REVIEW

The importance of microbiome in pediatric obesity

 Importanţa microbiomului în obezitatea pediatrică

First published: 30 octombrie 2023

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/Pedi.71.3.2023.8968

Abstract

Childhood involves aspects for interventions that con­fi­gure the microbiome to alleviate obesity-related dis­tur­bances. Children with obesity have gut microbiota com­po­si­tio­nal and functional differences, including in­creased pro­in­flam­matory bacterial characteristics. Re­sto­ra­tion of the gut microbiota to a healthy state may ame­lio­rate conditions associated with obesity and help main­tain a healthy weight. This review brings to the fore the consequences and aspects of childhood obesity, the im­por­tance of the developing microbiome in establishing meta­bolic path­ways, and the therapeutic attitude. It contributes basically to denote future research directions for the potential develop­ment of microbiome-based therapeutics to treat obesity.
 

Keywords
pediatrics, obesity, biochemistry, therapy, microbiome

Rezumat

Copilăria implică aspecte privind intervenţii ce configu­rea­ză microbiomul pentru a atenua tulburările legate de obezitate. Copiii cu obezitate prezintă diferenţe com­po­zi­ţio­nale şi func­ţio­na­le ale microbiotei intestinale, in­clu­siv caracteristici bacteriene pro­in­fla­matorii crescute. Re­sta­bi­lirea microbiotei intestinale la o stare sănătoasă poate ameliora condiţiile asociate cu obezitatea şi poate ajuta la menţinerea unei greutăţi sănătoase. Această re­vi­zuire aduce în atenţie consecinţele şi aspectele obezităţii in­fan­tile, importanţa microbiomului în curs de dezvoltare în sta­bi­lirea căilor metabolice şi atitudinea terapeutică, con­tri­bu­ind, practic, la indicarea direcţiilor viitoare de cercetare pentru dez­vol­tarea potenţială a terapiilor bazate pe microbiom pentru a trata obezitatea.
 

The human microbiome, composed of bacteria, viruses, fungi and archaea, is a high-interest topic and an intensive interest of study. These microbial populations are particularly relevant to pediatrics, since animal and human data attribute a critical role in immune development, growth and metabolism dynamics. In spite of the fact that it is not yet known what organisms constitute a healthy microbiome, the structure of the microbiome varies by age and by body area, and it appears that health is linked with higher bacterial diversity in most anatomical regions. Early changes in the microbiome composition have been associated to the development of diseases in the late life period, such as asthma, atopy, inflammatory bowel disease, obesity and type 1 diabetes(1), influencing the neurodevelopment(2). Also, certain bacteria in the microbiome may give protection against various pathogens or can make a child more susceptible to specific infections, including upper respiratory infections, malaria and Campylobacter infections(3). Ultimately, the microbiome may influence both vaccine responses(4) and medicaments’ metabolism(5).

There are 9.8 million microbial genes. In a single sample of human serum, more than 750,000 genes can be identified – i.e., 30 times more than the human genome. The intestinal microbial population includes more than 50 divisions (phyla), 90% belonging to the divisions Bacteroides and Firmicutes, the other divisions being Proteobacteria, Actinobacteria, Fusobacteria and Verucomicrobia. About 300,000 germs are commonly encountered, being present in more than 50% of individuals, but 600,000 are nonredundant, the ones that confer individuality, each individual having its own distinct bacterial characteristics.

Three microbiome enterotypes were isolated and individualized, according to the predominance of the bacterial division: enterotype 1Bacteroides, associated with a diet rich in proteins and fats; enterotype 2Prevotella, in those with carbohydrate and sugar consumption; enterotype 3Ruminococcus, mixed. The intestinal microbiota is involved in obesity in several aspects, namely: a) the absorption of food (which occurs only after the food has been broken down); b) the harvest of energy from the food that is ingested; c) the host’s metabolic pathways – hunger hormones, satiety, hormones that control mood, mental focus, sleep, and a multitude of inflammation pathways directly related to the immune system.

Recent publications from the specialized literature attest to the connection between obesity and the change in the composition of the intestinal microbiome. By efficiently breaking down undigested nutrients, intestinal bacteria can provide body additional energy.

