Sand et al., 2016; Wei et al., al., 2020; Larsen et al., 2021). Chemical components tak- 2019). An infection with Salmonella enterica disturbs the en with food provide the right environment for a specific composition of the gut microbiome in the colon and the microbiome which, together with its metabolites and the cecum of pigs where a statistically significant increase products of digestion, create an environment, which in in the population size of Anaerobacter, Barnesiella, turn affects the population size of specific bacteria (Lazar Pediococcus, Sporacetigenium, Turicibacter, Catenibac- Bioactive compounds, antibiotics and heavy metals in gut health 291 terium, Prevotella, Pseudobutyrivibrio and Xylanibacter plest fermentation is the conversion of sugar into lactate, is observed compared to healthy animals (Borewicz et but when the level of sugar is low, the bacteria are capa- al., 2015). By contrast, histopathology of the intestines ble of switching to fermentation producing acetate and of weaned pigs infected with Salmonella typhimurium formate (Van Immerseel et al., 2006). The acidic environ- showed epithelial damage together with an increase in ment resulting from fermentation suppresses the growth polymorphonuclear cells and macrophages, particularly of pathogenic microbes. Lactic acid bacteria suppress the in the jejunum and ileum (Bellido-Carreras et al., 2019). growth and proliferation of pathogenic strains by produc- ing antibacterial metabolites, for example, bacteriocins, effect of nutritional factors on the structure of the lysozyme, short-chain fatty acids, β-hydroxybutyrate and intestines and the microbiome ROS (Ren et al., 2019). In broiler chickens Lactobacil- 1. Bioactive compounds lus johnsonii strain BS15 enhanced gut development and Probiotics digestive capability, primarily through increasing the Probiotics used with feed can modulate the dynam- villi height/crypt depth ratio in the ileum, and increas- ics of changes in the population of microbes in order to ing the level of the epidermal growth factor (EGF) and determine the advantage of useful micro-organisms over insulin-like growth factor 1 (IGF-1) as well as the activ- harmful ones. The probiotic regulation of defensive func- ity of trypsin and lipase in the jejunum and ileum (Wang tions also covers (1) regulation of adhesion of micro-or- et al., 2017 a). Lactobacillus sp. included in the diet of ganisms to epithelial cells, (2) regulation of intracellular broilers increases the transport of glucose and improves adhesion, and (3) signalling and transport processes of absorption of nutrients in guts, which is connected with epithelial cells (Paone and Cani, 2020; Pothuraju et al., an improved gut architecture, but has no effect on the 2021). It was demonstrated that certain probiotics can intracellular transport properties of the jejunum and co- either prevent or minimise the epithelial transport dys- lon, which corroborates the idea that this supplement functions by breaking the inflammatory signalling cas- improves maintenance and functioning of the epithelial cade and reducing the production of chlorides participat- barrier (Awad et al., 2010). Supplementation of broiler ing in maintaining the electrolytic balance of epithelial chickens’ diet with probiotic strains of Bacillus spp. cells damaged by diseases (Emge et al., 2016). The use contributed to improvement in the body weight and gut of probiotics to reinforce the protective function of the morphology (Li et al., 2019 a). Chicks fed diets contain- epithelium in various diseases of the gastrointestinal tract ing Bacillus amyloliquefaciens strains of 30 or 60 mg/kg requires precise identification of their efficiency depend- showed an increased height of villi, depth of crypts and ing on the strain used, disease as well as the age and spe- villi height/crypt depth ratio in the duodenum, jejunum cies of the host. Current research implies that new mech- and ileum (Lei et al., 2015). Supplementation of the diet anisms exist that are specific to certain probiotic strains. with probiotic yeasts at a dose of 5 g/kg had a positive Selective transport of substances through the epithelial effect on the growth performance of weaned pigs, which tissue and respective epithelial cells makes use of intra- could stem from an improved height of villi and the villi cellular connections forming both a barrier and a system height/crypt depth ratio and a modulated immune re- of links between cells and tissue spaces. It was observed sponse of guts (van der Peet-Schwering et al., 2007; Shen that certain probiotics increase the expression of epithe- et al., 2009). Probiotic yeasts Candida utilis administered lial tight junction proteins, improving the efficiency of its with feed improved the villi height/crypt depth ratio in barrier function (Qin et al., 2005). the guts and increased microflora diversity in the cecum, Some bacteria and their metabolites modulate epithe- which contributed decisively to decreasing the frequency lial transcription in guts in a different way, as revealed of diarrhoea in weaned pigs (Yang et al., 2021 a). In rab- by studies on mice (Lukovac et al., 2014). Inclusion of bits receiving feed with commercial prebiotics and syn- Clostridium butyricum bacteria in the diet of weaned pig- biotics the evaluation of the mucosa in the ileum showed lets increases the height of villi and the depth of crypts, that the height and width of villi, the number of villi, the but does not change the population size of the gut micro- depth of crypts and the villi height/crypt depth ratio were biome (Casas et al., 2020). The use of probiotic strains similar and were significantly higher than in rabbits fed such as Clostridium butyricum and/or Enterococcus fae- with a commercial probiotic (Nwachukwu et al., 2021). calis in weaned piglets increased the length of villi and Similar results of feeding chicks with a commercial pro- the villi length/crypt depth ratio and reduced the depth biotic or a commercial synbiotic were reported by Awad of intestinal crypts, while in the large intestine a high- et al. (2009), where both experimental factors increased er concentration of volatile fatty acids and a beneficial the height of villi and the villi height/crypt depth ratio modulation of colonic microflora was observed (Cao et in the duodenum and ileum, while the depth of crypts al., 2019; Wang et al., 2019). Probiotic bacteria produce in the ileum decreased, which was directly associated metabolites such as short-chain fatty acids and bacteri- with improved performance parameters of chickens. Gut ocins beneficial to the animal since they reduce the risk histomorphometry in piglets orally receiving a probiotic of intestinal infections caused by pathogens, which is strain Pediococcus acidilactici showed that the villi were particularly important for weaned piglets (Yang et al., longer and the crypts were deeper compared to the con- 2018). Probiotic bacteria cause fermentation; the sim- trol group, and that the number of proliferating entero- 292 A. Winiarska-Mieczan et al. cytes was higher (Di Giancamillo et al., 2008). By con- the microbiota of the ceacum in both groups of piglets trast, Dela Cruz et al. (2019) found that supplementation was dominated by Firmicutes, followed by Bacteroidetes of a diet with probiotics (Bacillus subtilis, Enterococcus bacteria (da Silva et al., 2021). faecium, Bacillus subtilis or a blend of Enterococcus In Table 1 are presented selected probiotics com- faecium + Bifidobacterium spp. + Pediococcus spp. + pounds influencing the microbiome composition of mo- Lactobacillus spp.) had no significant influence on gut nogastric animals. morphometry (height of villi and depth of crypts in the duodenum, jejunum and ileum). Prebiotics Lactobacillus occurs commonly both in the proxi- Prebiotics are the ingredients of feed having a posi- mal and the distal section of the gastrointestinal tract of tive effect on the welfare and health of an animal through pigs, and forms colonies immediately after birth. A posi- selective stimulation of the intestinal microflora’s growth tive impact of Lactobacillus strains on the gut microbi- and/or activity, thanks to which they also affect the gut ome and intestine structure was also observed for broiler structure (Bogusławska-Tryk et al., 2021). Supplementa- chickens (Lei et al., 2015; Wang et al., 2017 a). Similar tion of the diet with a small dose of chitooligosaccharides results were obtained for rabbits which, after the use of (30 mg/kg) decreased the height of villi in the duodenum Clostridium butyricum, showed an increase of the popu- and jejunum of weaned pigs (Liu et al., 2008; Xiong et lation size of useful bacteria (Liu et al., 2019 a). Early- al., 2015). In addition, it was found that supplementation life colonisation of guts with Lactobacillus rhamnosus with chitooligosaccharides at this level can trigger an im- GG has a long-lasting positive effect on health and sup- mune response and oxidative stress in the small intestine presses the development of gut cancer in mice (Liu et and disturb the integrity of the intestinal barrier in young al., 2022). In turn, Lactobacillus johnsonii strain BS15 piglets. Inulin added to the diet of broiler chickens in- fed to piglets contributed to increasing the population creased the height of villi in the duodenum, the width of size of Clostridium, Peptococcus and Lactobacillus and villi and the villi height/crypt depth ratio and decreased decreased that of Escherichia coli (Xin et al., 2020). In the height of villi and depth of crypts in the jejunum and poultry, changes in the microbiota colonisation during ileum (Awad et al., 2011). Some prebiotics have a posi- the first two weeks post-hatch affect the gut function in tive effect on gut health due to selective stimulation of adult birds and the related feedback between microbiota intestinal bacteria, including Bifidobacteria (Petersen et and cells of the intestinal mucosa (Wisselink et al., 2017). al., 2010). It was demonstrated that indigestible oligosac- The cecum in poultry is considerably shorter in relation charides reduced an inflammatory condition in experi- to body length compared to other animals, so the micro- mental colitis in rat model study (Koleva et al., 2014). biota developing in such conditions must be specially In addition, in rats supplemented with oligosaccharides adapted for effective adhesion to the wall of the mucosa changes in microbiota (an increased share of Bifidobac - and proliferation. In the microflora of the chickens’ ce- terium and Enterobacteriaceae and a decreased share cum the population