http://dx.doi.org/10.4314/sajas.v55i2.01

 

Gut dysbiosis: Nutritional causes and risk prevention in poultry, with reference to other animals

 

 

A. Salahi^I, ; W.A. Abd El-Ghany^II; Y.A. Attia^III, ; N.M. Zabermawi^IV; F. Bovera^V; V. Tufarelli^VI,

^IDepartment of Animal Science, Faculty of Agriculture, University of Zanjan, Iran
^IIDepartment of Poultry Diseases, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
^IIIDepartment of Agriculture, Faculty of Environmental Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
^IVDepartment of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
^VDepartment of Veterinary Medicine and Animal Production, University of Napoli Federico II, Napoli, Italy
^VIDepartment of Precision and Regenerative Medicine and Jonian Area (DiMePRe-J), Section of Veterinary Science and Animal Production, University of Bari Aldo Moro, Bari, Italy

 

 

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ABSTRACT

The poultry gastrointestinal microbiome consists of more than 900 bacterial species and their metabolites; it serves as an indicator of bird health and is influenced by nutrition, medication, and other factors. Dysbiosis is a form of reduced microbial diversity, characterised by the loss of beneficial microbes, the expansion of opportunistic microbes, and the disruption of tight junctions, as well as raised pro-inflammatory cytokines (interleukin-6 and interleukin-17), tumour necrosis factor-α, and Enterobacteriaceae, and decreased short-chain fatty acids. Dysbiosis leads to various disorders, including liver disorders, metabolic disease, cardiovascular disease, and neurological problems. It also impacts several bodily systems, such as the gastrointestinal tract, kidneys, the gut-liver axis (liver disease, hepatocellular carcinoma, autoimmune liver disease, and metabolic-associated fatty liver disease), the gut-lung axis (pneumonia and chronic obstructive pulmonary disease), the gut-microbiota axis (irritable bowel syndrome, inflammatory bowel disease, and constipation or stool hardness), and the gut-islet axis (hypertension, hyperglycaemia, diabetes, and hypercreatinaemia syndrome). Many factors, including medications (antibiotics, anti-tumour, and immunosuppressants), environmental pollutants (heavy metals, pesticides, microplastics, and atmospheric particulates), high levels of nutrients (protein, fat, salt, and sugar), and others (age, disease, habits, and genes), cause and enable gastrointestinal dysbiosis to develop. Nutritional strategies such as the administration of probiotics, prebiotics, antibiotics, or phytogenic feed additives, and the consumption of a high-quality, balanced diet, as well as early detection of gut health malfunction and an emphasis on increasing bird resilience, can reduce the risk of dysbiosis, modify the gut microbial balance, and make microbial eubiosis possible.

Keywords broiler, dysbiosis, gut microbiota, nutrition

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Introduction

The human microbiome is estimated to contain roughly 10¹³-10¹⁴ microbial cells, with a ratio of one microbial cell for every human cell (Sender et al., 2016). The diverse gastrointestinal microbiome (GM) primarily consists of bacteria from three major phyla: Firmicutes, Bacteroidetes, and Actinobacteria (Marchesi et al., 2016). This intricate microbiome operates as an extension of the host's genetic material and is estimated to possess 50-100 times more genes than the host genome. The human GM weighs approximately 2 kg and consists of 5000 species, whereas in chickens, the GM consists of more than 900 bacterial species and 117 bacterial genera (Sender et al., 2016). By the third day after hatching, every gram of ileal and caecal content contains 10¹¹ and 10⁹ microbial cells, respectively, and in older chickens, the GM contains more than 10¹⁴ bacteria, fungi, viruses, and protozoa (Zmora et al., 2019). The dominant phyla in avian intestines are Firmicutes (particularly the Clostridium, Enterococcus, Lactobacillus, and Ruminococcus genera), Bacteroidetes (particularly the Bacteroides and Prevotella genera), and Proteobacteria (Choi et al., 2015).

Hippocrates, a Greek physician from 460-370 BC, believed that all diseases begin in the gut, and a Turkish proverb states, "A treacherous friend and a crazy enemy are both waiting; you will be in trouble" (Salahi & Raad, 2018), warning that many harmful bacteria are waiting for an opportunity to overcome the beneficial microbes and disrupt the GM balance. A healthy gut is the main foundation for poultry health, optimum performance, economic profit, immunity, and physio-endocrine functions. The maintenance of gut health depends on the intestinal mucous layer, the GM, the effectiveness of the immune system, and appropriate nutrition and feeding, in terms of feed quality, dietary antigens, anti-nutrients, and mycotoxins (Shehata et al., 2022a, b).

The small intestine produces enzymes that are responsible for the digestion and absorption of nutrients. Any alteration in the breeder flock's nutrition, in-ovo feeding, or hatched chick diet can influence the intestinal morphology and, thus, the performance of the chicks (Salahi et al., 2011; 2015). Despite the fact that six-week-old Hubbard F15, Ross 308 breeder, and yellow-feathered broiler chickens have small intestines that measure only 199, 198, and 164 cm in length, respectively, and caeca that are only 40.1, 41.1, and 38 cm long, respectively (Kokoszynski et al., 2017; Guo et al., 2023a), these birds face numerous pressures and challenges within this two-meter lumen world.

Eubiosis is the exact opposite of dysbiosis, with dysbiosis describing a disturbance in the GM balance and intestinal bacterial homeostasis, as well as an increase in the ratio of harmful to beneficial bacteria (Figure 1).

 

 

DeGruttola et al. (2016) divided dysbiosis into three types: the loss of beneficial bacteria, the loss of overall bacterial diversity, and the overgrowth of pathogenic bacteria. Dysbiosis in poultry negatively influences growth, performance, health, flock uniformity, and welfare (Blachier et al., 2017; 2019; El-Saadony et al., 2021). Gut dysbiosis is also implicated in inflammatory diseases (Dahal et al., 2023), psychological manifestations of the gut-brain axis (Mohan et al., 2023), and endotoxemia due to the disruption of the gut barrier after heat stress (Ringseis & Eder, 2022). Healthy flocks with high productive performance and health indicate eubiosis, but not dysbiosis.

There are several causes of dysbiosis, including reduced microbial diversity following disease or antibiotic treatment, excessive heat stress or cold stress, high stocking densities, poor-quality water, the absence of probiotic administration, the presence of environmental toxins, and poor-quality sleep (typically caused by a short dark period or insufficient resting time). Dietary factors, such as a sudden change in diet, a poor-quality diet, malnutrition, the ingestion of mouldy maize or soybean meal, feed containing rancid fats or putrefied animal proteins, and a low fibre intake, will also increase the risk of dysbiosis. Dysbiosis following avian influenza virus infection reduces the number of gut microbes and increases the number of secondary pathogenic bacteria, such as Escherichia coli, as well as increasing the gene expression of pro-inflammatory cytokines such as interferon (IFN)-r and IFN-α, and interleukin (IL)-1b, IL-6, IL-22, and IL-17A, and reducing the expression of genes responsible for the health of the intestinal mucin layer and mucosa (Abd El-Hack et al., 2022).

The quantity of feed and water intake and the environment surrounding poultry are important factors that are reflected in the risk of dysbiosis. The adverse effects of dysbiosis on bird health include decreasing performance, an increased risk of zoonotic pathogens and food contamination, as well as poorer health, welfare, and economic outcomes (El-Saadony et al., 2021). The duration of exposure to dysbiosis and pathogenic bacteria is also an important factor. Prolonged dysbiosis increases the sensitivity of the gut microorganisms to the overgrowth of harmful bacteria (Abd El-Hack et al., 2021).

Omics' sciences include genomics (DNA), transcriptomics (RNA), proteomics (proteins), and metabolomics (metabolite assays), and are strongly associated with bioinformatics and biostatistics to manage the large amounts of data that are generated. Omics technology is commonly used in human medicine to survey the microbial ecology of the digestive tract and gut health (Nibali & Henderson, 2016), but it has not received enough attention in poultry science. Extensive studies have been conducted on the human and mouse microbiomes, but few have focused on the microbiome's relevance in poultry production systems. Strict biosecurity measures and good nutrition, including high-quality diets, balanced diets, keeping anti-nutrients to a minimum, and the administration of next-generation probiotics, have been found to increase the proportion of beneficial microbes and reduce the numbers of pathogenic bacteria, thereby helping to optimise performance (Salahi & Abd El-Ghany, 2024) (Figure 2). This literature review therefore aims to discuss the relationship between gut dysbiosis and nutritional causes, as well as the assessment and amelioration of risk.