The microbiome and obesity

Obesity is an issue of great public concern. The increase in the proportion of obese people is recorded throughout the civilized world and is the most visible effect of the modern lifestyle – reduced physical effort and food with excess caloric intake. Genetic influences or insulin resistance cannot be neglected either(6). However, data describing the gut microbiome have also emerged. The most spectacular are those showing that obesity can be transferred from obese mice, through intestinal microbial content, to germ-free mice, without changing the diet(7). It was found that in obese people there is a different microbial population, with less diversity. Moreover, certain species of microbes, more numerous in the obese, are able to produce free fatty acids (energy sources) from indigestible polysaccharides. Furthermore, intestinal permeability is influenced by the microbial content. They can also produce metabolites that, through hormonal influences and free fatty acid receptors, can control satiety.

The role of intestinal microbiota in obesity

The germs most frequently associated with obesity are those belonging to the phyla Firmicutes and Bacteroidetes, with a ratio below 1 (normal). Obese people show significant differences in the composition of the intestinal microbial flora compared to normal weight subjects. These changes in the intestinal microbiota precede the clinical manifestation of excess weight. Through this evidence, the idea of early identification of people at risk of gaining weight can be suggested, opening up a new utility of these indicators. Experimental data suggest an important cau­sal role of the gut microbiota not only in the development of obesity but also in associated metabolic disorders such as diabetes and cardiovascular diseases. The proportion of bacteria from the two groups – Firmicutes and Bacteroidites – determines the degree of inflammation in the body, which influences the appearance of medical conditions, such as obesity, diabetes, coronary disease and chronic inflammation. A fluctuation by 10% in the proportion of Bacteroidites to Firmicutes can completely change the metabolic rate. An increased number of Firmicutes can cause a greater absorption of calories, causing weight gain. They can metabolize dietary fiber into short-chain fatty acids, producing sometimes additional abnormal energy.

In the case of overweight people, an increased Firmicutes/Bacteroidetes ratio and a low diversity of the intestinal microbiome are observed compared to normal weight people. In recent years, a number of bacterial species have been identified that are quantitatively reduced in the case of overweight people (for example, Akkermansia muciniphila, Lactobacillus gasseri, Faecalibbacterium prausnitzii, Bifidobacterium, Lactobacillus, Butyrivibrio, Alistipes, Akkermansia, Coprococcus, Methanobrevibacter). In experimental evidence, Gordon(8) showed that axenic mice (without microbiota) eat more, but accumulate less fat than conventional mice. Unlike conventional mice, axenic mice do not gain weight when fed with Western-type diets – high in saturated fat, with excess refined sugars and animal protein, but low in fiber. When axenic mice are colonized with bacteria, the animals gain weight and become fat. By transplanting the cecal microbiota of obese mice to axenic ones, it is possible to extract an increased amount of energy from food, with a more pronounced weight gain than the microbiota of lean mice allows. The microbiota induces, as well, the expression of proteins involved in the energetics of the body.

Transplants of microbiota from obese mice make lean mice fat, but microbiota from lean mice do not make obese mice slim. Obesity is a transmissible characteristic. Fecal transplantation (of fecal matter from obese mice to lean, germ-free mice) increases visceral fat by 20% in lean mice in just 14 days. Fecal matter transplantation has also been performed in humans: in obese people transplanted with microbiome from lean individuals, microbial diversity increased, as well as the amount of butyrate (anti-inflammatory role), with improved amelioration of insulin sensitivity(9).

The role of gut microbiome in obesity
and the metabolic syndrome

The role of the intestinal microbiome in obesity and metabolic syndrome is very complex, from influencing energy intake to achieving hyperglycemia, controlling satiety, inducing insulin resistance and increasing intestinal permeability, favoring increased nutrient absorption. Carbohydrate intolerance produced by synthetic sweeteners can be treated with antibiotics, thus proving the involvement of microbes in the pathophysiological process.

Involvement of the brain-gut-microbiome axis in obesity

The brain-gut axis regulates digestion, the appetite-satiety relationship, cognitive and other psychological functions. The brain-gut-microbiota axis influences eating behavior. Alteration of the microbiota can lead to either anorexia nervosa (when the microbiota favors the prevalence of anorexigenic hormones and peptides GLP-1, peptide YY, cholecystokinin, peptides from the corticotrophin-releasing factor family), or obesity (when the effects of ghrelin or neuropeptide Y predominate)(10). Enteroendocrine L cells and enterochromaffin cells are cells with a role in intestinal homeostasis, due to the pleiotropic effects of their secretory molecules (glucagon-like peptide 1, GLP1, peptide YY, serotonin). Among other biochemical compounds, it regulates insulin secretion and appetite. The microbiota influences the function of these enteroendocrine cellular effectors.