size of Bacteroidetes is positively of Clostridium cluster IV) as well as higher concentra- correlated with the content of propionate, butyrate and tions of short-chain fatty acids in the cecum content were isobutyrate, while the increase in the content of acetate observed. The study on transgenic HLA-B27 rats with is positively correlated with the population size of Fir- colitis showed that the use of long-chain inulin and oli- micutes bacteria (Wang et al., 2017 b). A blend of probi- gofructose in their diet decreased the concentration of otic micro-organisms added to broiler chicken feed had interleukin Il-1β and increased that of the transforming a beneficial effect on gut morphology and improved the growth factor β (TGF-β) in the cecum; at the same time, status and composition of the gut microbiota: the popu- the population of Lactobacillus and Bifidobacterium in lation size of pathogenic bacteria from the Firmicutes, the cecum increased (Hoentjen et al., 2005). Fructooli- Euryarchaeota and Ruminococcus class significantly de- gosaccharides administered to Wistar rats with induced creased, while the population size of bacteria from the inflammatory bowel disease reduced the symptoms of an Actinobacteria and WPS-2 increased (Ye et al., 2021). inflammation (Lara-Villoslada et al., 2006). This study The effects of probiotics can be modified though the demonstrated that oligosaccharides are fermented in the administration of other supplements. For example piglets upper sections of the large intestine, but their prebiotic orally receiving a mix of a probiotic (1.25 × 10 CFU/ effect extends to distal parts of the large intestine, which day) and zinc (2000 ppm/day) showed the presence of has a positive effect on the inflammation of the large in- stem cells at crypt base and elongation of the enterocyte testine. Finally, caramel enriched with prebiotic difruc- microvilli in the small intestine, which can suggest an tose dianhydrides (DFAs) fed to colitic rats decreased the increased capacity to absorb nutrients and efficient re- level of inflammatory cytokines in the colon, the tumour sistance (Kalita et al., 2021). On the other hand, weaned necrosis factor alpha (TNF-α) and interleukin IL-1β (Ar- pigs administered 2500 ppm of zinc oxide and/or a com- ribas et al., 2010). In the feces of weaned pigs receiving mercial mix of benzoic acid and probiotics (Bacillus li- chitooligosaccharides with feed of 100 and 200 mg/kg an cheniformis, Bacillus subtilis and Enterococcus faecium) increased count of Lactobacillus and a decreased count showed that zinc oxide administered alone had a stronger of Escherichia coli bacteria was found (Liu et al., 2008). influence on the composition of the microbiota, although In the large intestine of piglets receiving a prebiotic (oli- Bioactive compounds, antibiotics and heavy metals in gut health 293 gofructose), probiotic or synbiotic the total count of E. mals’ performance and health are related to the regulation coli bacteria was lower, whereas in the large intestine and of pH of the gastrointestinal tract and the improvement of in the ileum the population of Bifidobacteria was larger intestinal digestibility and utilization of minerals (Luise compared to the control group (Shim et al., 2005). Sup- et al., 2020). The immediate effect of organic acids on plementation of piglet feed with β-glucan improved gut bacterial cells is associated with their ability to permeate morphology and contributed to balancing the microbiota through the cell membrane, where the acid is dissociated and enhanced the concentration of fatty acids in the colon and the pH of the cytoplasm is reduced, which in turn (Luo et al., 2019). inactivates bacterial enzymes: decarboxylase and cata- In Table 2 are presented other selected prebiotics in- lase (Lückstädt and Mellor, 2011; Luise et al., 2020). To fluencing the microbiome composition of monogastric restore the balance and the normal pH of the cytoplasm, animals. the cell is forced to use energy to expel protons out across the membrane via the H -ATPase pump. Expelling pro- Organic acids tons leads to an accumulation of acid anions in the cell, Organic acids and their salts play an important role, which inhibits intracellular metabolic reactions, includ- in particular in ensuring gut health and increasing the ing the synthesis of macromolecules, slows down their growth performance of livestock animals. The main growth and disrupts internal membranes (Luise et al., mechanisms allowing organic acids to improve the ani- 2020; Lückstädt and Mellor, 2011). Table 1. Influence of selected probiotics on the microbiome composition of monogastric animals Target Animal The nutritional factor Experimental factor Effects on gut microbiome References site species Clostridium butyricum or 6 × 10 CFU C. butyricum per kg ↑ C. butyricum Colon Weaned Wang et al. Enterococcus faecali and 2 × 10 CFU E. faecalis per kg piglets (2019) Bacillus, Lactobacillus, 1 to day 42 – 0.2% Bacillus, Lac- Bacteroidetes positively correlated Cecum Newborn Wang et al. Pediococcus tobacillus and Pediococcus-based with content of propionate, butyrate, male (2017 b) probiotic fermented products; from and isobutyrate, whereas an increase chickens day 43 to day 76 – 0.15% probiotic in acetate content positively cor- fermented products related with Firmicutes Candida utilis Basal diet + 1 mL 1 × 10 CFU/ml ↓ Proteobacteria, ↓ Actinobacteria, ↑ Cecum Weaned Yang et al. C. utilis in 0.85% saline; basal diet Verrucomicrobia piglets (2021) + YSE (120 mg/kg) 1 ml of 0.85% saline; basal diet + 120 mg/kg YSE + 1 ml 1 × 10 CFU/ml C. utilis in 0.85% saline B. subtilis Bacillus coagulans TBC169, B. sub- B. subtilis: ↑ Pseudomonas, ↑ Burk- Jejunum Broiler Li et al. (2019 tilis PB6, and B. subtilis DSM32315 holderia, ↑ Prevotella chickens b) with a dosage of 1 × 10 CFU/kg B.subtilis DSM32315: ↑ Clostridiales Table 2. Influence of selected prebiotics on the microbiome composition of monogastric animals Target Animal The nutritional factor Experimental factor Effects on gut microbiome References site species Oligosaccharides Fructo-oligosaccharides or isomal- ↑ Bifidobacterium spp., ↑ Entero - Cecum Rats Koleva et al. to-oligosaccharides 8 g/kg bacteriaceae family, ↓ Clostridium (2014) cluster IV Oligofructose Combination of chicory-derived ↑ Lactobacillus, ↑ Bifidobacterium Cecum, Rats Hoentjen et al. long-chain i in-type fructans and colon (2005) short-chain inulin fraction oligof- ructose in a mixture of 1:1 in their drinking water at a dose of 5 g/kg body weight Fructooligosaccharides Fructooligosaccharides 50 g/kg ↑ Lactobacillus, ↑ Bifidobacteria Feces Female Lara-Villoslada Wistar rats et al. (2006) Chitooligosaccharide Chitooligosaccharide 100, 200 ↑ Lactobacillus, ↓ Escherichia coli Feces Weaning Liu et al. or 400 mg/kg; chlortetracycline pigs (2008) 80 mg/kg β-glucans Basal diet + 50 mg/kg addition of ↑ Bifidobacterium, ↑ Bacillus Feces Weaned Luo et al. high (2000 kDa) or low (300 kDa) (β-glucan 2000 kDa) piglets (2019) molecular weight β-glucan Oligofructose, probiotics, Basal diet + 0.2% oligofructose, ↑ numbers of coli forms, ↑ number of Colon, Suckling Shim et al. synbiotics basal diet+0.3% probiotics or 0.5% bifidobacteria (oligofructose, probiot - ileum piglets (2005) synbiotics; basal diet + 0.2% oligof- ics, synbiotics) ructose + 0.3% probiotics) 294 A. Winiarska-Mieczan et al. The mix of organic acids administered to piglets from Antibacterial activity of organic acids introduced into day 1 to 28 of their lives considerably increased the villi the gastrointestinal tract potentially depends on many height/crypt depth ratio in the jejunum and ileum com- factors, including the concentration of acids in the guts, pared to those receiving antibiotics (Ma et al., 2021). the place of action of the gastrointestinal tract, pH and Similarly, weaned piglets fed diets containing 1 mg/kg oxygen levels, species and age of the animal and ade- of benzoic acid had longer villi and a higher villi height/ quate composition of the population of resident gastro- crypt depth ratio in the duodenum, longer villi in the il- intestinal bacteria (Ricke et al., 2020). In addition, the eum and decreased depth of crypts in the jejunum com- population of anaerobic bacteria resident in the gastroin- pared to piglets fed the control diet (Wang et al., 2021). testinal tract, becoming more dominant in the lower part Moreover, piglets from the benzoic acid group showed a of the intestines of monogastric animals as they mature, higher concentration of acetate, propionate, butyrate and actively produces organic acids through fermentation all short-chain fatty acids in the ileum or cecum. The mix which in turn are also potentially antagonistic to transi- of organic acid administered to chicks with coccidiosis tory pathogens entering the gastrointestinal tract (Ricke mitigated pathological lesions in the jejunum, decreased et al., 2020). Organic acids have both a bacteriostatic and the depth of crypts and increased the villi height/crypt bactericidal effect. It was found that short-chain fatty ac- depth ratio (Mustafa et al., 2021). Sodium butyrate ad- ids and their esters can reduce the count of pathogens in ministered orally to Cobb broiler chickens that received guts and simultaneously increase the count of probiotic an intraperitoneal injection of lipopolysaccharide at a bacteria (Dibner and Buttin, 2002). dose of 500 μg/kg, inhibited the reduction of the villous Lower pH of chyme leads to modification of the mi- height in the duodenum and ileum caused by a stress fac- crobiological composition of the gut, which is primarily tor (Xiong et al., 2018). Other researchers also reported a a reduction or elimination of acid-sensitive pathogenic positive impact of butyrate supplementation to pregnant bacteria and a selection of acid-resistant bacteria such as sows on the structure of the small and large intestine of lactic acid bacteria, which was observed in the duode- their offspring (Dobrowolski et al., 2021; Tomaszewska num of piglets fed with 0.9% and 1.8% solution of po- et al., 2022, 2023). Zinc lactate is another agent having a tassium diformate after 65 hours of experiment (Mroz et positive effect on gut structure. Its use in broiler chicken al., 2002). In broiler chickens lactic acid reduces pH and feeding increased the height of villi in the duodenum and delays proliferation of enterotoxic E. coli bacteria (Ren ileum and decreased the villi height/crypt depth ratio in the et al., 2019). In turn, other authors observed an increase jejunum compared to the control group (Long et al., 2022). in pH in the