 

 

The relationship between nutrition and dysbiosis

The effects of dysbiosis on feed intake (FI) in poultry

A healthy GM is crucial for enhancing the absorption of dietary nutrients (Tassoni et al., 2023). Poultry, including chickens and turkeys, lack certain enzymes (such as cellulase) that are necessary to break down plant fibres (such as cellulose) in the diet. However, the GM can aid in the digestion of plant materials through fermentation. The GM is capable of producing enzymes that break down indigestible dietary polysaccharides and convert them into their compositional fermentable sugars and short-chain fatty acids (SCFAs), which can be utilised by poultry (Dunkley et al., 2007). The GM also stimulates nitrogen metabolism, which is essential for the formation of bacterial cellular proteins, allowing bacteria to act as a source of amino acids (AAs) and vitamins for the host (LeBlanc et al., 2013). Nevertheless, the ability of the GM to break down plant fibres is limited and cannot fully replace the function of digestive enzymes.

The SCFAs produced by bacterial fermentation include acetate, propionate, and butyrate (Morrison & Preston, 2016), which are important sources of energy for chickens. These SCFAs also contribute to maintaining the integrity of the intestinal mucosa, improving glucose and lipid metabolism, controlling energy consumption, and regulating the body's immune system and inflammatory responses (Agus et al., 2020; Shehata et al., 2022c). Short-chain fatty acids stimulate the proliferation of epithelial cells present in the gut, increasing the surface area available for nutrient absorption (Dibner & Richards, 2005). Furthermore, the bacteriostatic properties of SCFAs help inhibit foodborne pathogens, including Salmonella spp. (Ricke, 2003), and SCFAs improve feed efficiency by promoting sodium and water absorption (Clavijo & Flórez, 2018). Short-chain fatty acids also stimulate the production of IFN-α and IFN-β and enhance the function of T-regulatory cells. This process promotes the secretion of anti-inflammatory cytokines such as IL-22, as well as the humoral immune response through the production of immunoglobulin A and immunoglobulin G (Schuijt et al., 2016).

Over the past decade, few studies have focused on the role of the GM in the regulation of appetite, as most studies have focused on the interactions between the nervous and endocrine systems in this context. The GM generates metabolites (such as the SCFAs) that regulate appetite and stimulate gut hormone secretion by reducing energy intake and glucose output, consequently inducing energy homeostasis (Byrne et al., 2015; Chambers et al., 2015). The most dominant phyla in the gastrointestinal tracts of poultry are Firmicutes, which produce butyrate; Bacteroidetes, which produce acetate and propionate; and Tenericutes; Proteobacteria; and Actinobacteria (Wei et al., 2013). However, some Clostridium spp. (which belong to the Firmicutes phylum) can produce harmful metabolites that degrade cellulose and reduce SCFA production (Louis & Flint, 2009). In contrast, Actinomycetes produce nutrients and metabolise SCFAs, enhancing digestive efficiency and improving feed conversion rates (Polansky et al., 2016).

Acetate, propionate, and butyrate are produced by the GM in a ratio of 3:1:1 (Canfora et al., 2015), or a molar ratio of 60:25:15 (Mortensen & Clausen, 1996), and 70-140 mmol/L of SCFAs are produced in the human colon (Mortensen & Clausen, 1996). The fermentation of complex carbohydrates into SCFAs directly affects satiety; reduces appetite by changing the levels of glutamate, glutamine, gamma-aminobutyric acid (GABA), and neuropeptides (Babakhani & Hosseini, 2019); and stimulates gut hormone secretion, hypothalamus activity, and appetite regulation. The receptors involved in these pathways include the free fatty acid receptors, FFAR2 and FFAR3 (Kim et al., 2022).

Propionate, which makes up 15%-20% of the SCFAs produced in the gastrointestinal tract (Kim et al., 2022), is mainly used by the gut epithelium (Hosseini et al., 2011). Propionate is produced by a limited number of bacterial species, and propionate and butyrate are generated through three main pathways: the succinate pathway, which is the main pathway and is primarily used by Bacteroidetes and Firmicutes spp.; the acrylate pathway, which is used by Firmicutes spp.; and the propanediol pathway (also used by Firmicutes spp.). With the increase in pH from the caecum to the distal colon, the bacterial population shifts from butyrate-producing bacteria (Faecalibacterium prausnitzii and Roseburia spp.) to propionate and acetate-producing bacteria (Bacteroides) (Walker et al., 2005). Maintaining the balance of the gut SCFAs is important, as propionate reduces myeloperoxidase, while increasing catalase and superoxide dismutase in the serum and colons of mice (Tong et al., 2016). A ketogenic diet decreases the availability of glucose, and SCFAs are thus utilised as an energy source, whereas a high-fat diet increases the polyunsaturated fatty acid (PUFA), butyrate, and acetate uptake from the intestines (Eor et al., 2021). Propionate treatment for 40 days caused an increase in adenosine triphosphate, mitochondrial catalase, superoxide dismutase, glutathione peroxidase, and nicotinamide adenine dinucleotide, while decreasing 8-hydroxy-2'-deoxyguanosine and hippocampal neuronal loss (Cheng et al., 2019). The intraperitoneal injection of propionate in mice was found to reduce FI (Goswami et al., 2018), but this result was not observed in humans (Darzi et al., 2016). In pigs, propionate infusion did not reduce FI in the long term, possibly because of the fast metabolism of propionate (Zhang et al., 2022) or the absorption of sodium propionate in the portal veins for gluconeogenesis in the liver (Yu et al., 2019). The intra-caecal inoculation of propionate in pigs stimulated the release of the gut hormones glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), and upregulated the expression of both PYY and GLP-1R mRNA; it also upregulated FFAR2 and FFAR3 expression in the colon mucosa, consequently suppressing appetite (Zhang et al., 2022).

Acetate produced by the GM suppressed the appetites of rats either through its direct effect on the hypothalamus (Frost et al., 2014; Byrne et al., 2015) or by crossing the blood-brain barrier. Acetate was found to downregulate the expression of the agouti-related peptide (AgRP) in NPY/AgRP neurons and upregulate the expression of pro-opiomelanocortin (POMC) in POMC/CART neurons in the hypothalamus (Koda et al., 2005; Frost et al., 2014). Peptide YY and GLP-1 are intestinal hormones involved in satiety homeostasis that affect the main neural centre for feeding, behaviour, energy status sensing, and appetite signals in the hypothalamus (Zhang et al., 2022b), causing satiety (Greiner & Backhed, 2016). In addition, cholecystokinin and ghrelin secreted by enteroendocrine cells modulate FI (Han et al., 2021).

Feeding behaviour in mice is affected by the depletion of the GM, which leads to the over-consumption of palatable high-sucrose pellets and the reduction of Lactobacillus Johansson colonisation (Ousey et al., 2023). More research is needed to understand how the serotonergic and acidergic systems affect appetite and FI, and to determine the relationship between these systems and changes in the GM. The intra-cerebro-ventricular injection of serotonin (5-HT) in broiler chickens results in a reduction in FI, and the central serotonergic system plays a major role in the modulation of ingestion behaviour (Zendehdel et al., 2012; 2013). The regulation of appetite is controlled by neurotransmitters in the central nervous system (Parker et al., 2014). In poultry, the brain opioid receptors, including the μ, δ, and κ receptors (Le Merrer et al., 2009), play a direct role in FI regulation (Kozlov et al., 2013); injection of a μ-opioid receptor agonist reduced FI, but injection of δ- and κ-opioid receptor agonists increased it (Bungo et al., 2005).

It may be concluded that dysbiosis of the GM in poultry alters the population of propionate-producing microbes that are able to produce larger amounts of propionate (such as Bacteroidetes and Firmicutes). Propionate, after absorption from the digestive system, stimulates the secretion of the hormones PYY and GLP-1, both of which act as appetite suppressants. These hormones send satiety messages to the central nervous system and decrease FI. Dysbiosis also influences appetite centres within the brain by increasing systemic inflammation through an increase in the production of inflammatory metabolites, such as bacterial lipopolysaccharide (LPS), and the activation of the immune system through the production of cytokines such as IL-6 and tumour necrosis factor-α.

The relationship between dysbiosis and feed quality and particle size

Feed quality should be optimised by ensuring the provision of a balanced, palatable diet with high nutrient digestibility, availability, and uniformity. This diet should be appropriately processed, and should provide an adequate supply of macronutrients and micronutrients; it should have an ideal AA profile, and be free of harmful substances such as mycotoxins, pesticides, heavy metals, and pathogens. The provision of an optimal diet could decrease oxidative stress and inflammation (Bärebring et al., 2018), enhance total serum antioxidant capacity and saliva and urine secretion (Hassimotto et al., 2008), promote a healthy GM, and reduce the risk of dysbiosis (Figure 3). A combination of fermentable fibres and polyphenols in the diet has been found to have a positive effect on bacterial growth and metabolite production in the gut, in terms of an increase in SCFA production and a decrease in indole and ammonia production (Whitman et al., 2024).