Obesity risk factors

In childhood, the long-term impact of various risk factors (child sleep duration, parents’ body mass indices, parental restrictive/excessive feeding practices) can cause the development of childhood obesity. The environment is considered the most important risk factor that can affect people’s ability to make healthy choices, along with genetic, metabolic, lifestyle and dietary factors. In the last decade, less common obesity risk factors, such as antibiotic use and infections in early childhood, as well as the inflammatory nature of obesity are widely studied and recognized.

Recent investigations and clinical trials have highlighted the existence of mediating factors between diet, the host’s energy metabolism and the obese phenotype, suggesting in this regard that the indigenous intestinal microbiota (intestinal microbial flora) is not only influenced by diet, but it plays an important factorial-causal role in the initiation and development of obesity.

The forming of the microbiome occurs in early childhood, in the first years after birth. Initial “insemination” occurs at the time of birth, through the contact of the oral cavity of the fetus with the genital organs of the mother. Natural insemination only occurs if the birth is natural, not by caesarean section. Breastfeeding is another determining factor in the formation of the microbiome. Then, the subsequent nutrition matters, the environment in which the baby develops, with advantages for those with greater possibilities of “contamination” – farms, open and more varied environment, outdoor play, geographical area etc. The use of drugs, especially antibiotics, in the first hundred days after birth, can decisively and unfortunately change the composition of the intestinal microbiome, as well as the subsequent use of proton pump inhibitor medication. Without antibiotic intervention, the composition of the microbiome is stable over years or even decades, the most problematic being the period of the first year of life, when the microbiome is constituted and stabilized.

Bacterial colonization dependent
to the type of birth?

Caesarean section is associated with increased peripheral and central adiposity in young adults. After weighing the various factors associated in the first part of life, children born by caesarean section have an increased risk of adiposity(11).

The importance of breastfeeding
in the prevention of metabolic syndrome

Breastfeeding has long-term beneficial effects, by reducing the risk of obesity and type 1 and 2 diabetes. Moreover, an association between low blood cholesterol levels in adults and breastfeeding has been observed. The World Health Organization (WHO) recommends exclusive breastfeeding until the age of 6 months and thereafter up to 2 years, associated with complementary nutrition. The WHO recommendations are based on a suite of studies that have demonstrated a reduced incidence of obesity, type 1 and 2 diabetes, as well as lower cholesterol levels in adults who have been breastfed. Breastfed children have a half prevalence of obesity compared to non-breastfed children. And the correlation between obesity and volume of breast milk ingested is inversely proportional. Long-term protection against obesity is one of the mechanisms that can explain the prevention of diabetes. In addition, other mechanisms by which breast milk reduces the baby’s risk of developing diabetes in the long term are related to the rich content of polyunsaturated fatty acids. These fatty acids from breast milk are very important in the growth and development of cognitive and visual functions. Breastfeeding is associated with high cholesterol and high-density lipoprotein values in childhood, but with low values in adolescence and adulthood. Determinants of the evolution/stabilization of bacterial communities are essential for the optimal development of children in the first 2-3 years. Antibiotic exposure and especially the use of anti-anaerobic antibiotics in childhood, the use of proton pump inhibitors, the development of inflammatory intestinal diseases, obesity, the duration of sleep in childhood(12), and excessive hygiene can cause, as well, severe damage to the microbiota. Some other factors with a positive effect on the development of the microbiota are: increased diversity and richness of the intestinal microbiome in early childhood (the existence of several siblings) and the lack of organophosphorus products, pesticides and herbicides.

Antibiotics ± infections: causal role
in the appearance of obesity in children?

The results of several studies support the fact that antibiotics used to treat infections in infants have been associated with weight gain. Most antibiotic administrations in these studies were directed against respiratory tract, ENT, skin and urinary tract infections. Both infections and antibiotics have the potential to change the gut microbial flora, which in turn could impact the immune system and metabolic regulation. Infection, as a causative factor of obesity, imposes the need to evaluate the hitherto unknown contribution of pathogens in the etiology of human obesity and, eventually, to find solutions to prevent or treat the infectious origins of obesity. This relatively new concept was also called “infectobesity” (obesity of infectious origin).