small and large intestine for weaned piglets Oral administration of benzoic acid (1 mg/kg) to receiving 0.6%, 1.2%, 1.8% or 2.4% solution of formic weaned piglets altered the composition of the microbi- acid (Luise et al., 2020). Differences in results can be ome: reduced the population size of Streptococcus and explained by the time between the administration of the Escherichia-Shigella and increased that of Lactobacillus acid and the sampling (Luise et al., 2020). Canibe et al. (Wang et al., 2021). In a study by Kluge et al. (2006), (2005) found that formic acid added to feed has an ef- benzoic acid added to piglet feed reduced the count of fect on the gastrointestinal tract mainly through chang- aerobic, anaerobic, lactic acid bacteria and Gram-nega- ing the gut environment, which improves the growth tive bacteria in the stomach, reduced the count of Gram- performance of growing pigs. It is believed that organic negative bacteria in the duodenum, and reduced the count acids in the proximal part of the gastrointestinal tract is a of aerobic bacteria in the ileum, which was dosage-de- significant factor leading to a decrease in the population pendent. Sodium butyrate included in the diet of lactat- size of enterobacteria in the whole gastrointestinal tract. ing sows improved the growth rate of weaned piglets and Apajalahti et al. (2009) examined the effect of formic showed potential benefits to the health of gut microbiota: acid on ileal bacterial metabolism in in vitro and in vivo increasing the population size of useful bacteria such as studies, showing a double effect of formic acid on the gut Oscillospira, Blautia and Turicibacter, and decreasing microbiota of pigs: at concentrations lower than 0.5% it that of Veillonella and Sarcina (Wei et al., 2021). Even significantly stimulated bacteria, but higher concentra - small doses of butyrate down-regulate the expression tion (0.8%) strongly suppressed the growth of bacteria. of invasion genes in Salmonella spp., because bacteria A study conducted by Luise et al. (2017) aimed to evalu- that are unable to decrease intracellular pH accumulate ate the effect of two doses (1.4 g/kg or 6.4 g/kg) of formic organic acid anions in accordance with the pH gradient acid fed over six weeks to weaned piglets on the microbi- across their cell membranes (Van Immerseel et al., 2006). ota composition in the jejunum. The study demonstrated In turn, propionate decreases the ability of Salmonella that long-term supplementation of formic acid did not spp. to invade epithelial cells, in contrast to acetic acid significantly affect the microbiota composition depend- (Van Immerseel et al., 2006). A promising solution is ing on the dose, but greater diversity of the microbiota designing a diet that will stimulate the production of or- was observed for animals receiving 6.4 g of formic acid/ ganic acids in the cecum, which can facilitate controlling kg. Despite corroborating the positive effect of formic Salmonella spp., and at the same time is easier and more acid on the gut microbiome composition, no study indi- cost-effective compared to acids added to feed or drink- cates clearly that formic acid has a positive effect on gut ing water. histomorphology (Hernández et al., 2006). Bioactive compounds, antibiotics and heavy metals in gut health 295 Table 3. Influence of selected organic acids on the microbiome composition of monogastric animals The nutritional Animal Experimental factor Effects on gut microbiome Target site References factor species organic acids Benzoic acid 0%, 0.035%, 0.070% or 0.105% of sodium butyrate com- ↑ Oscillospira, ↑ Blautia, ↑ Turicibacter, ↓ Veillonella, ↓ Sarcina Feces Nursery pigs Wei et al. (2021) bined with 0.5% benzoic acid (basal diet + 0.5% benzoic acid+0.035% sodium butyrate) Organic acids Organic acids-based formulations (OABF): 1 g OABF/kg ↑ Clostridium leptum, ↑ Clostridium coccoides Cecum Cobb broilers Palamidi and Mount- diet (OA), avilamycin 2.5 mg active components/kg diet zouris (2018) (AV), combination of OA + AV Fumaric acid Basal diet + 1, 2 or 3% fumaric acid ↓ concentration of bacteria in the digestive tract Ileum Young pigs Blank et al. (2001) Organic acid Combinations of formic, propionic, and medium-chain ↓ Salmonella (sequences also declined over time) Cecum Broiler chickens Oakley et al. (2014) fatty acids in drinking water or feed (birds inoculated with nalidixic acid-resistant Salmonella typhimurium) Microencapsulated Microencapsulated blends of organic acids (OA) and ↑ Ruminococcaceae, ↑ Lachnospiraceae, ↓ Enterobacteriaceae, ↓ Ileum Male Ross 308 Abdelli et al. (2020) blends of organic nature identical aromatic compounds (AC): malic acid + Helicobacteraceae acids fumaric acid + AC – 2.5 g/kg; calcium butyrate + fumaric acid + AC – 1.7 g/kg; MCFA (capric-caprylic; caproic and lauric acid) + AC – 2 g/kg; MCFA + (calcium butyrate + fumaric acid + citric acid) + AC – 1.5 g/kg Organic acids Fumaric acid and an acidifier blend (calcium formate, ↓ E. coli Cecum Weaned piglets Grecco et al. (2018) calcium lactate, capric, caprylic) + (40 ppm) or halquinol (120 ppm) Propionic acids Formic and propionic acids 0.5 to 1.5%; birds challenged ↓ Salmonella pullorum Cecum Layer chicks Al-Tarazi and Alshawab- orally on day 3 with 10 CFU/ml/bird S. pullorum. keh (2003) Benzoic acid Basal diet + benzoic acid at or 10 g/kg; basal diet + potas- ↓ aerobic, anaerobic, lactic acid and gram-negative bacteria counts Stomach Piglets Kluge et al. (2006) sium diformate at 12 g/kg Benzoic acid Basal diet + benzoic acid at 5 or 10 g/kg; basal diet + ↓ the number of gram-negative bacteria Duodenum Piglets Kluge et al (2006) potassium diformate at 12 g/kg Benzoic acid Basal diet + benzoic acid at 5 or 10 g/kg; basal diet + ↓ the number of aerobic bacteria in a dose-dependent manner Ileum Piglets Kluge et al (2006) potassium diformate at 12 g/kg Benzoic acid Basal diet + 20 mg/kg flavomycin + 50 mg/kg quinocetone ↓ Streptococcus, ↓ Escherichia-Shigella, ↑ Lactobacillus Cecum Weaned piglets Wang et al. (2021) AGP; basal diet + 50 mg/kg Macleaya cordata extract + 1.000 mg/kg benzoic acid 296 A. Winiarska-Mieczan et al. Administration of a 1.1% mix of organic acids: four weeks after weaning decreases the metabolic activ- acetic, propionic, phosphoric, citric and lactic acid ity and concentration of bacteria in the gastrointestinal decreased the count of E. coli in the feces as early as tract. the fourth day post weaning and reduced the pH in In Table 3 are presented selected organic acids influ- the colon (Namkung et al., 2004). An experiment was encing the microbiome composition of monogastric ani- conducted in order to evaluate the effect of four differ - mals. ent microencapsulated mixes of organic acids (malic acid + fumaric acid, calcium butyrate + fumaric acid, Herbal active substances caprylic acid + caproic acid + lauric acid, calcium Herbal extracts and essential oils substantially im- butyrate + fumaric acid + citric acid) on gut health prove the structure of the intestinal epithelium and in 600 one-day-old Ross 308 male chicks (Abdelli the composition of the intestinal microflora. The im- et al., 2020). The study found an improved intestine proved structure of the epithelium is primarily mani- histomorphology, increased population size of Rumi- fested as longer and wider villi and deeper crypts in nococcaceae and Lachnospiraceae and a decreased different sections of the intestines (Tatara et al., 2005 population size of Enterobacteriaceae and Helico- a; Hanczakowska and Świątkiewicz, 2012; Ghazanfari bacteraceae. A study by Grecco et al. (2018) showed et al., 2015; Tomaszewska et al., 2015 a). By contrast, a positive effect of feeding a mixture of acidifiers (calci- a positive effect on the microbiome composition re- um formate + calcium lactate) and medium-chain fatty fers mostly to suppressing the growth of pathogenic acids (caprylic + caproic) to weaned piglets on the rel- bacteria and stimulating probiotic ones (Fujisawa et ative weight of the large intestine, the height of villi in al., 2009; Bento et al., 2013; Abu Hafsa and Ibrahim, the jejunum and the total count of E. coli in the cecum. 2018). Herbal extracts owe such an effect to their ac- Al-Tarazi and Alshawabkeh (2003) demonstrated that tive ingredients – phytobiotics. They can affect the gut a mixture of formic acid and propionic acid reduced microbiome composition directly or indirectly through the frequency of occurrence of S. pullorum in both the altering the pH in the gastrointestinal tract and the time crop and cecum. of passage through the gut; they can also promote the A signalling molecule regulating embryonic de- growth of strains beneficial to the animal or/and sup- velopment and playing an important role in fetal nutri- press the growth of pathogenic strains (An et al., 2019). tion is 2-oxoglutaric acid (α-ketoglutaric acid). It is Phenolic compounds present in herbs show an antibac- a primary source of energy for gastrointestinal epithelial terial and antiviral effect and increase cellular prolifera- cells which also induces proliferation of intestinal cells tion and tissue regeneration (Tretola et al., 2019; Ka- (Tomaszewska et al., 2012). An experiment was carried czmarek, 2020). They affect the growth of bacteria by out to examine changes in the morphology of the small suppressing extracellular microbes’ enzymes, depriving intestine damaged due to the prenatal exposure to dexa- the bacteria of substrates needed for their growth or di- methasone in piglets supplemented with 2-oxoglutaric rect impact on the metabolism of bacteria by inhibiting acid in which 3 mg of dexamethasone were adminis- oxidative phosphorylation as well as chelating the ions tered to sows intramuscularly every second day starting of metals essential to their development (Sieniawska, on the 70th day of pregnancy until the delivery, and their 2015). Flavonoids, polysaccharides and saponins can piglets were supplemented with 0.4 g/kg body weight of also act like probiotics, promoting the growth of Lac- 2-oxoglutaric acid over 35 days after birth (Tomaszew- tobacillus, Akkermansia muchiniphila and Bacillus (An ska et al., 2012). The study found that 2-oxoglutaric acid et al., 2019). eliminated intestinal damage due to the prenatal effect While it was found that tannic acid, a polyphenolic of dexamethasone, increasing rate of cellular prolifera- compound, has an adverse effect on rats’ feed intake and tion and the count and maturity of lymphocytes in the their general growth when given in large quantities (Wi- duodenum and jejunum. By contrast, a study involving niarska-Mieczan, 