 

 

Following inflammation, a decrease in the number of butyrate-producing bacteria facilitates the establishment of enteric pathogens such as Salmonella spp., as butyrate helps control pathogen proliferation and decreases the expression of pro-inflammatory cytokines (Chen & Vitetta, 2020). Feeding mice diets containing germinated barley malt resulted in increased butyric acid production in the caecum and increased the butyric acid concentration in the portal serum, with anti-inflammatory effects (Zhong et al., 2015). However, replacing maize-based diets with low-quality diets formulated using barley and wheat, which contain non-starch polysaccharides (NSPs), resulted in the activation of pattern recognition receptors (PRRs) for the initiation of the immune response and maintenance of homeostasis. This increased the expression of the LPS-recognising toll-like receptor gene (TLR4), stimulated the innate immune response, activated the pro-inflammatory pathway, and enhanced the production of cytokines to reduce inflammation (Shi et al., 2006). Toll-like receptor signalling pathways activate nuclear factor-κΒ (NF-κΒ, a component of the innate host defence), and NSPs have negative regulatory effects on NF-κΒ. The effects of pathogen-associated molecular patterns on PRRs lead to cell death programmes, and the binding of microbial pathogen-associated molecular patterns activates the NF-κΒ and IFN regulatory factor pathways (Singh & Pollard, 2015). Four families of PRRs, including TLRs, C-type lectin receptors, nucleotide oligomerisation domain-like receptors, and retinoic acid-inducible gene I-like receptors, have extensive functions (Neerukonda & Katneni, 2020), and ten and 13 types of TLRs have been identified in chickens and mammals, respectively (Turin & Riva, 2008).

Imbalanced rations may lead to an increase in gut permeability, intestinal dysbiosis, the abundance of harmful bacteria, disharmony of the GM, impairment of digestive system function, and acceleration of the onset of chronic liver disorders (Figure 4). There are more than 26 symptoms of dysbiosis, including those related to the digestive system (gas production, stomach rumbling and flatulence, constipation or diarrhoea, acid reflux or heartburn, thickened tongue, strong fluctuations in appetite, abdominal pain, nausea, irregular bowl movements, and belching and bloating) and other physiological systems (anxiety, nervousness, chronic fatigue, hair loss, heart failure, and chest pain).

 

 

Feed quality changes the diversity of the GM and the ratios of bacterial species. An increase in the ratio of Firmicutes to Bacteroidetes results in metabolic diseases such as obesity in humans, and causes changes in energy acquisition, digestive tract permeability, bile acid (BA) metabolism, central nervous system function, and immune system regulation (Thursby & Juge, 2017). In addition, increasing microbiome diversity in hens led to enhanced feed efficiency by optimising nutrient absorption and increasing the proportions of fibrolytic bacteria, such as Alistipes and Anaerosporobacter (Bernard et al., 2024).

The recommended ratio for omega-6/omega-3 PUFAs is 4-6:1 (Tan et al., 2016), and the recommended ratio for saturated fatty acids/monounsaturated fatty acids/omega-3 and omega-6 PUFAs is 1:1.5:1 in humans (WHO, 2008), or 1:1:1 in mice (Tan et al., 2016). The optimal saturated fatty acid/monounsaturated fatty acid ratio is 1:1-2, and the recommended omega-3 to omega-6 ratio for broilers is 1:5. The consumption of diets rich in omega-6 fatty acids enhanced the growth of LPS-producing bacteria (Kaliannan et al., 2015). Dietary omega-3 PUFAs have been found to modulate the abundance and type of gut microbiota; alter the levels of the pro-inflammatory IL-17, LPS, SCFAs, and acid salts (Fu et al., 2021); and inhibit IL-17A secretion (Chehimi et al., 2019). Polyunsaturated fatty acids have anti-inflammatory properties and cause the release of IL-10, thereby reducing intestinal inflammation (Zeyda et al., 2002; Wenderoth et al., 2024).

Microbial metabolites play a central role in metabolic homeostasis and the maintenance of physiological functions (Neis et al., 2015). These metabolites have been detected in human and bird faeces, urine, liver, cerebrospinal fluid, and blood serum samples. Short-chain fatty acids, AA, choline, lipid metabolites, vitamins, and BAs are the most important metabolites, as they are necessary for intestinal homeostasis and the pathogenesis of some diseases (Agus et al., 2020; Lavelle & Sokol, 2020). Other metabolites, including SCFAs and quorum-sensing agents, are produced only by the intestinal microbiota and not by the host (Li et al., 2018). The caecal microbiota produce vitamins, indole, SCFAs, and bacteriocins, which play a vital role in improving avian gut health and performance parameters (Aruwa et al., 2021).

Poultry ration feed particle size influences FI, growth rate, and gastrointestinal development (Gabriel et al., 2008; Safaa et al., 2009). For example, coarse feed particles increased gizzard weight by decreasing gut pH (Amerah et al., 2007); promoted intestinal motility (Ferket, 2000); triggered the secretion of cholecystokinin and pancreatic enzymes (Svihus, 2004); modulated gastrointestinal reflux (Duke, 1992); improved intestinal villi height, crypt depth, and surface area (Novotný et al., 2023); increased the acidification of the hindgut and stomach; controlled E. coli and Salmonella counts (Kiarie & Mills, 2019); and resulted in improved gut health. A coarse particle size (0.9 mm) has also been found to cause an increase in the death rate of Salmonella enterica serovar Typhimurium DT12 (Huang et al. 2006). Different-sized coarse maize particles increased the relative gizzard weight and quantity of Peptostreptococcaceae, but reduced Lactobacillaceae abundance. In contrast, fine-ground maize particles increased the relative abundance of Acinetobacter (Yan et al., 2022). Particle size is more important in mash diets than in crumble and pelleted diets. Therefore, the ideal particle size recommended for maize-soybean meal-based diets is 0.6-1.0 mm for starters and 1.0-1.5 mm for growers. It has also been suggested that particle size can be coarser in diets for male chickens than female chickens, and that the optimal feed pellet size is 3-4 mm.

The relationship between dysbiosis and AA

Although some intestinal AA are of host bacterial origin, most are of feed origin. All 20 types of AA play a role in the homeostasis of the GM (Li et al., 2017). The gut microbiota produce lysine and threonine, which influence diseases such as obesity and diabetes in humans (Neis et al., 2015). Amino acids such as arginine, glutamine, and threonine play a key role in maintaining the intestinal health of broilers, and it is recommended that their dietary levels are increased by 0.5%-1.0% in times of intestinal challenge (Chalvon-Demersay et al., 2021a). Amino acids have a protective effect on all four pillars of health of the digestive system, namely the microbiome, immunity, epithelial function, and oxidative stress (Chalvon-Demersay et al., 2021b). Threonine is necessary for the function of mucin-producing epithelial cell barriers (Bortoluzzi et al., 2018), and glycine, glutamate, and cysteine are constituents of glutathione, which is necessary for reducing free radicals and oxidative stress (Song et al., 2016). Eimeria spp.-induced coccidiosis was found to reduce FI, bird performance, AA transportation and availability (Tan et al., 2016), digestibility (Rochell et al., 2016), and plasma concentrations of arginine, glutamine, asparagine, and aspartate, but increased ornithine and lysine concentrations (Rochell et al., 2016).

Tryptophan is an α-AA used in protein biosynthesis, and is a precursor for the biosynthesis of 5-HT and melatonin, which are endocrine neurotransmitters (Agus et al., 2018; 2020). Serotonin 5-hydroxytryptamine is a biogenic amine that serves as a neurotransmitter in the gut and brain, which is produced by serotonergic neurons in the brain (1%-2%) and by enterochromaffin cells and intestinal mucosa (95%) (Gershon & Tack, 2007). Serotonin plays a key role in various physiological body functions, including feeding, temperature regulation, mood, aggression, stress, depression, sexual behaviour, pain perception, motor control, circadian rhythm, and sleep (Walther et al., 2003; Nonogaki et al., 2008; 2009). Alberghina et al. (2020) reported that the normal plasma level of 5-HT in healthy layer hens was 4.24 μmol/L, and that this was significantly lower than in hens with foot pad dermatitis (6.88 μmol/L) (Figure 4). Approximately 95% of blood 5-HT is carried by platelets in mammals (Anderson et al., 1987). However, the measurement of 5-HT in plasma is more reliable than the measurement in whole blood for the assessment of the inflammatory response and the evaluation of chicken welfare (Alberghina et al., 2020).

Tryptamine is an indolamine metabolite of tryptophan that transmits local signals to the intestinal mucosa and the brain (Agus et al., 2018). Synbiotic bacteria, such as Clostridium, Lactobacillus, Blautia, and Ruminococcus, degrade tryptophan into tryptamine, which has a structure similar to that of 5-HT (Williams et al., 2014; Agus et al., 2018). The manipulation of the GM changes the balance of the microbial metabolism of tryptophan and thus the production of 5-HT. Bacteria belonging to the genera Streptococcus, Lactobacillus, Lactococcus, Escherichia, and Klebsiella produce 5-HT by expressing tryptophan synthase (Hoseini-Tavassol et al., 2022). Approximately 10% of humans have intestinal bacteria that encode decarboxylases and degrade tryptophan (Williams et al. 2014). The effects of tryptophan metabolites produced by intestinal microbes on metabolic diseases, such as fatty liver disease, osteoporosis, obesity, diabetes, inflammatory bowel disease (IBD), cardiovascular diseases, kidney diseases, nerve disorders, mental depression, anxiety, and autism, have been studied (Agus et al., 2018). In patients with diabetes, the oral administration of a probiotic containing Lactobacillus rhamnosus GG induced changes in the level of tryptophan and the qualitative pattern of metabolite formation, and also decreased the production of inflammatory cytokines (Mondanelli et al., 2020).

