The gastrointestinal tract is the main site of bacterial colonization in the body, and the bacteria inhabiting the gastrointestinal tract weighs about 1000g, with about 30?genera and 400-500?species, with an overall number of 1014?or more, which is 10?times more than that of human cells; the bacteria colonized in the gut are characterized by huge number, diversity, complexity and dynamics, and the intestinal flora (intestinal? microflora) is currently the core of human microecological research concerns.
With deeper understanding and application of molecular biology techniques, it is confirmed that intestinal flora plays a decisive role in the development and maturation of important physiological functions such as immunity, metabolism and nutrition in children, and is closely related to infectious diseases, chronic inflammatory diseases of the intestine, allergic diseases, autoimmune diseases and metabolic diseases. This paper reviews the new progress of research on the physiological function of intestinal flora and related childhood diseases in children in recent years.
1.The physiological function of intestinal flora
The intestinal microecology carries human acquired genes and participates in the normal physiological and pathological processes of human diseases, and is inseparable from human health. Research shows that intestinal flora can defend against infection and enhance intestinal barrier function, and has a strong biological antagonistic effect on the invasion of foreign pathogenic bacteria and conditionally pathogenic bacteria; intestinal flora can synthesize vitamins and promote nutrient absorption, stimulate the development of host immune organs and their functions; the metabolites generated by intestinal flora such as ammonia, hydrogen sulfide, amines and toxins are harmful, and also promote the body to improve the immune mechanism to remove them. In recent years, the role of intestinal flora on the metabolism and immunity of the organism has attracted special attention.
1.1 Intestinal flora and nutrient metabolism function
Intestinal flora plays an important role in the digestion and absorption of food. Scientists from European Molecular Biology Laboratory found that there are three different dominant community types of intestinal flora, among which Bacteroides (Bacteroides spp.) are good at breaking down carbohydrates, while Prevotella (Prevotella spp.) tend to break down intestinal mucus, and Ruminococcus (Ruminococcus spp.) will help cells absorb sugars, all of which are helpful for food digestion and absorption of food.
There is a lot of evidence that intestinal flora can competitively consume nutrients from pathogenic bacteria, promote the absorption of inorganic salts such as calcium, magnesium and iron, and participate in the synthesis of many vitamins in the body; more importantly, they participate in the metabolism of proteins, peptides and amino acids and have a role in improving lipid metabolism: intestinal flora can use specific enzymes? (such as galactosidase, etc.) to decompose nutrients not hydrolyzed and absorbed by the upper gastrointestinal tract to produce short-chain fatty acids (SCFA) such as acetic acid, propionic acid and tyrosine, which can be used by the body as energy substrates (e.g. tyrosine provides energy to the colonic epithelium, acetic acid and propionic acid can reach the liver and peripheral organs with the portal vein to become substrates for glycogen and lipid synthesis), and can also regulate the expression of human anti-histidine deacetylase genes It also plays an anticancer role and acts on G?protein-coupled receptor gene expression and thus regulates lipid synthesis in peripheral metabolic organs.
In the study of obesity and its related metabolic diseases, it has been found that changes in the number or composition of intestinal flora are present in animals or adults with obesity, diabetes or NAFLD. Animal model experiments have shown that increased intestinal bacteriophage spp. increase accumulation and obesity, and that higher intestinal Bacteroides fragilis and Staphylococcus decreases in infancy are associated with higher body mass index at school age.Kalliomaki?et al., in order to clarify whether early intestinal flora is associated with childhood obesity, found in a prospective study of 25?overweight 7?year-old children that, compared with children of the same age with normal body mass , there was a decrease in intestinal bifidobacteria and an increase in enterococci.
Furet et al. analyzed changes in fecal flora before and after bariatric surgery in obese patients and found that Clostridium pratense was low before surgery and negatively correlated with inflammatory material, and that the bacteria maintained an increasing trend after surgery, independent of the host’s food intake.Larsen et al. detected intestinal flora in type 2 diabetic patients by fluorescence quantitative PCR and found a significant decrease in Clostridium spp. and the genus was positively correlated with blood glucose levels, suggesting that intestinal flora may be involved in the formation of diabetes.