2013), due to antioxidant effect (Gül- laying hens showed that 2-oxoglutaric acid contributed cin et al., 2010) it has a beneficial effect on the composi- to reducing the length and width of villi, and hence the tion of the intestinal microflora. Therefore, the possibil- absorptive surface of the small intestine (Tomaszewska ity of feeding piglets with microencapsulated tannic acid et al., 2020). is being tested. Tannic acid microcapsules improved the Another experiment aimed to determine the effect of morphology of the duodenum, intestinal transport of nu- different levels of fumaric acid (1, 2 or 3%) included in trients and gut microbiota composition compared to the the diet with a low or high dietary buffering capacity on control group (Wang et al., 2020 b). the concentration of microbiological metabolites and li- Essential oils are important aromatic components popolysaccharides as indicators of the presence of Gram- of herbs featuring an antibacterial, antifungal, antioxi- negative bacteria in the ileum of 14-day-old piglets dant, genotoxic and anti-inflammatory effect (Bento et (Blank et al., 2001). Inclusion of fumaric acid reduced al., 2013; Puvaca et al., 2021). The positive effect of es- the concentration of lactic acid, ammonia, spermidin and sential oils on the microbiome composition comprises lipopolysaccharides in the ileum, which indicates that fu- stimulation of the development of probiotic bacteria (Li maric acid added to piglets’ diet during the first three or et al., 2020), which inhibits the adhesion of pathogenic Bioactive compounds, antibiotics and heavy metals in gut health 297 bacteria to epithelial cell walls and decreases intracellu- counteracts many pathogenic intestinal bacteria causing lar invasion and colonisation by these bacteria (An et al., diarrhoea in humans and animals. Garlic turned out to 2019). In addition, they produce antibacterial metabolites effectively counteract even those strains that developed against pathogenic bacteria, e.g. organic acids, short- resistance to antibiotics (Sivam, 2001). Allicin present chain fatty acids, hydrogen peroxide, reuterin, diacetyl in garlic shows a strong antibacterial effect against many and bacteriocins (Tharmaraj and Shah, 2009). Many pathogenic bacteria, including the methicillin-resistant studies imply that interactions between the mucus bar- Staphylococcus aureus (Fujisawa et al., 2009). It was rier and pathogenic bacteria or their toxins trigger oxi- demonstrated that allicin induces thiol stress in bacte- dative stress leading to damage of the intestinal mucosa ria through S-allylmercapto modification of cysteines and lipid peroxidation (Ali et al., 2021). Therefore, the (Müller et al., 2016). phytocomponents of herbs, having a strong antioxidant An experiment conducted to examine the effect of effect (phenolic compounds, saponins, alkaloids, and ter- essential oils of thyme and/or anise included in broil- penoids) help in reducing free radicals and maintaining er diets on histological changes in the small intestine normal intestinal mucosa. found that the structure and efficiency of the small in- A positive effect of garlic and allicin (allyl 2-pro- testine improved (Al-Mashhadani et al., 2013). A mix penethiosulfinate) fed to sows over the final 24 days of of essential oils (eugenol, nerolidol, piperine, thymol, pregnancy and 28 days of lactation on the development linalool and geraniol) also had a positive effect on of the piglets’ gastrointestinal tract, e.g., the length of the laying hens’ gut morphology (Arslan et al., 2022). the sections of the small intestine, was found (Tatara et Thyme essential oil positively influenced gut integrity al., 2005 b). The most prominent changes in the mor - in the duodenum of rabbits (Placha et al., 2013) and in phology of piglets’ intestinal villi under the influence broiler chickens (Placha et al., 2014). However, exces- of garlic and allicin were observed between day 7 and sive dosage of thyme essential oil can deteriorate gut 35 of life (Tatara et al., 2005 a). Similarly, positive integrity, as shown by studies on laying hens (Placha et results after the use of garlic extract (1 ml or 2 ml/kg al., 2010). By contrast, thyme and savory essential oils body weight daily) and allicin (1.0 mg/kg body weight affect the height of villi in the duodenum, jejunum and daily) were recorded when the piglets were reared us- ileum, and reduce the depth of crypts, as demonstrated ing an artificial sow (Tatara et al., 2008). The width of by studies on Japanese quails (Dehghani et al., 2018). villi and the depth of crypts and the thickness of the Studies involving pigs revealed that a mix of thyme and duodenal mucosa were increased in piglets receiving peppermint essential oils and a plant extract of oregano garlic extract, whereas piglets receiving 2 ml of the ex- had a positive effect on the microbiological profile of tract performed better (Tatara et al., 2008). Dried gar - the large intestine, which was manifested by a signifi- lic fed to Ross 308 chicks from the first day post hatch cant increase in the count of probiotic bacteria (Ruzaus- increased the height of villi in the duodenum, jejunum kas et al., 2020). Thymol fed to piglets decreased the and ileum compared to the control group, and increased count of Escherichia coli in the proximal part of the the width of villi in the ileum (Rastad, 2020). Positive small intestine compared to control piglets (Van Noten effects on the width and number of villi were also ob- et al., 2020). served for piglets receiving allicin. It was found that Ross 308 chicks that received 100, 200 or 300 mg/kg improved nutrition at early stages of postnatal develop- of coriander essential oil for 42 days had longer villi and ment, as the main intrauterine factor, can be beneficial deeper crypts, reduced epithelial thickness and number not only right after birth but can have lifelong conse- of goblet cells in the small intestine, which contributed to quences leading to permanent changes in the structure, increasing the feed conversion rate and chicken weight physiology and metabolism of offspring (Tatara et al., gain compared to control birds (Ghazanfari et al., 2015). 2008). The results of these studies are particularly Inclusion of 2% coriander seed powder in broiler diets valuable since rapid changes in the gut microflora as reduced the population size of Escherichia coli com- a consequence of weaning and a radical diet change were pared to the control group; simultaneously, an increased deemed as factors responsible for histological changes immune response was noted (Hosseinzadeh et al., 2014). in guts (e.g. villous atrophy) resulting in impairment Coriander seeds are also effective at smaller doses. of digestion and absorption and even diarrhoea. Garlic A study involving 480 Arbor Acres broiler chickens polysaccharides show anti-inflammatory, antioxidant showed that 0.1%, 0.2% or 0.4% of coriander seed pow- and immunomodulation properties. Administration of der fed to them for 42 days reduced the count of Escheri- polysaccharides extracted from garlic (200 or 400 mg/ chia coli and Clostridium perfringens in the ileum (Abu kg/day) to mice models with dextran sulfate sodium Hafsa and Ibrahim, 2018). Similarly, chickens receiving (DSS)-induced colitis increased colon length, reduced oil of coriander showed lower levels of Escherichia coli colonic mucosa damage and inhibited the expression of in the cecum compared to control treatment (Ghazanfari inflammatory factors (IL-1β, IL-6 and TNF-α), as well et al., 2015). Coriander essential oil, primarily because as improved the composition of gut microbiota (Shao et it contains thymol, shows antimicrobial activity against al., 2020). Raw garlic extract has bactericidal properties Staphylococcus aureus, Streptococcus haemolyticus, due to the content of active ingredients and effectively Bacillus subtilis, Pseudomonas aeruginosa, Escherichia 298 A. Winiarska-Mieczan et al. coli and Proteus vulgaris (Bento et al., 2013). While es- and an increased count of Bacteroidales, as well as bac- sential oils in the first place stimulate the growth of pro- teria producing short-chain fatty acids (SCFA) (Li et al., biotic bacteria also have antioxidant and genotoxic prop- 2020). Furthermore, the correlation analysis showed that erties (Li et al., 2020; Puvaca et al., 2021). the level of toll-like receptor 4 (TLR4) and TNF-α was Essential oils contained in herbs and spices show an positively correlated with the count of Helicobacter and antimicrobial effect, but their use in animal feed is lim- negatively correlated with bacteria producing SCFA. ited since they are quickly absorbed in the upper part of Studies on broiler chickens receiving green tea pow- the gastrointestinal tract. Therefore, a study on feeding der (0.25%, 0.5%, 0.75% or 1% added to feed) showed 50 or 100 mg/kg microencapsulated cinnamaldehyde to an increased diameter of the colon and width of the jeju- Cobb broiler chickens was carried out (Yang et al., 2021 num compared to control chicks (Liu et al., 2021 b). An- b). The study found a significantly higher villi height/ other study investigated whether regular consumption of crypt depth ratio in broilers receiving cinnamaldehyde in green, black, red and white tea had a protective effect on the duodenum and jejunum. Supplementation of broiler the guts of adolescent and adult rats exposed to Cd and diets with essential oil of cinnamon increased the height Pb in feed containing 7 mg Cd and 50 mg Pb/kg for 12 and surface area of villi in the duodenum and jejunum, weeks (Tomaszewska et al., 2015 a, b). No major dam- which ameliorated the efficiency of absorption and di- age to the guts of adolescent rats were observed, which gestion of nutrients. These results were attributed to the proves the protective effect of teas on these organs. In antioxidative activity of cinnamon essential oil (Devi et turn, for adult rats the protective effect of tea on heavy al., 2018). In the process of digestion reactive oxygen metals action was limited. It was also demonstrated that species (ROS) are formed that have an adverse effect on age-related changes in the morphology of the jejunum of the intestinal mucosa and reduce the length of villi, so rats can be mitigated by long-term supplementation of the antioxidative effect of cinnamon supports processes green tea extract, which leads to the recovery of the nor- dependent on normal gut structure. Furthermore, cinna- mal histological structure of the intestinal mucosa (Has- mon essential oil has a bactericidal and bacteriostatic ef- san et al., 2017), mainly through