Tryptophan positively influences hormone secretion, immune organ development, and the quality and quantity of meat and eggs (Fouad et al., 2021). Tryptophan and its metabolites have the ability to pass through the blood-brain barrier and affect the metabolism of neurotransmitters; therefore, any decrease in dietary tryptophan can cause the induction of neurological diseases (Agus et al., 2018). Indole is the main tryptophan metabolite produced by the intestinal bacteria (Gao et al., 2018). Other microbial metabolites of tryptophan, including indole-3-acetic acid and indole-3-propionic acid, inhibit central nervous system inflammation (Rothhammer et al., 2016), intestinal permeability, and the innate and acquired immunity of the host. Gut microbiome dysbiosis affects intestinal tryptophan metabolism through the neurohormonal pathway in patients with chronic kidney disease (Jazani et al., 2019). Indole affects brain function and behaviour (Whitfield-Cargile et al., 2016) through communication with the intestinal epithelium (Jennis et al., 2018), the creation of resistance in tight junctions, and the expression of anti-inflammatory cytokines. In addition, indole-3-propionic acid is produced by Peptostreptococcus russellii and some Lactobacillus spp. (Jennis et al., 2018; Lavelle & Sokol, 2020), contributing to the anti-inflammatory effects of the intestinal microbiome (Jennis et al., 2018). The administration of grape extract containing polyphenols, in conjunction with L-arginine, L-threonine, and L-glutamine, was found to improve gut permeability (Barekatain et al., 2021) and the ileal digestibility of AAs in broiler chickens under stress (Chalvon-Demersay et al., 2021b).

Future research should focus on the precise mechanisms by which AA (particularly arginine, glutamine, threonine, and tryptophan) and microbial metabolites (particularly indole and tryptamine) influence the balance of the GM, intestinal homeostasis, immune health, and neurological function in poultry under normal and challenging conditions. More investigation into the effects of combining AAs with probiotics, prebiotics, and polyphenols on bird health and performance is required, especially under stress or disease conditions. However, there are many research gaps, and a deeper understanding of these interactions could help reduce antibiotic use, improve meat and egg quality, and enhance disease resistance. Further investigations will be fundamental for creating more effective strategies in sustainable poultry farming, improving bird welfare, and ensuring overall health.

The relationship between dysbiosis and branched chain AAs (BCAAs)

Branched chain AAs, such as leucine, isoleucine, and valine, are essential AAs that positively impact performance, growth, immunity, intestinal health, energy homeostasis, and transamination. They also act as signalling molecules for glucose and lipid regulation, as well as protein synthesis in poultry (Kim et al., 2022). Moreover, BCAAs are important for liver cell proliferation, insulin resistance, and thermogenesis control in brown adipose tissue (Hoseini-Tavassol et al., 2022). Branched chain AAs are important nutrients for protein biosynthesis and the maintenance of intestinal barrier function (Zhou et al., 2018). However, the addition of cereals containing high levels of leucine to low-protein diets has a negative effect on growth (Kim et al., 2022). In contrast, the addition of arginine and BCAAs to diets with low crude protein contents improved the immune response and intestinal integrity of broiler chickens challenged with Eimeria spp. (Liu et al., 2023).

There is a complex relationship between the diet, the GM, and disease. The supplementation of mouse diets with BCAAs promoted the health of some microbiota, such as Akkermansia and Bifidobacterium, but reduced the counts of Enterobacteriaceae (Agus et al., 2020). In addition, supplementing the diets of colon cancer patients with high amounts of BCAAs and aromatic AAs aided in adjusting the intestinal microbiota and their metabolites, as well as preventing disease progression (Yachida et al., 2019).

A high level of BCAAs in the blood is considered a potential indicator of metabolically associated fatty liver disease in humans. Supplementing mice's diets with BCAAs was found to improve the diversity, composition, and abundance of the GM when the mice had high-fat diet-induced metabolically associated fatty liver disease (Zhang et al., 2022).

The relationship between dysbiosis and dietary protein balance

The GM stimulates nitrogen metabolism and produces bacterial cellular proteins, allowing bacteria to act as sources of AAs or proteins for the host (LeBlanc et al., 2013). Improving the balance of the GM can be achieved by ensuring a proper protein/carbohydrate ratio in the diet. High-protein diets have many effects on the intestinal microbiota (Alou et al., 2016), and increasing the dietary protein content decreases the share of carbohydrates but increases the abundance of butyrate-producing bacteria such as Bacteroides, Clostridium cluster XIV, Roseburia, Eubacterium rectale, F. prausnitzii, Bifidobacteria, and Lactobacilli, which exhibit proteolytic activity (Graf et al., 2015; Maukonen & Saarela, 2015; Alou et al., 2016).

Imbalanced diets can induce intestinal dysbiosis directly or indirectly. For instance, a ration containing a high crude protein/metabolisable energy ratio may lead to the occurrence of excessive undigested protein in the caeca, and consequently the overgrowth of proteolytic microbes, producing hydrogen sulphide and ammonia. Rations with an imbalanced protein content also have harmful effects on the GM (Blachier et al., 2017; 2019), as a high protein content results in the production of toxic metabolites, N-nitroso compounds, amines, indolic and phenolic compounds, and gaseous products that suppress the expression of pro-inflammatory genes (Yao et al., 2016; Blachier et al., 2017; 2019; Tassoni et al., 2023) (Figure 5).

 

 

The relationship between dysbiosis and BAs

The Aviagen guides for Ross 308 broiler chickens show that energy requirements for starter, grower, finisher one, and finisher two diets were 3010, 3175, 3175, 3225, and 3225 kcal/kg, respectively, in 1999, decreasing to 2975, 3050, 3075, 3100, and 3125 kcal/kg, respectively, in 2022 (Aviagen, 2022). This indicates a decreasing trend in terms of the energy requirements of broiler chickens during the five periods of rearing. The dietary supplementation of BAs was found to increase growth and improve carcass quality and lipid metabolism in broiler chickens (Ge et al., 2019), decrease mortality rates and enhance lipid metabolism in layers (Sun et al., 2023), and treat non-alcoholic fatty liver disease in humans (Jiao et al., 2018). Bile acids are small molecules that are synthesised from cholesterol in liver cells and act as detergents for emulsifying fats, as well as being involved in the digestion and absorption of lipids and fat-soluble vitamins. Approximately 95% of BAs are absorbed in the ileum by active transport and reach the liver through the hepatic portal system (Ahn et al., 2003), whereas BAs are absorbed through passive diffusion in the jejunum (Tancharoenrat et al., 2014).

Bile acids enhance glycogen synthesis and insulin sensitivity in the liver; increase insulin secretion by the pancreas (Hoseini-Tavassol et al., 2022); facilitate energy consumption in the liver, brown adipose tissue, and muscle; and play a role in thermogenesis (Agus et al., 2020). There are two types of BAs: primary BAs (PBAs) and secondary BAs (SBAs). Primary BAs consist of chenodeoxycholic acid and cholic acid conjugated to glycine or taurine before secretion, and are necessary for the digestion and absorption of lipids and vitamins. Primary BAs are the products of cholesterol breakdown in the liver, where they are recycled and then passed into the intestine to be converted into SBAs by the intestinal microbiota (Ridlon et al., 2016). Secondary BAs include deoxycholic acid, lithocholic acid, and ursodeoxycholic acid (National Institute of Diabetes and Digestive and Kidney Diseases, 2012), and activate macrophages to produce inflammatory cytokines (Joyce & Gahan, 2017). Low concentrations of SBAs in humans have anti-inflammatory effects, whereas high concentrations cause heart damage (Rasouli & Zeighami, 2023). The dietary supplementation of BAs in broilers increased their body and breast muscle weights and improved the serum lipid profile and microbial diversity (Hu et al., 2024).