The intestinal flora may cause obesity and metabolic disorders by affecting energy absorption, fat metabolism and bacterial endotoxins. With the change of living conditions, human habits and diet structure also change, and long-term high-fat diet leads to excess energy and obesity; high-fat diet may interact with intestinal flora to cause inflammation: high-fat diet changes the structure of intestinal flora, decreases intestinal bifidobacteria, increases intestinal permeability, increases intestinal epithelial fine synthetic celiac particles, promotes lipopolysaccharide absorption and operation to target groups, causes free fatty acid The increase in free fatty acid levels and inflammatory factor expression leads to an increase in metabolic disorders such as diabetes mellitus.
Cani et al. found that rats with significantly increased intestinal bifidobacteria had significantly reduced visceral, epididymal and subcutaneous fat content, and plasma levels of proinsulin peptides, which are positively associated with the development of obesity and diabetes, were also significantly reduced; bifidobacteria were also able to promote the differentiation of intestinal precursor cells to secretory cells, resulting in significantly increased plasma levels of glucagon-like peptide 1? and glucagon-like peptide. The alteration of intestinal flora structure and fermentation products in obese patients causes a series of metabolic process changes, leading to insulin resistance; the fermentation of dietary fiber by colonic bacteria releases SCFA, which further increases the body’s energy intake and regulates lipid synthesis in peripheral metabolic organs; the alteration of intestinal flora structure leads to intestinal mucosal barrier damage and non-alcoholic fatty liver through intrinsic immune mechanism, etc.
1.2 Intestinal flora and immune function
Intestinal flora and intestinal mucosa constitute the most important peripheral immune organ in human body. The immune mechanisms that maintain homeostasis of intestinal bacteria and intestinal epithelium: mucosal layer, intestinal epithelial antimicrobial polypeptide, and secretory immunoglobulin (sIgA) secreted by plasma cells. sIgA is an important factor in the development of the immune system, and sIgA?expression has an important role in the establishment of homeostasis between intestinal flora and host in vivo and in immune tolerance to gastrointestinal flora. Both normal intestinal flora and food-borne pathogenic microorganisms enhance SIgA?-mediated intestinal surface barrier and promote oral tolerance by altering the activity of cells in the neonatal period, thus creating a new balance of cytokines later in life.
Dendritic cells are an extremely important immune cell, and Latvala?et al. found that Lactobacillus rhamnosus, Bifidobacterium bifidum, and Streptococcus thermophilus stimulate dendritic cells to express CD86?and HEHLA-DR and promote their maturation, but different bacteria promote their secretion of cytokines differently. Intestinal flora also regulates the differentiation and maturation of T?cell subpopulations such as NK?cells, eosinophils, and Treg?cells: Gram(+) flora of the intestine are stimulators that induce IL-17?differentiation and maturation, and filamentous fragmented bacteria (SFB) are the main species that induce IL-17?differentiation and maturation and enhance the antagonism of the small intestine against the pathogenic bacterium Citrobacter rhamnosus; Clostridium spp. are stimulators that induce colonic mucosa to express Clostridium spp. are functional flora that induce the differentiation of Foxp3+?Treg?cells in the colonic mucosa, ameliorating colonic mucosal inflammation and IgE?
mediated allergic response; Bifidobacterium infantis can promote Treg?cell differentiation and proliferation by stimulating dendritic cells. Metabolites of intestinal bacteria are also involved in the regulation of the immune system: Vinolo?et al. demonstrated that short-chain fatty acids (SCFA) can affect the ability of leukocytes to migrate toward inflammation and destroy pathogenic microorganisms, and that this effect is mediated through the production of cytokines (TNF-α,?IL-2,?IL-6,?IL-10), arachidonic acid analogs, and cytochemical factors.