inducing a considerable fect, so it contributes to decreasing the count of intestinal transforming growth factor-β1 (TGF-β1) expression in pathogenic bacteria, which also improves gut morphol- the jejunal mucosa (Mathew et al., 2017). Chlorogenic ogy (Windisch et al., 2008). Cinnamon fed to poultry acid, an ester of caffeic acid and quinic acid, is a poly- promotes the growth of useful bacteria such as Lacto- phenolic compound occurring, for instance, in tea. Chen bacillus spp., simultaneously suppressing the growth of et al. (2018) found that chlorogenic acid (1000 mg/kg) Campylobacter spp. and E. coli in the ileum and cecum fed to weaned piglets decreased the level of inflamma- (Rashid et al., 2020). Lactobacillus spp. is responsi- tory interleukins in blood serum, increased the height ble for maintaining balance in the intestinal ecosystem and width of villi and the villi height/crypt depth ratio, through fermentation and reducing the pH of chyme, which the authors attributed to an improved immune which inhibits the growth of pathogenic bacteria (Yang et defence and suppressed excessive apoptosis of intesti- al., 2021 b). Bioactive cinnamon compounds show anti- nal epithelial cells. Diets rich in chlorogenic acid are bacterial activity against many pathogenic bacteria (such also beneficial in the maintenance of the morphological as Enterococcus faecalis, Enterobacter cloacae, Vibrio integrity of guts and selective regulation of gut micro- parahaemolyticus, Pseudomonas aeruginosa, Salmonel- biota. In weaned piglets receiving 250, 500 and 1000 la spp., Klebsiella pneumoniae, Staphylococcus epider- mg/kg of chlorogenic acid an increase in the duodenal mis, Staphylococcus aureus, and Escherichia coli), fungi villi height and the villi height/crypt depth ratio was ob- (such as Rhizopus oligosporus and Aspergillus niger) and served along with an increase in the population size of yeasts (Candida albicans) (Yang et al., 2021 b). Jamroz Lactobacillus and a decrease in the population of Es- et al. (2005) observed that the guts of broilers receiving cherichia coli in the colon (Zhang et al., 2018). In turn, feed supplemented with cinnamaldehyde, carvacrol and Chen et al. (2019) found that chickens receiving green capsaicin contained more Lactobacillus bacteria and less tea powder (2% share in a diet) showed greater diversity E. coli and Clostridium perfringens. However, Pathak et of intestinal bacteria, which was due to promoting the al. (2017) reported that cinnamaldehyde administered growth of Proteobacteria. However, the population size to broiler orally had no influence on the total count of of potentially pathogenic Gallibacterium was observed E. coli and Lactobacillus bacteria, though the popula- to be higher than in the control group. Recently, in the tion size of Clostridium and Salmonella was smaller in course of the progressing studies, many experiments the ileum and cecum compared to the control group. In have been conducted that provide strong evidence of the contrast, in vitro studies revealed that after eight hours capacity of polyphenols contained in tea to regulate the of fermentation using trans-cinnamaldehyde the concen- intestinal flora, as a result of their protective effect on tration of Clostridium and Campylobacter jejuni was re- the intestinal mucosa and a preventive and therapeutic duced with no impact on the natural intestinal microflora effect (Wang et al., 2022). (Johny et al., 2010). Mice receiving feed with cinnamon In Table 4 are presented selected bioactive herbal essential oil showed increased diversity of gut micro- compounds influencing the microbiome composition of biota, a reduced count of Helicobacter and Bacteroides monogastric animals. Bioactive compounds, antibiotics and heavy metals in gut health 299 Table 4. Influence of selected herbs and herbal active substances on the microbiome composition of monogastric animals The nutritional factor Experimental factor Effects on gut microbiome Target site Animal species References −1 Chlorogenic acid Basal diet containing 250, 500 or1000 mg kg chlorogenic acid ↑ Lactobacillus, ↓ Escherichia coli Colon Weaned piglets Zhang et al. (2018) Chlorogenic acid Basal diet + 2% green tea powder; basal diet + 4% mulberry leaf ↑ pathogenic Gallibacterium Intestines Chickens Chen et al. powder (2019) Cinnamon essential oil Dextran sodium sulfate 3% in the drinking water from day 1 to day ↓ Helicobacter, ↓ Bacteroides, ↑ short-chain fatty acids Feces Female KM mice Li et al. (2020) 7; (SCFA)-producing bacteria (Alloprevotella and Lachno- dextran sodium sulfate 10 mg/kg body weight ceftriaxone sodium; spiraceae_NK4A136_group) dextran sodium sulfate – 10 mg/kg or 15 mg/kg body weight cin- namon essential oil Trans-cinnamaldehyde, Appropriate quantities of TC, CAR, THY, and EUG added to each ↓ Clostridium, ↓ Campylobacter jejuni Cecum Chickens Johny et al. eugenol, carvacrol, and 10 ml sample of cecal contents to obtain a final concentration of 10, (2010) thymol 15, and 25 mM of TC; 10, 50, and 75 mM of CAR or EUG; or 25, 50, and 75 mM of THY for Salmonella enteritidis; and 10, 20, and 30 mM of all compounds for C. jejuni Cinnamaldehyde AGP (NC + 125 mg enramycin (containing 80 mg active ↓ Clostridium, ↓ Salmonella Ileum, cecum Broiler chickens Pathak et al. enramycin/g) per kg feed; organic acids (NC + organic acids con- (2017) taining 10% formic acid), 500 mg/kg; essential oil + organic acids (NC + cinnamaldehyde 15% + calcium formate 500 mg/kg feed) Capsaicin, cinnamaldehyde, Basal diet + 100 mg/kg plant extract consisting of capsaicin, cin- ↑ Lactobacillus, ↓ E. coli, ↓ Clostridium perfringens Small intestine, Hubbard Hi-Y Jamroz et al. carvacrol namaldehyde and carvacrol cecum broiler hybrids (2005) Phytogenic feed additives Basal diet + 40 g/t antibiotic growth promoter; basal diet + 3 kg/t ↑ Lactobacillus spp. ↓ Campylobacter spp. ↓ E. coli Ileum, cecum broiler chickens Rashid et al. and organic acids organic acids; basal diet + 3 kg/t phytogenic feed additives; basal (2020) diet + 3 kg/t organic acids+phytogenic feed additive combination Coriander essential oil Basal diet + 600 mg/kg of a flavophospholipol antibiotic, 100, 200 ↓ Escherichia coli Cecum Ross 308 broiler Ghazanfari et al. or 300 mg/kg coriander essential oil chickens (2015) Coriander seed powder or Basal diet + 750, 1000 or 1250 ppm coriander extract in drinking ↓ Escherichia coli (2% coriander powder form) Ileum broiler chickens Hosseinzadeh et extract water al. (2014) Thymol or thymol α-D- Origanum vulgare extract + Mentha piperita + Thymus vulgaris ↓ Escherichia coli Proximal part of Weaned pigs Van Noten et al. glucopyranoside essential oils the small intestine (2020) Origanum vulgare plant Basal diet + 986 mg of oregano extract, 3 mg of peppermint essen- ↑ number of probiotic bacteria Colon Pigs Ruzauskaset al. extract+Mentha piperita tial oil and 7 mg thyme essential oil (2020) and Thymus vulgaris es- sential oils 300 A. Winiarska-Mieczan et al. 2. antibiotics nal tract. Administration of 0.8 mg of amoxicillin to one- While a prohibition of the use of antibiotics as growth day-old chicks over 24 hours had a short-term impact on promoters in livestock production systems in the EU was the gut microbiota, however, it influenced mucosal gene implemented in 2006, it was decided that antibiotics have expression, which altered biological activity of jejunum to be presented as factors not only influencing micro- for over 2 weeks (Schokker et al., 2017). The use of biome, but also having a potential impact on intestinal amoxicillin or enrofloxacin in chicken feeding from day morphology. In the study of Smirnov et al. (2005) the 15 post-hatch over five days initially led to slight modifi- administration of growth-stimulating antibiotics to one- cations in the microbiota composition of the jejunum, but day-old Cobb chicks increased the share of Bifidobacte - these changes disappeared 16 days after the application rium species in the duodenum compared to the control of amoxicillin and 27 days after the application of enro- group. It was also found that while antibiotics were not floxacin (Wisselink et al., 2017). Avilamycin was widely found to affect the thickness of the mucous layer in the used as an antibiotic stimulating the growth of poultry guts, the villous surface area was increased in the jeju- until its use was banned in certain regions of the world. num, and goblet cell density was greater in the jejunum The study on broiler chickens demonstrated that the di- and ileum. An administration of virginiamycin to Ross versity of bacteria in the ileum was higher in chickens 308 chicks for 42 days increased the height and width of fed with avilamycin than in the control group, contrary to the villi in the duodenum, jejunum and ileum compared the situation in the cecum; this mainly referred to Lacto- to the control group (Rastad, 2020). Samples of the jeju- bacillus reuteri, Lactobacillus crispatus and Clostridium num collected from broiler chickens receiving avilamy- (Choi et al., 2018). In another study young laying hens cin on days 1, 3, 7, 21 and 42 of the experiment showed were orally administered an antibiotic cocktail consist- no effect of the antibiotic on the height of the villi and the ing of vancomycin, neomycin, metronidazol and ampho- total count of mesophilic and lactic acid bacteria; howev- tericin B every 12 hours and ampicillin and colistin in er, avilamycin suppressed the growth of Weisella, Ente- drinking water during the first week post-hatch, followed rococcus faecium and Pediococcus acidophilus bacteria by ampicillin and colistin in drinking water during the and stimulated that of Pseudomonas (La-ongkhum et al., subsequent two weeks (Simon et al., 2016). While fecal 2011). An antibiotic (carbadox/copper sulfate) adminis- microbiota of birds during antibiotic treatment was main- tered to 24-day-old weaned pigs did not affect the height ly composed of Proteobacteria, primarily E. coli, and the of the villi and the depth of crypts in the ileum, but the fecal microbiota of control birds contained mostly Firmi- height of the villi in the jejunum increased compared to cutes bacteria (Lactobacillus and Clostridia strains), the the control group, which increased the villi height/crypt composition of microbiota of experimental chickens was length ratio (Oliver and Wells, 2013). On the other hand, similar to that of control chickens after two more weeks. in chickens that from the 15th day post hatch received Also in newborn piglets the variability of the envi- drinking water mixed with amoxicillin or enrofloxacin, ronment at an early stage of life