The GM plays an important role in BA metabolism. Bile acids are broken down by bile salt hydrolase produced by Lactobacillus, Clostridium, Bifidobacterium, and Enterococcus spp. in the gastrointestinal tracts of humans. In addition, Clostridium scindens, which has α/β-7 dehydroxylation activity, is capable of converting PBAs to SBAs, thereby decreasing the amount of BA entering the intestine and reducing the number of some gram-positive bacteria, such as Blautia and Rumminococcaceae (Hoseini-Tavassol et al., 2022). An increase in the concentration of PBAs is associated with an increase in Firmicutes and deoxycholic acid-producing Clostridium spp., and a decrease in Bacteroidetes and Actinobacteria (Ridlon et al., 2014; 2015). The Ruminococcaceae family promotes the production of SCFAs (specifically butyrate) and plays a key role in gut health, as their deficiency results in human IBD (Sokol et al., 2008; Morgan et al., 2012) and hepatic encephalopathy (Bajaj et al., 2012). Some probiotic-producing bacteria, such as Lactobacillus, Bifidobacterium, and C. scindens, show resistance to BAs due to the activation of glycolysis (Hoseini-Tavassol et al., 2022). Bile acids rapidly affect bacterial metabolism, causing membrane damage and altering AA, nucleotide, and carbohydrate metabolism (Tian et al., 2020). The BAs also play a key role in the function and permeability of the intestinal epithelium, and in maintaining intestinal homeostasis (Agus et al., 2020). They prevent the overgrowth of bacteria and the production of mucosal damage factors such as pro-inflammatory cytokines, IL-8, inducible nitric oxide synthase, and carbonic anhydrase-12 (Hoseini-Tavassol et al., 2022). In obese individuals, dysbiosis, including changes in microbial metabolism, is associated with the occurrence of liver cancer (Yoshimoto et al., 2013). Dysbiosis induces SBA deficiency and reduces the abundance of Ruminococcaceae, whereas supplementation with SBA ameliorates inflammation-induced colitis (Sinha et al., 2020). The protective effects of SBAs depend mainly on the Takeda G protein-coupled receptor 5, a BA receptor (Sinha et al., 2020).

The supplementation of BAs increased the microbial diversity in broiler chicken caecal digesta (increasing the abundance of Firmicutes, Lactobacillus, Anaerostipes, and Sellimonas), but reduced liver and abdominal fat weights, triglycerides, total cholesterol, the abundance of Barnesiella and Akkermansia, and the occurrence of fatty liver disease, via modulation of the GM (Hu et al., 2024). Most bile salts are not tolerated by Akkermansia (Hagi et al., 2020). Bile acids increase the permeability of bacterial cell membranes and produce antimicrobial activity, particularly against gram-negative bacteria (Tian et al. 2020). Moreover, BAs modulate the GM and its metabolites to resist heat stress in broiler chickens (Yin et al., 2021). Proteobacteria are an indicator of hepatic steatosis in mice; therefore, BAs could be used to inhibit the abundance of Proteobacteria that is induced by a high fructose diet (Vasques-Monteiro et al., 2021). In addition, the presence of Ruminococcus torques in the gastrointestinal tract is vital for lipid deposition in poultry (Lyu et al., 2021).

The relationship between dysbiosis and dietary carbohydrates and fats

Fermentable ß-glucans, β-fructans, inulins, pectins, and oligosaccharides are fermented to produce SCFAs (Canfora et aí., 2015), and carbohydrates are thus associated with GM changes in humans (Table 1).

 

 

Dietary fibres and fats also affect the GM (Alou et al., 2016), by enhancing the abundance of butyrate-producing bacteria (Blautia, E. rectale, Roseburia, F. prausnitzii, and other Faecalibacterium spp.), Lactobacilli, and Bifidobacteria. Different fibre fermentation processes occur in the distal colon of the human intestine to enhance the proportions of different Bacteroidetes spp. (Dominianni et al., 2015; Graf et al., 2015; Maukonen & Saarela, 2015). High-carbohydrate diets lead to an increase in the number of bacteria that are involved in fermentation, such as Clostridium cluster XVIII, Lachnosporaceae (Clostridium colostridioforme), Ruminococcaceae (F. prausnitzii), and Prevotella (Alou et al., 2016).

The effects of fats on the diversity of the intestinal microbiota are indirect. Increasing the quantity of dietary fat stimulates the production of BAs and consequently accelerates the growth of bacterial species that metabolise BAs (Graf et al., 2015; Maukonen & Saarela, 2015). Diets rich in fats therefore increase the abundance of BA-tolerant bacterial species, such as Alisitpes, Bacteroides, and Bilophila (Alou et al., 2016).

The relationship between dysbiosis and mycotoxins

Mycotoxins are metabolites produced by the fungi Aspergillus, Fusarium, and Penicillium. The most common mycotoxins in poultry feed are the fumonisins (FUM) and deoxynivalenol (DON), both of which negatively affect the GM composition. The main damaging effects of mycotoxins on the gut health of broiler chickens are changes in GM homeostasis, changes in the caecal microbiome composition, increases in diversity and microbial richness, intestinal damage, and the activation of gut inflammation (Elmassry et al., 2022; Shanmugasundaram et al., 2023). Changes in the intestinal microbiota due to various mycotoxins are summarised in Table 2.

 

 

Mycotoxins mainly target intestinal epithelial cells; however, the GM plays a prominent role in mycotoxin detoxification (Grenier & Applegate, 2013). Gut microbial diversity can be increased by subclinical doses of DON (Lucke et al., 2018) and FUM (Antonissen et al., 2015). In piglets, feeding FUM (fumonisin B1) at a dose of 12 mg/kg increased intestinal Lactobacillus but decreased the abundances of Lachnospiraceae and Veillonellaceae families (Mateos et al., 2018). In addition, mycotoxins, including DON, fumonisin B1, aflatoxin B1, ochratoxin A, zearalenone, and patulin, have adverse effects on the number of goblet cells that produce mucus, epithelial cell function and integrity, and GM composition (Attia et al., 2016; Robert et al., 2017). Diets containing subclinical levels of FUM and DON (3 and 4 mg/kg, respectively), resulted in increases in Defluviitaleaceae and Lachnospiraceae counts, decreases in Moraxellaceae and Streptococcaceae counts, and changes in caecal microbial composition and intestinal function (Shanmugasundaram et al., 2023). The United States Food and Drug Administration recommends maximum levels of 5 and 50 mg/kg for DON and FUM, respectively, in poultry finisher diets.

Studies on the effects of mycotoxins on the GM, and vice versa, have typically been conducted using high doses of mycotoxins, and research on the interactions between the GM and mycotoxins is still in its initial stages. It is therefore not possible to reach a conclusion about the impact of mycotoxins on health (Guerre, 2020). Administering a detoxifying compound at a dose of 1 g/kg to broiler chickens fed an aflatoxin-contaminated ration resulted in a stable GM, reduced the histopathological lesions of organs, and decreased some serum enzyme activities (Guo et al., 2023b). It can therefore be concluded that to prevent intestinal dysbiosis, the use of mycotoxin binders in poultry rations should be mandatory in high-risk areas (areas with high temperatures and humidity), in cases where feed has been improperly stored, in unsafe and low-quality feed, or for preventative purposes. Furthermore, better results have been obtained with multi-component binders that combine clay (bentonite or montmorillonite), yeasts (including glucomannans), and enzymatic detoxifiers (fumonisin esterase and zearalenone hydrolase).

The relationship between dysbiosis and anti-nutrients

Anti-nutritional factors and low-quality diets adversely affect the GM, gut health (intestinal mucosal integrity), and immunity. Therefore, it is important to prevent factors that cause dysbiosis through nutritional manipulation.

Phytate and NSPs are soluble and non-digestible nutrients in monogastric animals, and they are the main anti-nutritional factors in poultry nutrition. High levels of anti-nutrients increase the viscosity of the intestinal contents and consequently create the opportunity for infection, as they produce a suitable environment for the growth of harmful bacteria such as E. coli and Clostridium perfringens, and decrease the nutrient passage rate and adsorption (Raza et al., 2019). Some physico-chemical intestinal conditions, such as mucus secretion and composition, acidity, inflammation, and the secretion of bacteriostatic peptides by the pancreas, decrease nutrient absorption and change the GM and metabolite composition (Bushra et al., 2020). Generally, the total NSP contents and soluble NSP contents of poultry diets are 10%-12% and 1%-2.5%, respectively (Bach Knudsen, 1997). The most important NSPs are the arabinoxylans, β-mannans, and galactomannans (sugar gum). Some enzymes, such as xylanases, are used in carbohydrate degradation, while NSPs change the composition of the avian GM (Saeed et al., 2019). Feeding poultry with barley containing high levels of NSPs increases the incidence of C. perfringens infections and leads to necrotic enteritis in the intestines of broilers (Choct, 2002). Dysbiosis caused by necrotic enteritis, associated with a decrease in ileal fungal populations, leads to dysregulation of the GM (Xu et al., 2023).