Li et al.(13) examined the effects of infection and antibiotic use separately. They compared antibiotic users with those with a similar diagnosis of infection, but who did not use antibiotics. According to this study, children diagnosed with an infection during the first year of life but not given antibiotics were 25% more likely to become obese, compared to controls without infections. Although they do not exclude a potential effect of antibiotics (when prescribed in the absence of infection) on the composition of the gut microbiota and, by implication, a risk for obesity, the authors suggest that there was no increased risk for obesity associated with the use of antibiotics for the treatment of infections common during the first year of life, compared to infants with untreated infections. The conclusion of this study is that untreated infections in childhood may be associated with obesity later in life, and measures to reduce childhood infections are urgently needed to prevent childhood obesity.

The role of antibiotics in obesity

Using young mice as a model, Cox and Blaser (2013)(14) showed that different low doses of antibiotics administered for seven weeks increased adiposity and produced changes in hormone levels related to metabolism. This study advances the possibility that modulation of the newborn/infant microbiome through antibiotic use could have long-term metabolic consequences on the development of adiposity(15). As we have shown before, the increased Firmicutes/Bacteroides ratio is associated with obesity. Firmicutes bacteria help regulate human metabolic genes and are more numerous in overweight individuals. They adversely affect metabolism and changes genetic expression, which predisposes to diabetes, obesity, cardiovascular diseases, renal diseases and ocular diseases.

Substantial increases in AGLS (SCFA) are correlated with changes in gut microbiome composition. They provide energy directly to colonocytes, and the rapid absorption into the portal circulation stimulates adipogenesis.

Do viral infections have a causal role
in obesity?

Over the past two decades, 10 adipogenic pathogens have been reported, including human and non-human viruses, bacteria and gut flora, as well as prions (proteinaceous infectious agents lacking any nucleic acid that cause a group of animal and human transmissible neurodegenerative diseases). Four viruses can cause obesity (“infectobesity”) in animal models (chickens, mice, sheep, goats, dogs, rats and hamsters), but cannot infect humans(16).

In 2002, Dhurandhar et al.(17) demonstrated, in experimental models of infected animals (chickens, mice and monkeys), that the human adenovirus 36 (Ad-36) can induce visceral adiposity, with weight gain and a decrease in serum cholesterol and triglycerides. The study of genetic and molecular mechanisms showed that Ad-36 induces replication, differentiation and lipid accumulation in 3T3-L1 cells (a cell line derived from mouse 3T3 cells used in biological research on adipose tissue) and primary human preadipocytes.

In 2015, Dhurandhar et al.(18) performed a review of studies published in the literature (343 studies, between January 1980 and July 2014), investigating the associations between infections and increased Body Mass Index in humans, as well as the differential responses of overweight and obese individuals to infections. The conclusions of the analysis of these studies indicated that viral infection with human adenovirus Ad-36 and the eradication of Helicobacter pylori by antibiotic therapy were followed by weight gain. It has also been observed that infections can influence Body Mass Index, and Body Mass Index can also influence the response to certain infections, as well as prevention and treatment measures.

The importance of “infectobesity” prevention

Childhood overweight/obesity can have consequences in adulthood that will be difficult to treat in the long term. Efforts made to prevent childhood obesity must take into account the risk factors, the identification of which is essential to help reduce this pathological phenomenon. Oral bacteriotherapy with probiotic microorganisms could provide a means of modulating both the gut microbial community and host physiology. Several studies support the association between childhood obesity and repeated administration of broad-spectrum antibiotics in children aged 0 to 23 months(19). Prudent use of antibiotics is essential not only to reduce the spread of antibiotic-resistant bacteria, but also to reduce the potentially harmful long-term metabolic consequences of early antibiotic exposure. Nutritional interventions to influence the microbiota appear to be necessary to establish a normal weight in childhood.

Fat or obesity is not bad in itself, but rather a symptom of everything inflammation means in the body, being an inflammatory syndrome that affects the vessels, heart, liver, pancreas, joints etc. Even fatty tissue is inflamed, and because of this, we cannot get rid of it quickly, even though we follow countless diets. First of all, we have to intervene on the inflammation of the system, an essential role having the intervention on the microbiome and the promotion of intestinal health. A diet high in carbohydrates and sugars gives rise to an “inflammatory microbiome”, and fructose increases the level of circulating inflammatory lipopolysaccharides by 40%. Processed fructose contributes to the obesity epidemic, feeds pathogenic gut bacteria, disrupts intestinal balance and stimulates insulin production just like glucose. Fructose is processed by the liver, leading to a decreased production of leptin (a hormone associated with appetite suppression).