has an influence on the intestinal morphology and development were not clearly gut microbiota composition and the development of the affected compared to the control group. No differences immune system. In a study by Schokker et al. (2014) the were observed between the villi height/crypt depth ratios piglets received subcutaneous injections of tulathromy- and numbers of PAS+ and PCNA+ cells in the duodenum cin on the fourth day of their life. The antibiotic treat- and jejunum (Wisselink et al., 2017). ment increased the share of Bifidobacterium , Erysipel- Numerous studies emphasise the significance of mi- otrichi, Eubacterium, Faecalibacterium prausnitzii and crobial colonisation of the guts at an early stage of life Solobacterium moorei and decreased the population as a condition for the correct development of resistance size of Bacillus and Staphylococcus aureus. Preventive and the necessity to determine the possibilities of regulat- use of antibiotics in the feed efficiently reduced the fre- ing animals’ health through nutritional and environmen- quency of diarrhoea in weaned piglets. However, exces- tal factors at an early stage of life. Dysbiosis of the gut sive use of antibiotics as preventive or therapeutic drugs microbiota at the early stage of life can affect the spe- in feed leads to the development of drug-resistant bacte- cific immune response at later stages of life (Simon et ria, changes in the intestinal epithelium and leaves resi- al., 2016). Therefore, many studies investigate how the dues of antibiotics in the pigs’ bodies (Klebaniuk et al., use of antibiotics during the first weeks, post-hatch, af- 2018). Ruczizka et al. (2019) evaluated the short- and fects the response in specific antibodies at later stages of long-term effect of ceftiofur on the development of fe- the chickens’ life. Antigenic keyhole limpet hemocyanin cal microbiota in sucklings and growing pigs (n = 64). (KLH) oral immunisation of two-week-old chicks receiv- Piglets from the experimental group received an intra- ing orally ampicillin and neomycin increased the produc- muscular injection of the antibiotic 12 hours after birth. tion of antibody response (IgM, IgA, and IgY) two- or The administration of ceftiofur disturbed the maturation- three-fold compared to the control group, and the count al changes in the fecal microbiome, whereby the effects of Lactobacillus in the chickens’ feces decreased (Murai were sex-specific. et al., 2016). The use of antibiotics temporarily disturbs In Table 5 are presented selected antibiotics influ- the microbiological balance, and decreases the diversity encing the microbiome composition of monogastric ani- and abundance of micro-organisms in the gastrointesti- mals. Bioactive compounds, antibiotics and heavy metals in gut health 301 Table 5. Influence of selected antibiotics on the microbiome composition of monogastric animals The nutritional Animal Experimental factor Effects on gut microbiome Target site References factor species Amoxicillin Enrofloxacin 5 mg/kg or amoxicillin ↑ Lactobacillus reuteri, Ileum Broiler Choi et al. 11 mg/kg for 5 days ↑ Lactobacillus crispatus, ↑ Clostridium chickens (2018) Amoxicillin Enrofloxacin 5 mg/kg or amoxicillin ↓ Lactobacillus reuteri, Cecum Broiler Choi et al. 11 mg/kg for 5 days ↓ Lactobacillus crispatus, ↓ Clostridium chickens (2018) Avilamycin Avilamycin 5 mg/kg or probiotic 2 ↑ Bifidobacterium Duodenum Cobb Smirnov et or probiotic g/kg for 14 days broilers al. (2005) Avilamycin Avilamycin 5 mg/kg ↓ Weisella, ↓ Enterococcus faecium, Jejunum Broiler La-Ong- chickens khum et al. ↓ Pediococcus acidophilus, ↑ Pseudomonas (2011) Ampicillin Ampicillin 0.25 g/l and neomycin ↓ Lactobacillus Feces Chickens Murai et and neomycin 0.5 g/l in drinking water al. (2016) Tulathromycin Tulathromycin 0.1 ml ↑ Firmicutes, ↑Proteobacteria, ↑Bacteriodetes, Jejunum new-born Schok- ↑ Spirochaetes, ↑ Actinobacteria, piglets ker et al. ↑ Bifidobacterium, ↑ Erysipelotrichi, (2014) ↑ Eubacterium, ↑ Faecalibacterium prausnitzii, ↑ Solobacterium moorei, ↓ Bacillus, ↓Staphylococcus Vancomycin, Antibiotic cocktail (vancomycin, Feces Laying Simon et neomycin, neomycin, metronidazole, ampho- hens al. (2016) metronidazole, tericin-B) by oral gavage every 12 amphotericin- h; ampicillin and colistin in drinking B, ampicillin, water for the first week of life; after colistin ampicillin and colistin in drinking water for two more weeks 3. heavy metals (Zn), affects the metabolism of energy and proteins and Essential minerals the biosynthesis of amino acids (Cu), and mitigates oxi- Essential non-toxic heavy metals (zinc (Zn), copper dative stress (Cu, Mn, Se) (Dostal et al., 2015; Artym and (Cu), manganese (Mn), iron (Fe), and selenium (Se)) Zimecki, 2020; Pajarillo et al., 2021). Simultaneously, it influence both the gut structure and the microbiome. It was demonstrated that intestinal bacteria, both commen- is achieved by a complex mechanism including: (1) an sal and pathogenic, develop resistance to trace elements antioxidant effect (Zn, Cu, Mn, and Se); (2) bactericidal and an accompanying antimicrobial cross resistance properties (Cu and Zn) and (3) their key role in bacte- (Yazdankhah et al., 2014). rial metabolism (Fe, Zn, Cu, and Mn) (Jiao et al., 2017; Since the form in which minerals are administered to Winiarska-Mieczan et al., 2021; Pajarillo et al., 2021). animals (organic, inorganic) has an influence on how they A deficiency of Zn is associated with an impaired per - are absorbed and utilised, a study was made comparing meability of the guts and a general deterioration of gas- the effect of Cu glycinate chelate (organic) supplemented trointestinal health (Koren and Tako, 2020). The antioxi- at different doses (50, 75 and 100% of the daily demand) dant effect of Zn consists of two mechanisms: protecting and standard (100%) dose of copper sulphate (CuSO , protein sulfhydryl groups and reducing the intensity of inorganic) on gut health in 12-week-old Wistar rats (To- formation of the hydroxyl radical OH from hydrogen maszewska et al., 2016, 2017). The above-mentioned peroxide due to an antagonistic effect on redox-active study, based on histomorphometry of jejunal epithelium, transition metals such as Cu and Fe (Winiarska-Mieczan found that Cu administered in an organic form covering et al., 2021). Mn and Zn form part of many enzymes, 100% of the demand thinned the mucosa and submucosa including superoxide dysmutase (SOD), citric acid de- layer and reduced the depth of crypts with no effect on hydrogenase and farnesyl pyrophosphate synthase dem- the enteric system in the jejunum, while Cu administered onstrating a high reduction potential (Winiarska-Mieczan in an organic form covering 75% of the demands had no et al., 2021; Zandi and Schnug, 2022). Essential miner- influence on the morphology of the rats’ intestines. Also als regulate the survival of bacteria by modulating the rats receiving organic Cu (at an amount covering 75% key metabolic pathways, including through riboflavin and 100% of the demand) showed an increased amount biosynthesis and regulation of energy uptake from food of young collagen compared to rats receiving sulphate at (Fe), metabolising carbohydrates, lipids and protein and the standard dose. Concluding, it was found that Cu ad- influencing the replication of DNA (Mn), regulating ri- ministered to rats in an organic form with a diet covering bosomal protein expression, maintaining cellular activity 50 or 75% of the demand is less harmful for the intestinal and reducing glucose metabolism by suppressing the key epithelium than when administered at an amount cover- glycolytic enzymes, which results in decreased virulence ing 100% of the demands. Copper sulphate (CuSO ) fed 4 302 A. Winiarska-Mieczan et al. to pigs at an amount supplying 225 mg of Cu increased tion of Mn, since both metals use the same transporters the height of the villi in the duodenum and decreased it in (Pajarillo et al., 2021). Fe stimulates the growth of Bi- the jejunum compared to the control, no Cu-supplemen- fidobacteriaceae , and Mn – as a cofactor of many cell ted group (Shannon and Hill, 2019). Conversely, in enzymes – is necessary for the growth of Lactobacillus chicken feeding, CuSO (30 or 70 mg) contributed to in- (Artym and Zimecki, 2020). creasing the height of the villi in the jejunum (Levkut Mn, although necessary for the correct functioning et al., 2017). Zinc oxide (ZnO) administered at 380 or of the body, is still a heavy metal. Poisoning with Mn 570 mg of Zn/kg of feed improved intestinal immunity can alter the gut microbiota, which was demonstrated and regulated the composition of the microbiota in weaned in studies on pigs and mice (Chi et al., 2017 b; Peng et pigs; the villi in the duodenum were longer, the villi height/ al., 2019; Wang et al., 2020 a). Modulation of the gut crypt depth ratio was higher and the crypts were deeper microbiota with Zn decreases the frequency of diarrhoea (Shen et al., 2014). Interestingly, excessive dose of ZnO as zinc mitigates intestinal damage and reinforces the (2250 mg/kg) was not equally efficient. Supplementation anti-inflammatory agents and integrity of the mucosa of the fattening pigs’ diet with ZnO affected the morphol- in weaned pigs (Pieper et al., 2012). Moreover, sup- ogy of the mucosa of the small intestine. The mucosa was plementation of the diet with Zn decreases the count of found to become thicker, the villi were longer and wider Enterobacteria, Clostridium cluster XIV and E. coli, in- and the crypts were deeper compared to the control group creases the content of acetate and butyrate and improves (Li et al., 2001). Similar effect of ZnO was observed in the gut function of pigs (Pieper et al., 2012; Kociova et poultry, where villi were longer and the villi height/crypt al., 2020). Exposure to high levels of Cu can induce tox- depth ratio in the duodenum increased when compared to icity and trigger the development of resistance to Cu in control group (Shannon and Hill, 2019). Similarly, the use certain pathogenic bacteria, but, on the other hand, re- of yeasts enriched with Se in the case of weaned pigs ex- duce the relative population size of potential pathogens, posed to oxidative stress (provoked with diquat) resulted in including Enterobacter, Escherichia and Streptococcus longer villi and increased the villi height/crypt depth ratio (Villagómez-Estrada et al., 2020; Pajarillo et al., 2021). in the jejunum and the cecum; it also decreased the overall Long-term exposure to Cr(VI) substantially changes the ratio of the intestinal epithelial cells’ apoptosis compared diversity and