The relationship between dysbiosis and nucleic acids

DNA damage plays an important role in cancer progression. Reactive oxygen species, ionising radiation, and polycyclic aromatic hydrocarbons are DNA-damaging agents that lead to cell apoptosis and mutations (tumour formation). Gut dysbiosis has an undesirable effect on the GM and cancer progression, but the underlying mechanism is not well understood. The interactions between the host's microbiota and methylome DNA can influence the gene functions associated with metabolic disease, inflammation, and oxidative stress of the intestinal wall and blood cells in Crohn's disease (Xu et al., 2023). Also, this issue leads to inflammation and immune system activation, as well as gut barrier integrity damage, leading to an increase in permeability and the entrance of toxins into the blood and liver. Gut microbiome metabolites, vitamins, bioactive compounds, and mRNAs affect DNA and histone methylation, acetylation, or lactylation, which then influences the levels of gene expression. Furthermore, mRNAs produced by the GM cause RNA degradation and inhibit viral RNA and transposons. However, the methylation of DNA and interference of RNA prevents gene expression and the methylation of histones. In contrast, the acetylation and lactylation of histones stimulates gene expression (Mostafavi Abdolmaleky & Zhou, 2024). An increase in pathogenic bacteria leads to the production of genotoxins that damage DNA in poultry host cells. Responses to DNA damage can cause the arrest of the cell cycle, apoptosis, or the induction of natural killer group 2-member D ligands (Espinoza & Minami, 2018). It has been reported that Helicobacter pylori, genotoxins, and colibactin from Enterobacteriaceae spp. affect DNA alkylates (Hsiao et al., 2023). Gram-negative bacteria such as E. coli, H. pylori, Campylobacter spp., Shigella dysenteriae, Haemophilus ducreyi, Proteus mirabilis, and Klebsiella pneumonia release genotoxins, cytolethal distending toxins, colibactin, and uropathogen-specific proteins that cause DNA pathway damage (Espinoza & Minami, 2018). The normalisation of sialic acid metabolism reduces dysbiosis, whereas the zebrafish tp53-mutant gene disrupts sialic acid metabolism and induces inflammation, pathogen overgrowth, and dysbiosis (Lee et al., 2022).

Dietary competitive exclusion compounds play a key role in ameliorating the effects of the composition of the GM and its metabolites (Aleksandrova et al., 2017; Al Theyab et al., 2020). For instance, a diet containing high concentrations of carbohydrates or fats enhanced the production of Firmicutes (Clostridium spp.), Prevotella, and Methanobrevibacter, but reduced Lactobacillus, Bacteroides, Bifidobacterium, and Akkermansia, changing the production of SCFAs. These changes are usually linked to compromised intestinal barrier integrity, increased production of reactive oxygen species, and dyslipidaemia (Amabebe et al., 2020). Moreover, a high-fibre diet and acetate supplementation could alleviate gut dysbiosis by increasing the abundance of Bacteroides acidifaciens and modulating the ratio of Firmicutes to Bacteroidetes (Marques et al., 2017).

The relationship between dysbiosis and vitamins

The choline requirements for Ross 308 starter, grower one, grower two, and finisher rations were 1600, 1500, 1500, and 1400 mg/kg, respectively, in 2007, and increased to 1700, 1600, 1500, and 1450 mg/kg, respectively, in 2022. Choline, phosphatidylcholine, and L-carnitine are precursors that are used to produce trimethylamine N-oxide (TMAO) and betaine by the GM (Ebrahimzadeh Leylabadlo et al., 2020). Trimethylamine N-oxide negatively influences human health (Yu et al., 2020), reducing renal function (Zixin et al., 2022), increasing inflammatory and cardio-metabolic risks (Fu et al., 2020), and inducing chronic diseases such as metabolic syndrome (Yu et al., 2020), obesity, insulin resistance, cancer, and arteriosclerosis. Trimethylamine N-oxide metabolites also play a role in cholesterol changes, BA metabolism, and inflammatory pathway activation (Velasquez et al., 2016; Janeiro et al., 2018). Trimethylamine N-oxide also increases the incidence of cardiovascular complications, such as vessel blockage or coronary failure, by a factor of 1.5 (Heianza et al., 2017), and type 2 diabetes by 54% (Zhuang et al., 2019). Trimethylamine N-oxide is a sign of a change in the intestinal microbiome balance or dysbiosis (Landfald et al., 2017), while some species of Eubacterium, Bacteroides, Clostridium, and Collinsella have the potential to reduce this dysbiosis (Romano et al., 2015; Rath et al., 2017).

Bifidobacteria and lactic acid-producing bacteria in the intestines produce vitamin B complex groups and vitamin K2 (a pathogen survival factor). Vitamin B2 increases non-specific resistance against pathogens. Vitamin B6 strengthens cellular and humoral immunity in the body and prevents pathogen growth (Li et al., 2018). Vitamin B9 is produced by Bifidobacteria and Lactobacilli spp. in the human body, and its deficiency reduces lymphocyte proliferation and natural killer cell activity, as it plays a central role in the survival of regulatory T (Treg) cells. Propionibacterium freudenreichii and Lactobacillus reuteri synthesise vitamin B12 (LeBlanc et al., 2013). In addition, different Bifidobacterium and Lactobacillus spp. produce folate in the intestines (LeBlanc et al. 2013).

In poultry, vitamin K synthesis in the intestine is insufficient to meet the body's requirements. The Ross 308 requirements for menadione (vitamin K) in starter, grower, and finisher rations were 3.2, 3.0, and 2.2 IU/kg, respectively, in 2019, and 4.0, 3.6, and 3.2 IU/kg, respectively in 2022, whereas the 1994 NRC recommendations were 0.5, 0.5, and 0.5 mg/kg, respectively. The administration of sulfaquinoxaline increased vitamin K requirements by four to seven times in chickens and eight times in pheasants (Korver, 2023).

Although vitamin D3 has a positive influence on the abundance of Bacteroides in the human gut, it has a negative effect on the abundance of Prevotella (Wu et al. 2011). Administration of vitamin D3 for eight weeks decreased Proteobacteria but increased the abundance of Bacteroidetes in the human gut (Bashir et al., 2016). Mice supplemented with vitamin E (DL-α-tocopherol) showed a decrease in some caecal microbiome diversity measures, such as the Firmicutes/Bacteroides ratio (Choi et al., 2019), while vitamin B12 supplementation increased Enterobacteriaceae abundance (Zhu et al., 2019). It can therefore be concluded that it is necessary to slightly increase the vitamin intake of broilers to meet their requirements according to breed-specific recommendations. Furthermore, the standard recommendations for vitamin supplementation should be revised.

Relationship between dysbiosis and other bacterial metabolites

Bacteriocins are antimicrobial compounds that are produced more by gram-positive bacteria than by gram-negative bacteria. They produce cell pores, leading to bacterial cell destruction and the inhibition of pathogenic agent release (Li et al., 2018). Bacteriocins synergise with beneficial bacteria to increase the speed of pathogen clearance from infected cells (Hoseini-Tavassol et al., 2022). For instance, bacteriocin-producing bacteria such as Enterococcus faecium and Pediococcus pentosaceus have been used as probiotics to prevent the growth of pathogenic bacteria in chickens (Shin et al., 2008).

Succinate is produced by both host cells during energy metabolism and the Krebs cycle and by the intestinal microbiota. It acts as an important pro-inflammatory signal (Mills et al., 2016), as its level increases in diseases related to metabolism and inflammation, such as high blood pressure, ischemic heart disease, type-2 diabetes, obesity, and IBD (Fernández-Veledo & Vendrell, 2019; Lavelle & Sokol, 2020). Oral gavage of Hyline brown hens with 3 mL of probiotic solution containing Prevotella melaninogenica and Prevotella copri (10⁷ colony forming units/mL), along with the dietary supplementation of 0.25% sodium succinate, changed the caecal GM and reduced the fatty livers of the treated layers (Liu et al., 2024). Imidazole propionate (ImP) is a metabolite produced by the GM, with the level of production being affected by the populations of some microbes, such as Clostridium bolteae, Ruminococcus gnavus, and Cenarchaeum symbiosum (Fujisaka et al., 2023). Imidazole propionate levels have been found to be higher in patients with prediabetes, type-2 diabetes, and chronic inflammation, and elevated levels of ImP are thus considered an early warning sign for these diseases. An increase in the level of ImP is associated with a reduction in the Bacteroides count (Agus et al., 2020).

 

Increasing the host's resilience and reducing the risk of dysbiosis

The gut is a dynamic, adaptable organ, and various methods can be used to adjust and modulate its function and reduce the risk of dysbiosis. Improving the balance of the GM can be achieved by avoiding high-fat diets, high NSP diets, and a high protein/carbohydrate ratio in the diet, as well as by administering certain microbiome-promoting factors, such as whole grains, fermented foods, prebiotics, probiotics, phytogenic plants, herbal extracts, or organic acids. In addition, genetics, age, and improving environmental conditions can also help alter the GM composition towards a more favourable balance (Gill et al., 2006; Shehata et al., 2022a). Food additives can either have a positive effect on the microbial composition of the intestine, such as the addition of curcumin, omega-3, or polyphenols, or a negative effect that increases the incidence of diseases caused by microbial changes (such as the use of emulsifiers and the sweeteners intended to reduce obesity and diabetes) (Dudek-Wicher et al., 2018).