It has been shown that intestinal flora promotes the maturation of the postnatal intestinal mucosal immune system and the systemic immune system and is associated with the later development of immune-related diseases such as allergy, obesity and diabetes.Olszak?et al? investigators found that accumulation of large numbers of NK?cells in the subintestinal mucosa and lung tissue of neonatal germ-free rats increased tissue inflammatory response and enhanced susceptibility to IBD?and allergies, while implantation of intestinal flora, by inducing CXCL16?expression, inhibited NK?cell accumulation in intestinal mucosa and lung tissue, concluding that microbial exposure in early neonatal life limits NK?cell accumulation in intestinal mucosa and lung tissue and regulates host susceptibility to IBD and allergies. The interaction between the intestinal flora and the host immune system can both lead to increased risk of type 1?diabetes due to B?cell damage and metabolic inflammation through bacterial lipopolysaccharides, etc.
2.Childhood diseases associated with dysbiosis
Intestinal flora is closely related to health, and maintaining a dynamic balance between the flora and the body can effectively prevent the translocation of bacteria and endotoxins in the intestine; when the normal microbial community is affected by the body and the external environment, the micro-ecological balance is disrupted can make the body disease-causing.
Diarrheal disease and chronic constipation are common gastrointestinal diseases in children, and their relationship with intestinal flora disorders and the effectiveness of probiotic therapy are widely known. Necrotizing small intestinal colitis is common in preterm infants, and early studies suggested that delayed colonization of the intestinal tract with normal flora is one of the pathogenic factors; recent studies found a significant increase in the incidence of NEC in newborn preterm pigs treated with antibiotics, suggesting that antibiotic use is associated with NEC, and meta-analysis showed that preterm infants given a gestational age of less than 34?weeks and a weight of less than 1500?g? were given intestinal probiotics for 10?days after birth. probiotics for more than 7 days reduced the incidence of NEC by 30% and reduced mortality.
H. pylori (HP) infection can cause esophageal reflux, gastritis, and peptic ulcers, as well as malnutrition and growth retardation, and is more common in older children, with higher rates of infection in developing countries; classical triple eradication therapy, while controlling HP? infection, also disrupts the dynamic balance of the intestinal flora; studies have confirmed that probiotics, although controversial in increasing the eradication rate of HP? in children, can correct the flora. is controversial, it can correct flora imbalance and reduce the side effects of drug therapy.
Inflammatory bowel disease (IBD) is a group of chronic nonspecific inflammatory diseases of the gastrointestinal tract of unknown origin, including Crohn’s and ulcerative colitis, whose pathogenesis is still unclear. Sokol et al. demonstrated that the proportion of thick-walled bacteria and anaphyla in the intestinal flora of patients with IBD? Another study showed a decrease in bifidobacteria and lactobacilli in the intestinal flora of children with Crohn’s.
Irritable bowel syndrome (IBS) refers to a group of clinical syndromes including abdominal pain, bloating, change in bowel habits and abnormal stool patterns, mucus stools, etc., which persist or recur, and is the most common functional intestinal disorder; although the pathogenesis of IBS is unknown, intestinal microecological imbalance is associated with both diarrhea and constipation: the intestinal flora of patients compared to healthy individuals is mainly composed of Lactobacillus spp. Saulnier et al. used gene chips to detect 22 cases of school-age and prepubertal IBS?
Infantile colic can also be seen as a functional intestinal disorder that presents with paroxysmal irritability, extreme pain, abdominal distention, and excessive exhaustion in children with IBS compared to normal children, and usually develops 2 to 4 weeks after birth. Most of them are cured by 3 to 4 months. Savino et al. studied 50 cases of exclusively breastfed infants with colic, and the duration of crying was significantly reduced after Lactobacillus royi intervention, while there was a significant increase in lactobacilli and a decrease in E. coli and ammonia in the stool.