composition of the chickens’ gut microbi- to piglets not receiving the supplements (Liu et al., 2020). ome. Bacterial strains that were dominant in the gut mi- Fe affects the composition of the gut microbiota crobiota of chickens receiving Cr(VI) were Firmicutes through regulation of the uptake of energy from food and Actinobacteria, while in the control group these consumed by the host (Dostal et al., 2015). Bacteria take were Firmicutes and Bacteroidetes (Li et al., 2021). The Fe from food in the gut thanks to transportation via the taxonomic analysis of bacteria showed that the relative receptors of iron-bound proteins (transferrin and heme) population size of three classes and seven genera clearly and through capturing Fe by releasing Fe carriers. Stud- increased, while that of eight classes and thirty genera ies show that Fe carriers, for example, the Fe capturing radically decreased during the induction of Cr(VI). In- system and the Fe transportation system, are expressed in testinal bacteria are the body’s first front line, convert- certain bacteria (Pajarillo et al., 2021). In addition, some ing toxic Cr(VI) into less toxic Cr(III), as demonstrated bacteria produce hemophore-like proteins that transport by studies on Wistar rats that were administered drink- the heme using the receptor capture. A strong dysbiosis of ing water containing 10 ppm of Cr(VI) over 10 weeks the gut microbiota accompanied by a decrease in the con- (Shrivastava et al., 2005). Moreover, it was observed that tent of its main metabolites, observed at very low levels long-term exposure to Cr(VI) promotes the development of Fe, can weaken the barrier effect of the microbiota and of colon cancer in mice, which is attributed to modifica - thus negatively affect gut health, as demonstrated during tions in the gut microbiota and the occurrence of oxida- in vitro studies involving rats into whose intestines the tive stress (Zhang et al., 2020). In their studies involving human fecal microbiota was transplanted (Dostal et al., mice, Zhao et al. (2022) demonstrated that the patho- 2013, 2014). Supplementation of an Fe-deficient diet of logical effect of Cr(VI) on the microflora of the ileum rats with 35 mg Fe/kg significantly increased the popu- and cecum can be effectively mitigated by Se treatment. lation size of the dominant groups of bacteria, mostly Studies on mice found that intestinal bacteria can com- Bacteroides spp. and Clostridium cluster IV compared pete with the host for Se where its availability is limited to the group with zero supplementation (Dostal et al., (Hrdina et al., 2009). Other research involving mice de- 2014). In addition, the supplementation of Fe increased void of the microbiome showed significant differences in the concentration of butyrate in the gut microbiome six- the levels of about 70% of the determined metabolites of fold compared to Fe deficiency and had no impact on the the gut microbiota, including fatty acyls, glycerolipids, histological assessment of colitis. The absorption of Fe glycerophospholipids and steroids in mice supplemented is stimulated by Lactobacillus acidophilus, while it is with Se compared to those not receiving the supplement suppressed by Bifidobacterium infanti. In contrast, Bifi- (Callejón-Leblic et al., 2022). In that study a strong re- dobacteriaceae synthesise Fe carriers, which leads to the lationship was also found between the metabolites and peroxide reduction and decreases the risk of gut diseases the profile of intestinal bacteria – in particular the popu- (Pajarillo et al., 2021). Fe has an influence on the absorp- lation size of Lactobacillus spp. – was higher in mice Bioactive compounds, antibiotics and heavy metals in gut health 303 supplemented with Se. A beneficial effect of the supple- In Table 6 are presented selected non-toxic essential mentation of Se on the microbiome’s composition was minerals influencing the microbiome composition of mo- also found by other researchers for mice (Callejón-Leblic nogastric animals. et al., 2021) and laying hens (Muhammad et al., 2021). Table 6. Influence of essential minerals on the microbiome composition of monogastric animals The nutritional Target Animal Experimental factor Effects on gut microbiome References factor site species Copper, Cu 5 mg/kg body weight (CuCl ); Hg 2 mg/kg ↓ Rikenella, ↓ Jeotgailcoccus, Cecum Mice Ruan et al. mercury body weight (HgCl ); Cu + Hg (Cu 2.5 mg/kg ↓ Staphylococcus, ↑ (2019) body weight, Hg 1 mg/kg body weight) Corynebacterium in the group with Cu; ↓ Sporosarcina, ↓ Jeotgailcoccus, ↑ Staphylococcus in the group with Hg and Cu + Hg ↑ Anaeroplasma in the group with Cu+Hg Copper Cu 5 mg/kg body weight (CuCl ) ↑ Corynebacterium,↓ Staphylococcaceae, ↓ Cecum Mice Cheng et al. Odoribacter, ↓ Rikenella, ↓ Jeotgalicoccus (2020) Copper Cu 5 mg/kg body weight (CuCl ) ↑ Dehalobacterium, ↑ Coprococcus, Rectum Mice Cheng et al. ↑ Spirochaetales, ↓ Salinicoccus, (2020) ↓ Bacillales, ↓ Staphylococcus, ↓ Lactobacillales Copper CuSO (350 ppm) after 30, 60, and 90 days At the phylum level: ↑ Proteobacteria, ↑ Cecum Chicken Huang et al. Actinobacteria, ↓ Bacteroidetes (2021) At the genus level: ↓ Rikenellaceae_RC9, ↑ Ruminococcaceae UCG-014, ↑ Lachnoclo- stridium, (Eubacterium) coprostanoligenes Copper 0.04, 0.20, or 1.00 mg/kg body weight Cu ↓ Firmicutes Feces Rats Dai et al. (CuSO ) in 0.9% saline for 15 days to Bacteroidetes (2020) Copper Cu 5 mg/kg body weight (CuCl ) ↓ Rikenella, ↓ Jeotgailcoccus, ↓ Staphylo- Cecum Mice Ruan et al. coccus, ↑ Corynebacterium (2019) Copper Basal diet + CuO NPs at dosage of 2.13 mg/kg No effect on microbiota Feces Broiler Sizentsov et of feed (with Cu 1.7 mg/kg) chickens al. (2018) Zinc ZnO (500, 1000, and 2000 mg of Zn equiva- ↓ Enterobacteria, ↓ Clostridium cluster XIV, Feces Weaned Kociova et lent/kg diet) for 10 days. ↓ E. coli piglets al. (2020) Zinc Zn biofortified wheat (75% Zn wheat based ↑ Firmicutes (Lactobacillus Small Gallus Reed et al. diet, 46.5 ± 0.99 μg Zn/g) Reuteri, Dorea, Clostridiales, Ruminococ- intestine gallus (2018) cus, Lachnospiraceae) Zinc Nano-ZnO (ZnO at a dose of Zn 250 mg/kg Zinc sulfate increased the proportion of the Cecum Male Wang et al. body weight); zinc sulfate (0.2 ml zinc sulfate enteric group. mice (2017 c) solution at a dose of Zn 250 mg/kg body Nano-ZnOs did not affect the intestinal weight) for 7 weeks bacterial population (Bifidobacterium and Enteric groups) Zinc Nanocomposite of half-fin anchovy hydro - ↑ Firmicutes, ↓ Bacteriodetes, ↑ Lactobacil- Feces Mice Song et al. lysates (HAHp) and ZnO nanoparticles – daily lus, ↑ Bifidobacterium, ↑Clostridia class (2018) dose of 1.0 g/kg body weight for 14 days) Zinc Basal diet + nano-ZnO (ZnO 150, 300, 450 or ↓ Escherichia coli (ZnO 450 Cecum, Weaned Pei et al. 3000 mg/kg) for 21 days and 3000 mg/kg) colon, pigs (2019) and rectum Manganese 100 ppm MnCl ↑ Firmicutes ↓ Lactobacillus Feces Male Chi et al. mice (2017) Manganese 100 ppm MnCl ↓ Firmicutes Feces Female Chi et al. mice (2017) Manganese Manganese chloride (MnCl ), 200 mg/l in ↑ Firmicutes bacterium ASF500, ↑ Fae- Feces Sprague- Wang et al. drinking water calibacterium prausnitzii, ↑ Ruminococ- -Dawley (2020) cus,↑ Clostridium celatum, ↑ Lactobacillus male rats johnsonii, ↑ Fusobacterium sp. CAG:815, ↑ Clostridium sp. CAG:813, ↑, Clostridium sp. JCC, ↑ Firmicutes bacterium CAG:475, ↑ Clostridium sp. CAG:349 Vanadium Vanadium 10 mg (V10) per kg; no influence on the number of Lactobacil - Cecum Laying Yuan et al. basal diet + V10 per kg; V10 + 600 mg tea lus, Escherichia coli, and total bacteria hens (2016) polyphenols per kg; V10 + 1000 mg tea poly- phenols per kg 304 A. Winiarska-Mieczan et al. Toxic heavy metals protein kinase) and NF-κB (nuclear factor kappa-light- The toxicity of metals is primarily due to their abil- chain-enhancer of activated B cells) signalling cas- ity of producing reactive oxygen species (ROS) and oxi- cades (Zhai et al., 2016; Jiang et al., 2018). Bolan et al. dising proteins and fat building cell membranes, which (2021) confirmed that the permeability of the guts to tox- results in oxidative stress (Winiarska-Mieczan, 2018). ic metals (As, Cd, Pb, Hg) is reduced under the influence Studies involving human Caco-2 cells showed that the of intestinal micro-organisms and chelating agents, using intestine is an organ that can take part in the pre-systemic an in vitro intestinal epithelium model made of Caco-2 metabolism of inorganic arsenic (As) (Calatayud et al., cells. 2012). The body’s inflammatory and oxidative response Gokulan et al. (2018) investigated the relationship be- to exposure to As can be responsible for structural and tween short-term exposure to As and the composition of functional modifications in the mucosal layer, which the gut microbiome and the immune status of intestines leads to the loss of the epithelial barrier function (Chioc- in adult and young CD-1 mice. Single doses of As admin- chetti et al., 2019). Subchronic exposure to As affects the istered to young mice gave rise to different populations structure of the epithelium, causing the loss of microvilli, of bacteria, which demonstrates that exposure to As at structures essential to intestinal absorption and digestion an early stage of life can have long-lasting consequences processes, and may change the intestinal homoeostasis, for the development of a healthy gut microbiota. In turn, at the same time affecting the intestinal mucosa (Chi- repeated exposure increased the population size of bacte- occhetti et al., 2018). The effect of chronic exposure of ria resistant to As and induced the methylation of As for young and adult Wistar rats to cadmium (Cd) and lead detoxification. A decreased count of bacteria engaged in (Pb) of 7 mg Cd/kg and 50 mg Pb/kg for 12 weeks on transforming protein to butyrate, together with signs of the histomorphology of the jejunal epithelial cells and immune modulation was also found. Studies involving liver was examined (Tomaszewska et al., 2015 a, b). mice showed that exposure to As and Cd significantly These experiments demonstrated that exposure to Cd and altered the gut microbiome and metabolome through Pb significantly decreased the thickness of the intestinal their influence on bile acids, amino acids and taxons as- mucosa and submucosa and the depth of crypts. In turn, sociated with metabolic health (Lu et al., 2014; Li et al., exposure to mercury (Hg) causes degenerative lesions 2019 b). Moreover, not only does As disturb the species of various sections of the gastrointestinal tract, which in composition of the gut microbiome but also deeply al- the first place are