Antibiotics

Although the use of antibiotics in animal production systems decreased by 13% between 2017 and 2019 (WOAH, 2022), the global use of antimicrobials increased to 99500 t in 2020, with a predicted increase to 107470 t (an 8% increase) by 2030 (Mulchandani et al., 2023). Abuse of antibiotics influences the gut microbiota (Borre et al., 2014), and can increase the risks of cardiovascular diseases (Rasouli & Zeighami, 2023) and degenerative skeletal diseases (Lyu et al., 2023). Antibiotic administration suppresses TMAO levels, but these levels increase following the discontinuation of antibiotic treatment (Tang et al., 2013). Plasma TMAO levels are potential markers for predicting the risk of cardiovascular disorders in patients with chest pain (Tang et al., 2013; Rasouli & Zeighami, 2023).

Most research on antibiotics focuses on their effectiveness and mechanisms, while the pathophysiology of dysbiosis in poultry remains poorly understood. Another important issue regarding antibiotics is the duration of their use, with long-term use causing a decrease in microbial diversity and a change in the ratio of Bacteroidetes to Firmicutes, leading to the overgrowth of Clostridium and opportunistic bacteria such as Salmonella typhimurium, E. coli, and Klebsiella (Dudek-Wicher et al., 2018). A comprehensive study on the effects of antibiotics on dysbiosis risk and the resilience of poultry, and the emergence of diseases due to the indiscriminate and unprincipled use of antibiotics, has not been conducted. One antibiotic-related disease known in humans is called drug-induced liver injury. Drug-induced liver injury has an occurrence of 2-19 cases per 100000 people, and is attributed to the use of amoxicillin-clavulanate, which can affect the diversity of the GM and its metabolites, potentially causing liver damage (Fu et al., 2022).

Dietary supplementation with antibiotic growth promoters (AGPs) has been used in poultry production to improve digestion, growth, and health (Rafiq et al., 2022), and reduce enteric bacterial infections with C. perfringens (Gadbois et al., 2008), S. enterica (The European Food Safety Authority, 2019), E. coli, and Staphylococcus aureus (de Mesquita Souza Saraiva et al., 2022). However, the misuse and long-term administration of AGPs induces adverse effects on the host's health and modifies the GM, leading to resistance in commensal and pathogenic microbiota (Rodrigues et al., 2021). The addition of AGPs to poultry diets could decrease the proportions of C. perfringens and other gram-positive bacteria, including Lactobacilli, Streptococcus, and Bifidobacteria, which are considered beneficial gut bacteria in the gastrointestinal tract (Broom, 2017), and increase the abundance and propagation of gram-negative bacteria such as Salmonella and Campylobacter spp., because of the absence of competition for nutrients (Kairmi et al., 2022).

Abbas et al. (2024) demonstrated that the administration of a broad-spectrum antibiotic cocktail (neomycin, ampicillin, metronidazole, vancomycin, and kanamycin, 0.5 g/L each) in the drinking water of broilers for seven or 14 days increased the abundance of antibiotic-resistant species, produced dysbiosis of the GM, delayed intestinal development, disturbed intestinal barrier function, and lowered immunity. Administration of this cocktail for two weeks also significantly decreased the abundances of Firmicutes, Lactobacillus, and Bacillus, and increased the abundances of Bacteroidetes, Proteobacteria, Cyanobacteria, and Enterococcus in the ileums of the broiler chickens. Furthermore, the administration of this cocktail for more than a two-week period significantly reduced the abundances of Firmicutes, Lachnospiraceae, Oscillospiraceae, R. torques, and Ruminococcaceae, but elevated the abundance of Enterococcus. Moreover, the addition of the antibiotic cocktail to the drinking water for one and two weeks significantly downregulated the ileal germinal centre cell numbers and the expression of occludin, zonula occludens-1, and mucin 2 genes (Abbas et al., 2024). The levels of claudin 1 mRNA were significantly diminished after 14 days of antibiotic cocktail treatment, which suggested the dysfunction of the intestinal tight junction barrier (Abbas et al., 2024). Similarly, the antibiotic cocktail disturbed the tight junction proteins, including claudin, occludin, and zonula occludens, which maintain the gut barrier, possibly leading to increased permeability of the intestines (Feng et al., 2019). A significant decrease in the abundance of Lactobacillus spp. in chickens' caecal contents was noticed after treatment with bacitracin methylene disalicylate, ampicillin, neomycin, tylosin, virginiamycin, and the ionophores, monensin and salinomycin (Engberg et al., 2000; Murai et al., 2016; Robinson et al., 2019). Treatment of broiler chickens with monensin, monensin-virginiamycin, and monensin-tylosin induced a marked reduction in the caecal abundance of Bacilli (Danzeisen et al., 2011). Moreover, the addition of a coccidiostat and antibiotic complex to the diets of broiler chickens decreased the abundances of caecal Ruminococcaceae and Lactobacillaceae (Kairmi et al., 2022). Also, antibiotic treatment with a cocktail containing neomycin and ampicillin increased the abundances of Firmicutes, Ruminococcaceae, and Lachnospiraceae, and introduced Rikenellaceae and Enterobacteriaceae (Zhang et al., 2021).

Probiotics, prebiotics, and synbiotics

Antibiotic alternatives, including probiotics, prebiotics, antimicrobial peptides, organic acids, hyperimmune serum, phytobiotics, enzymes, bacteriophages, clays, and others, have shown a positive influence on dysbiosis modification (Shehata et al., 2022c). Modification of the GM composition and health restoration are possible through the administration of a mixed combination of probiotics and prebiotic compounds (synbiotics) (Attia et al., 2023). The prevention and treatment of cardiovascular diseases is being advanced by the ability of synbiotics to alter the intestinal microbiome (Jin et al., 2019). Probiotics containing Lactobacillus plantarum and L. rhamnosus can reduce blood lipid levels in patients with coronary artery disease (Akbarzadeh et al., 2012) and myocardial infarction, improve left ventricular hypertrophy and endothelial vessel function (Lam et al., 2012), and reduce systemic inflammatory biomarkers (Malik et al., 2018).

Table 3 shows the effects of dietary nutrients on dysbiosis (Brown et al., 2012). Rations enriched with probiotics increased the gut counts of Lactobacilli, Lachnospiraceae, F. prausnitzii, and Bacteroides (Flint et al., 2015; Maukonen & Saarela, 2015; Chung et al., 2016). Moreover, the short-term administration of synbiotics reduced the symptoms of inflammatory diseases; however, the long-term effects are not known, as dysbiosis in most inflammatory diseases changes the GM composition and the immune response (Brown et al., 2011).

 

 

Piglets' resistance to cold stress was increased by the dietary addition of probiotics or by the adjustment of the composition of the diet to modify the GM structure (Zhang et al., 2024). Cold stress has significantly adverse effects on energy balance and increases purine degradation by Acholeplasma, Proteiniphilum, and Olsenella spp. in the colon and ileum; Ruminococcaceae spp., Butyricicoccus, and Lachnospiraceae FCS020 in the mucosa of the colon; and Sphingomonas, Helicobacter, Cutibacterium, and Bradyrhizobium in the mucosa of the ileum (Zhang et al., 2024).

Probiotics can modify behaviour and brain function by suppressing the production of IL-6 and IL-4, stimulating the production of IL-10, and consequently preventing and treating neurological diseases and high blood pressure (Babakhani & Hosseini, 2019). In broiler chickens, treatment with probiotics containing Bacillus subtilis increased 5-HT levels in the hypothalamus (raphe nuclei), decreased norepinephrine and dopamine levels in the hypothalamus, and improved bone mineral density (Yan et al., 2018). L. rhamnosus administration to broiler chickens prevented tibial dyschondroplasia (TD) by improving tibia weight, length, and diameter (Liu et al., 2021), and improved trabecular bone volume and bone formation in mice (Tyagi et al., 2018). In rats, Bifidobacterium longum increased bone mineral density and stimulated calcium and phosphorous absorption (Rodrigues et al., 2012).

Faecal microbiota transplantation (FMT)

During the past decades, the total microbial communities from healthy adult chickens have been transplanted to newly hatched chicks via FMT. Faecal microbiota transplantation from healthy donors assists in the modulation and alteration of the GM in patients with IBD, reaching a remission rate of 35%-40% (Cammarota et al., 2017; Imdad et al., 2023). Inoculating young broilers with the microbiomes from highly feed-efficient donors positively affected the composition of the caecal microbiota and the host's intestinal development (Metzler-Zebeli et al., 2019). Nonetheless, the use of FMT to control enteric foodborne infections in poultry (e.g., Salmonella and Campylobacter spp.) has had varying results (Gilroy et al., 2018; Chintoan-Uta et al., 2020; Aruwa et al., 2021; Taha-Abdelaziz et al., 2023; Pottenger et al., 2023).