Celiac disease (coeliac?disease), also known as maltose enteropathy, has a high incidence in North America, Northern Europe, and Australia, but is rare in China. The peak age of onset is mainly in children and young adults, and in infants and young children it is mainly characterized by growth retardation, weight loss, vomiting, diarrhea, abdominal pain, bloating, and irritability. Palma et al [26] studied infants at genetic risk and found large numbers of Bacteroides fragilis and Staphylococcus spp. and Bifidobacterium longum in the gut.
The incidence of metabolic diseases associated with obesity and diabetes is on a steep rise worldwide, and genetic, environmental, behavioral and psychosocial factors have been shown to play an important role in the development of such diseases. Recent studies have demonstrated that microorganisms present in the gut are important environmental factors in the development of obesity. Breast milk is rich in bifidobacteria and breastfed infants are less likely to become overweight and obese later in life, and the duration of breastfeeding is negatively associated with the incidence of overweight; while maternal BMI during pregnancy, fetal growth pattern and the use of antibiotics during infancy are all associated with the risk of obesity in subsequent childhood. Both obese and diabetic children have abnormal intestinal flora: a recent study confirmed a decrease in the intestinal flora Bacteroidetes?in Kazakh female obese children and a decrease in the proportion of Bacteroidetes/thick-walled phylum; the intestinal flora of diabetic patients had significantly fewer thick-walled and Clostridium spp. and more abundant Aspergillus. A prospective study of 138 infants aged 3?weeks to 1 year showed that early intestinal enrichment with Bacteroides fragilis and lower Staphylococcus was associated with the risk of obesity in preschool. luoto et al. found that the addition of Lactobacillus and Bifidobacterium during pregnancy reduced gestational diabetes and lowered the risk of high birth weight infants.
Allergic diseases are a major health problem in the world today, and common diseases in children include eczema, atopic dermatitis, and asthma, etc. The “hygiene theory” is an important mechanism to explain the rise of allergic diseases. The majority of scholars agree that it is related to the decrease of intestinal flora due to the “westernization of lifestyle”, and that the use of antibiotics from 0 to 1?years of age is significantly and highly correlated with the increase of allergies such as asthma, allergic rhinitis, conjunctivitis and eczema in childhood. Epidemiological data show that allergic children have higher levels of Clostridium perfringens than non-allergic children, with a corresponding decrease in bifidobacteria; Bisgaard’s group has shown that reduced intestinal bacterial diversity in infancy is associated with allergic sensitization, allergic rhinitis and increased peripheral eosinophils in the first 6 years of life; Pelucchi et al. Pelucchi et al. administered probiotics to women during pregnancy or to infants early after birth, resulting in a significant reduction in the incidence of atopic dermatitis in infancy.
Autism, also known as autism, is a pervasive developmental disorder, and social communication impairment is the biggest problem for children with autism. We observed the intestinal flora of children with autism, and found that the phylum Desulfovibrio and Actinobacteria were significantly increased in children with severe autism, while the feces showed higher levels of Desulfovibrio and Bacteroides?vulgatus, and whether the latter specific changes were the cause of the pathogenesis or the result of the disease could not be determined, but the intestinal bacteria However, metabolic disorders due to abnormalities of enterobacteria may be one of the pathogenic mechanisms.
Cystic fibrosis? (Cystic?fibrosis) is a genetic disease that affects the lungs and digestive system most severely and is more common in Caucasians and less common in Africans and Asians. It has been found that the intestinal flora of children with cystic fibrosis also has abnormalities early in life, and the administration of probiotic intervention can reduce intestinal inflammation and delay the repair of respiratory damage, suggesting an association between intestinal flora disorders and the disease, the exact mechanism of which still needs to be studied.
In conclusion, the intestine, as the largest immune organ and microecological system of the body, directly affects the normal growth and development, morbidity and long-term health of the body, and it is crucial to maintain its normal function. The intestinal flora of children has dynamic and fragile characteristics, and the early flora is closely related to the immune system and metabolic development of the body; intestinal flora dysbiosis can induce a variety of diseases, and a variety of diseases can lead to intestinal flora dysbiosis, which are mutually causal.