inflammations and infiltrations, as ob- ters many important bacterial functional pathways (Chi served in studies involving mice (Jiang et al., 2018). et al., 2017 a). The size and intensity of changes are Heavy metals that are essential and toxic have an an- sex-specific (Chi et al., 2016). Studies by Breton et al. tibacterial effect, which can be beneficial for suppressing (2013 b) involving mice demonstrated that intestines are growth or killing pathogens, but is also harmful to com- poor accumulators for Cd and Pb; however, changes in mensal and useful bacteria forming the gut microbiota the gene expression of specific intestinal markers showed (Bist and Choudhary, 2022). The antibacterial activity of that these metals stimulated the epithelial inflammation heavy metals results from the oxidative stress they in- in the duodenum, ileum and colon. They also found that duce and can also be based on disturbed gene expression Cd had a genotoxic effect both in the upper and the lower and damage to DNA (Zhou et al., 2008). Exposure of the part of the gastrointestinal tract. Based on studies involv- gut microbiota to toxic metals can affect its composition, ing C57BL/6 mice it was discovered that exposure to Pb depending on the location, microenvironment and the disturbs the development of the gut microbiome, the key population size of susceptible and/or resistant strains (Gi- metabolites and metabolic pathways. The performed 16S ambò et al., 2021). Furthermore, host-related factors such rRNA sequencing revealed that exposure to Pb altered as diet, sex, age and immunity status can have an influ- the gut microbiome’s trajectory and phylogenetic diver- ence on this interaction (Assefa and Köhler, 2020). It is sity, and metagenomic sequencing and metabolomic pro- significant that biotransformations induced by intestinal filing demonstrated that certain metabolic pathways (e.g., bacteria such as reduction, oxidation, methylation and of vitamin E, bile acids, energy transformations, and oxi- demethylation, can modulate the toxicity of metals, as dative stress) were considerably disturbed by exposure to demonstrated in studies involving mice devoid of micro- Pb, which can have a significant effect on the toxicity of flora after six-week oral exposure to Cd and Pb (Breton this metal in the body (Gao et al., 2017). Other study in- et al., 2013 a). In turn, studies on Caco-2 cells suggested volving mice implied a possibility of reducing the toxic- that oral uptake of heavy metal binding bacteria Lacto- ity of Pb through modulation of the gut microbiota, as the bacillus spp. can be a simple and efficient method of re- administration of Faecalibacterium prausnitzii and Os- ducing the amount of heavy metals absorbed with food cillibacter ruminantium increased the rate of production (Daisley et al., 2019; Jiang et al., 2018). This is probably of short-chain fatty acids by the microbiota of the large due to the protective role of the intestinal barrier (associ- intestine (Zhai et al., 2020). Pb can damage the intestinal ated with the mitigation of oxidative stress induced by barrier and enhance the permeability of guts, so inflam- heavy metals and the chelating properties of probiot- matory cytokines, agents affecting the immune system, ics) and the modulation of the inflammatory condition as well as microbial metabolites such as bile acids and due to the interaction of the MAPK (mitogen-activated short-chain fatty acids, easily penetrate into the hepatic Bioactive compounds, antibiotics and heavy metals in gut health 305 portal vein and ultimately lead to numerous changes in The 16S rRNA sequencing for tracing changes in the gut the body functions (Liu et al., 2021 a). Perinatal exposure microbiota composition of rats exposed to As, Cd, cobalt of mice to Pb decreased aerobes and increased anaerobes (Co), Cr or nickel (Ni) for five days showed significant compared to the control group (Wu et al., 2016). Mer- alterations to the microbiota composition, whereas the cury (Hg) is a toxic metal that can be microbiologically response to As, Cd and Ni was observed to be dependent converted into bioaccumulative methylmercury (MeHg), on the dose (Richardson et al., 2018). which results in a potentially toxic load on the body, as In Table 7 are presented selected toxic heavy metals study involving adult CD-1 mice found dysbiosis of the influencing the microbiome composition of monogastric gut microbiome after Hg exposure (Nielsen et al., 2018). animals. Table 7. Influence of selected toxic heavy metals on the microbiome composition of monogastric animals The nutritional Animal Experimental factor Effects on gut microbiome Target site References factor species 1 2 3 4 5 6 Arsenic As 3 mg/l, Fe 5 mg/l and 3 As mg/l + Fe 5 ↑ Firmicutes, ↑ Proteobacteria, Feces Mice Guo et al. mg/l for 90 days ↓ Bacteroidetes (2014) Arsenic 10 ppb or 250 ppb of sodium arsenite ↑ Bacteroidetes, ↓ Firmicutes Colon Mice Dheer et al. (NaAsO ) for periods of 2, 5 and 10 weeks (2015) Arsenic Sodium arsenite (NaAsO ) (10 ppm) in ↓ class Clostridia (in the phylum Feces Mice Lu et al. drinking water for 4 weeks Firmicutes) (2014) Cadmium Cd (20 or 100 ppm) or Pb (100 or 500 ppm) ↑ Lachnospiraceae abundance Feces, Cecum Mice Breton et al. for 8 weeks (2013 c) Cadmium 20 and 100 mg/kg cadmium chloride respec- ↓ Bacteroidetes, ↓ Lactobacillus, Feces Mice Liu et al. tively for 3 weeks ↓ Bifidobacterium (2014) Cadmium 100 mg/l Cd + low dietary fiber diet; Cd+ Feces Mice Li et al. (2016) ↑ Verrucomicrobia 10% IDF: 100 mg/l Cd + native wheat bran at 100 g/kg diet Cadmium, Sodium arsenite (NaAsO – 15, 22, or 31 mg/ ↑ Proteobacteria, ↓ Firmicutes, Feces Rats Richardson et arsenic, cobalt, kg/day); cadmium chloride (CdCl – 35, ↓ Bacteroidetes al. (2018) chromium, 54, or 85 mg/kg/day); sodium dichromate nickel (Na Cr O – 44, 62, or 88 mg/kg/day); cobalt 2 2 7 chloride (CoCl – 27, 47, or 82 mg/kg/day); nickel chloride (NiCl – 177, 232, or 300 mg/ kg/day) for 5 days Chromium Cr-enriched Bacillus subtilis (CEBS): basic ↓ E. coli, ↓ Staphylococcus (CEBS Cecum Mice Yang et al. diet+clean water (Cr 0.06 μg/ml); basic diet or normal B. subtilis); ↑ Lactobacil- (2016) + water + CEBS (0.30 μg Cr/ml, 10 CFU/ lus, ↑ Bifidobacterium (CEBS and ml B. subtilis); basic diet + water + 1.537 normal B. subtilis) μg/ml CrCl ·6H O (0.30 μg Cr/ml); basic 3 2 7 7 diet + water + 10 CFU (10 /ml B. subtilis) Mercury 80 mg/L HgCl in drinking water for 90 days ↑ Coprococcus, ↑ Oscillospira, Cecum, rectum Mice Zhao et al. ↑ Helicobacter, ↓ Ignatzschineria, (2020) ↓ Salinicoccus, ↓ Bacillus Mercury Methylmercury (4 mg/kg body weight by 28 ↓ Bacteroidetes, ↑ Firmicutes in Feces Rats Liu et al. days; 29th day – methylmercury- (2019 b) group methylmercury compared poisoned + sodium selenite (Na SeO ) (2.74 with the control group; 2 3 mg/kg body weight sodium selenite) ↑ Bacteroidetes, ↓ Firmicutes in group methylmercury+sodium selenite compared with the methyl- mercury group Mercury Mercury sulfide (HgS) (α-HgS, 30 mg/kg), the 10 phyla HgS: ↑ Rikenellaceae, Duodenum, Mice Zhang et al. Zuotai (β-HgS, 30 mg/kg), HgCl (33.6 mg/ ↑ Lactobacillaceae, ↑ Helicobacte- ileum (2019) kg, equivalent Hg as HgS), or methylmer- raceae, ↓ Prevotellaceae cury (MeHg) (3.1 mg/kg, 1/10 Hg as HgS) HgCl : ↑ Odoribacteraceae, ↑ for 7 days Porphyromonadaceae, ↓ Lactobacil- laceae the 79 families HgS: ↑ Rikenellaceae, ↑ Lactobacil- laceae, ↑ Helicobacteraceae, ↓ Prevotellaceae HgCl : ↑ Odoribacteraceae, ↑ Porphyromonadaceae, ↓ Lacto- bacillaceae 306 A. Winiarska-Mieczan et al. Table 7 – contd. 1 2 3 4 5 6 Mercury Mercuric chloride (HgCl , 250 ppm, drink- On day 30: ↑ Proteobacteria, ↑ Cecum Chicken Zhou et al. ing water) after 30, 60, and 90 days of Tenericutes broilers (2020) exposure On day 60: ↑ Tenericutes Mercury Hg 2 mg/kg body weight (HgCl ); Cu + Hg ↓ Sporosarcina, ↓ Jeotgailcoccus, Cecum Mice Ruan et al. (Cu 2.5 mg/kg body weight, Hg 1 mg/kg ↑ Staphylococcus in the group with (2019) body weight) Hg and Cu+Hg ↑ Anaeroplasma in the group with Cu+Hg Nickel 300, 600 and 900 mg/kg NiCl for 42 days 300 to 900 mg/kg: ↓ Bifidobacteri - Ileum, cecum Broilers Wu et al. um spp., ↓ Lactobacillus, ↑ Escheri- chicks (2014) chia coli, ↑ Enterococcus spp. Nickel Drinking water containing 400 µM ↑ Bacteroides, ↑ Intestinimonas, Cecum Mice Zhou et al. NiSO ·6H O, for 21 days ↓ Lachnospiraceae_NK4A136, ↓ (2019) 4 2 Lachnospiraceae_UCG-001 ↓ Firmicutes/Bacteroides Lead 0.2 ml Pb solution at 20, 100, 500, or 1000 ↓ Coprococcus, ↓ Oscillospira, ↑ Feces, colon Mice Yu et al. mg Pb/kg body weight for 3 days Lactobacillus in linear manner with (2021) the Pb exposure dose. −1 Lead PbCl (1.34 g L in drinking water) and/or ↑ Helicobacter, ↓ Lachnospiraceae Cecum Mice Cheng et al. chlorogenic acid (30 mg per kg mouse per (Pb + chlorogenic acid) (2019) day) for 8 weeks Lead Chronic Pb exposure (50 ppm and 50 ppm Pb: ↓ Ruminococcus, ↓ Cecum Japanese Kou et al. 1000 ppm) Faecalibacterium, ↑ Bacteroides quails (2019) 1000 ppm Pb: ↓ Faecalibacterium,↑ Bacteroides Lead, cadmium Cd – CdCl or Pb – PbCl (5, 20 and 100 ↑ Lachnospiraceae Feces Mice Breton et al. 2 2 ppm) for 8 weeks (2013 c) Figure 1. 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Annals of Animal Science de Gruyter

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Bioactive compounds, antibiotics and heavy metals: Effects on the intestinal structure and microbiome of monogastric animals – a non-systematic review

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Publisher: de Gruyter
ISSN: 1642-3402
eISSN: 2300-8733
DOI: 10.2478/aoas-2022-0057
Publisher site: See Article on Publisher Site

Abstract

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Annals of Animal Science – de Gruyter

Published: Apr 1, 2023

Keywords: bioactive compounds; heavy metals; intestine structure; microbiome; monogastric animals

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Bioactive compounds, antibiotics and heavy metals: Effects on the intestinal structure and microbiome of monogastric animals – a non-systematic review

Bioactive compounds, antibiotics and heavy metals: Effects on the intestinal structure and microbiome of monogastric animals – a non-systematic review

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Bioactive compounds, antibiotics and heavy metals: Effects on the intestinal structure and microbiome of monogastric animals – a non-systematic review

Bioactive compounds, antibiotics and heavy metals: Effects on the intestinal structure and microbiome of monogastric animals – a non-systematic review

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