Reshaping the GM using FMT could enhance chicken growth by balancing T helper 17 (Th17) and Treg cells. Transferring the faecal microbiota from healthy chicks that have good growth performance parameters and a high abundance of Lactobacillus in droppings to one-day-old chicks enhanced their growth performance, reduced Th17 cell-associated transcriptional factors and cytokines, and elevated jejunal cytokines and Treg cell-associated transcriptional factors (Ma et al., 2023). Faecal microbiota transplantation and inulin supplementation synergistically affected both the intestinal barrier and immune function in chicks (Song et al., 2024). It promoted the development of gut-associated lymphoid tissue, which promoted early intestinal immunity by regulating the cluster of differentiation 28 protein and the cytotoxic T-lymphocyte-associated protein 4 in broilers (Song et al., 2024). Moreover, FMT used synergistically with inulin supplementation elevated the secretion of transforming growth factor-β, and increased the intestinal goblet cell number and mucin 2 expression in week two of treatment. The β-cell activating factor, the transcription factor Pax5, the C-X-C motif chemokine ligand 12, and IL-2 expression were elevated in week one, and C-X-C motif chemokine receptor 4 and IL-2 expression in the caecal tonsils were elevated in week two of treatment (Song et al., 2024). Moreover, oral treatment of young broilers with FMT using adult caecal microbiota could enhance the development of the GM, and has been found to prevent the colonisation of Campylobacter (Pang et al., 2023). Further research on the use and effectiveness of FMT using a synthetic microbiome designed for the control of foodborne pathogens in poultry would be of interest.

Reducing stress and inflammation

Lactobacillus johnsonii and L. reuteri increased oxytocin production by cells in the brain (Bray, 2016), while Bacteroidetes, Actinobacteria, and Firmicutes decreased oxytocin production in mice (Dinan & Cryan, 2017). Mice reared under conditions inducing stress and anxiety showed changes in the intestinal microbiota, with a concomitant reduction in brain-derived neurotrophic factor, which is involved in the prevention of β cell exhaustion, and the regulation of glucose and energy metabolism (Autry & Monteggia, 2012; Prinsloo & Lyle, 2015). Decreases in the brain-derived neurotrophic factor level are associated with three neurodegenerative diseases (Bathina & Das, 2015).

Gamma-aminobutyric acid produced by Lactobacillus brevis can affect brain health and assist in the treatment of diabetes (Dinan & Cryan, 2016); can help regulate blood pressure, heart rate, anxiety, and depression; and can regulate neuronal pain (Hyland & Cryan, 2016). In addition, GABA is regarded as a neurotransmitter inhibitory substance and is used for stress reduction (Park et al., 2023). A dietary concentration of GABA of 100 mg/kg downregulated AgRP (NPY/AgRP) neuropeptides and stimulated the FI of broilers (El-Naggar et al., 2019).

Gut microbial modification leads to a reduction in inflammation in patients with chronic kidney disease (Li & Tang, 2018). Short-chain fatty acids regulate immunity and modulate inflammation by inhibiting deacetylases or G protein-coupled receptors (Chang et al., 2014). The loss of butyrate-producing bacteria causes the passive leakage of microbial receptors, such as LPSs, and these bind to TLRs and other intrinsic innate immune receptors, causing colonic inflammation (Furusawa et al., 2013). The levels of SCFAs produced by the intestinal microbiota are reduced in type-1 diabetic patients (Siljander et al., 2019), as these fatty acids reduce serum glucose levels, insulin resistance, and inflammation, and increase the secretion of GLP-1 in type-2 diabetic patients (Puddu et al., 2014). T-regulatory cells and SCFAs produced by intestinal microbiota such as Lactobacilli, Bifidobacteria, and Saccharomyces boulardii reduce bone loss by regulating inflammatory factors (Celiberto et al., 2018). Administration of glycerol monolaurate also induces anti-inflammatory and anti-apoptotic properties by suppressing ROS and the tumour necrotising factor-κΒ signalling pathway in avian macrophages (Kong et al., 2024).

Regarding the environment, climatic and litter conditions could affect the complex poultry GM (Shang et al., 2018). It has been reported that the diversity and richness of the caecal microbiome was higher in summer than in winter (Oakley et al., 2018; Diaz Carrasco, 2019). Other management factors in poultry flocks, such as feed type, feeding time, free-range access, stocking density, litter type, heating, ventilation, biosecurity, hygiene, medical treatment, and vaccination, could also influence the birds' GM (Wang et al., 2018; Diaz Carrasco et al., 2019; Göransson et al., 2023). Reusing moist litter increases the pathogenic bacterial load on poultry farms and increases the possibility of pathogen transfer to humans or consumers through the poultry supply chain (Cressman et al., 2010).

Modification of the microbiome to reduce stress levels is possible through the administration of probiotics, prebiotics, synbiotics and postbiotics, as well as through the development of the early-life microbiome, nutritional interventions (herbal extracts, essential oils, and yeast extracts), the reduction of antibiotic use, the improvement of water quality, the monitoring and adjustment of the diet, and the management of stressors. The best strategies to minimise stress in poultry farming are to optimise environmental conditions (temperature, humidity, ventilation, and lighting), improve housing conditions, avoid overcrowding, provide a balanced diet, reduce handling and disturbances, implement disease prevention and health management, and offer enrichment and behavioural support (perches and pecking objects).

Increasing FI and appetite

The administration of GABA, or its producer L. brevis, increased the FI of commercial broiler chickens (El-Naggar et al., 2019). Clostridium sporogenes and R. gnavus affect appetite and mood by producing tryptamine, a product of tryptophan decarboxylation (Williams et al., 2014). Tryptophan is involved in the production of 5-HT, which is necessary for the regulation of colon movement and the improvement of appetite, behaviour, and mood (Neuman et al., 2015; Jenkins et al., 2016; Agus et al., 2018; Malinova et al., 2018).

Modifications in physiological conditions

Tibial dyschondroplasia accounts for 30% of all skeletal afflictions in chickens worldwide (Mehmood et al., 2018). According to Xu et al. (2023b), TD in broilers resulted in distinguishable GM structures, with perturbations in the GM effecting bone homeostasis through unknown mechanisms. Specifically, there was a 45.5% decrease in the Bacteroidetes count and a 53.6% increase in the Firmicutes count, when compared to the abundance of each phylum in the control group (Bacteroidetes 73% and Firmicutes 26.3%). The abundance of Blautia and Coprococcus in TD-affected broilers was also higher than that in the control group, leading to higher blood glucose levels (Xu et al., 2023b). In the same study, the treatment of TD-affected broilers with total flavonoids from Rhizoma drynariae for two weeks led to the modulation of blood glucose levels, the recovery of gut barrier damage, the modification of the diamine oxidase enzyme level in plasma, and the upregulation of intestinal tight junction proteins (claudin 1 and occludin), by reducing gut barrier permeability (Xu et al., 2023).

In humans, the reduction of disease incidence by nutrition modification is particularly important. For instance, SCFA levels in faecal samples decrease in active IBD (ulcerative colitis and Crohn's disease) (Parada Venegas et al., 2019), and rectal inoculation with butyrate has been shown to help treat patients with colitis (Scheppach et al., 1992). Any imbalance in the GM composition leads to an increase in uremic toxicity compounds, including TMAO, indoxyl sulphate and p-cresyl sulphate, as well as dysbiosis and intestinal permeability.

 

Conclusions

There are many strategies for optimising poultry gut health, including supplementing feed additives such as prebiotics, probiotics, synbiotics, and postbiotics; providing a balanced AA profile; reducing the use of antibiotics; synergising the effects of fibres and probiotics; reducing stress and inflammatory agents; optimising drinking water quality; avoiding sudden changes in diet; and striving to provide maximum welfare and comfort for the birds. Despite this article and others focusing on understanding the poultry microbiome and its impact on general health and disease, further investigations are required to explore the factors affecting the gut ecosystem and its interactions with the host, especially in poultry. Furthermore, it is important to develop various effective methodologies to identify the beneficial strains of bacteria that play key roles in maintaining poultry health.

In this review, we have attempted to provide an insight into the world of the poultry microbiome and the many research gaps in understanding the precise mechanisms of GM dysbiosis and its impacts on the immune system, reproduction, oxidative stress, egg and meat quality, growth and performance, gut health, and vaccines. In addition, the use of advanced genomics and metagenomics technologies, such as next-generation sequencing, the development of specific probiotics and prebiotics to reduce GM dysbiosis, and the creation of animal models to study GM dysbiosis in greater detail will also be valuable contributions to the field.

 

Author contributions

AS: concept and study design and writing of the first draft. WAAE: Critical review, and editing of the article, YAA, NMZ, FB, VT, revision, editing and overall review of the manuscript. All authors read and approved the final version.

 

Conflicts of interest declaration

The authors declare no conflict of interest.

 

Funding

This research was carried out by the authors without financial support.

 

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Submitted 12 August 2024
Accepted 4 February 2025
Published February 2025

 

 

# Correspondence: vincenzo.tufarelli@uniba.it, ahmad.salahi@znu.ac.ir, yaattia@kau.edu.sa