A recent meta-analysis(20) shows the importance of microbiome manipulation in the prevention and treatment of various metabolic disorders, given first of all the safety of long-term administration, the absence of side effects (at recommended doses) and the multiple benefits.

Personalized treatment based on the analysis of the microbiome associated with dietary changes plays an essential role in the patient’s weight by reducing fat mass, influencing carbohydrate and lipid metabolism, increasing insulin sensitivity and reducing chronic systemic inflammation. The most studied and with promising results are the various classes of Lactobacillus and Bifidobacteria (especially Lactobacillus rhamnosus and Lactobacillus gasseri or Bifidobacterium longum), but there are ongoing studies on Saccharomyces cerevisiae var. boulardii, Enterobacter halii and Akkermansia muciniphila. New ways of their action are also being researched. The limitations of these studies are the small number of participants and the lack of long-term follow-up.

Conclusions

Considering the aspects discussed throughout this article, we turn our thoughts to certain primordial aspects that should not be neglected at all. The constitution and composition of the microbiome undergo physiochemical, biochemical and bacteriological changes during childhood. In certain pathological conditions and under the impact of certain treatment schemes, this microbiome also undergoes certain cellular and compositional metamorphoses. These particularities can often be the starting point of a process of weight gain which, uncontrolled by the dietician and parents, but also by the pediatrician, could lead to real catastrophes of the body mass. Given that children and adolescents possess a dynamic gut microbiome, while an adult’s gut microbiome is more static, children and adolescents are the main targets for studies to better understand the mechanistic role of the gut microbiome in the development and treatment of obesity. The interdisciplinary collaboration between specialists, but also between parents and specialists, is one of the primary goals in thinking and establishing a personalized protocol.


 

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.

 

Bibliografie

  1. Rampelli S, Guenther K, Turroni S, et al. Pre-obese children’s dysbiotic gut microbiome and unhealthy diets may predict the development of obesity. Commun Biol. 2018;1:222.
  2. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444(7122):1027-1031.
  3. Turnbaugh PJ, Bäckhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008;3(4):213-223.
  4. Cryan JF, O’Riordan KJ, Cowan CSM, et al. The Microbiota-Gut-Brain Axis. Physiol Rev. 2019;99(4):1877-2013.
  5. Huh SY, Rifas-Shiman SL, Zera CA, et al. Delivery by caesarean section and risk of obesity in preschool age children: a prospective cohort study. Arch Dis Child. 2012;97(7):610-616.
  6. Miller MA, Kruisbrink M, Wallace J, Ji C, Cappuccio FP. Sleep duration and incidence of obesity in infants, children, and adolescents: a systematic review and meta-analysis of prospective studies. Sleep. 2018;41(4):10.1093/sleep/zsy018.
  7. Miller MA, Kruisbrink M, Wallace J, Ji C, Cappuccio FP. Sleep duration and incidence of obesity in infants, children, and adolescents: a systematic review and meta-analysis of prospective studies. Sleep. 2018 Apr 1;41(4). doi:10.1093/sleep/zsy018.
  8. Skelton J. Pediatric Gastrointestinal and Liver Disease. Elsevier; Amsterdam, 2020. Obesity; pp. 135–147.
  9. Simmonds M, Burch J, Llewellyn A, et al. The use of measures of obesity in childhood for predicting obesity and the development of obesity-related diseases in adulthood: a systematic review and meta-analysis. Health Technol Assess. 2015;19(43):1-336.
  10. Jebeile H, Kelly AS, O’Malley G, Baur LA. Obesity in children and adolescents: epidemiology, causes, assessment, and management. Lancet Diabetes Endocrinol. 2022;10(5):351-365.
  11. Heymsfield S, Aronne LJ, Eneli I, Kumar RB, Michalsky M, Walker E, Wolfe BM, Woolford SJ, Yanovski S. Clinical Perspectives on Obesity Treatment: Challenges, Gaps, and Promising Opportunities. National Academy of Medicine. https://nam.edu/clinical-perspectives-on-obesity-treatment-challenges-gaps-and-promising-opportunities/.
  12. Kansra AR, Lakkunarajah S, Jay MS. Childhood and Adolescent Obesity: A Review. Front Pediatr. 2021;8:581461.
  13. Dhurandhar NV, Bailey D, Thomas D. Interaction of obesity and infections. Obes Rev. 2015;16(12):1017-1029.
  14. Cox LM, Blaser MJ. Pathways in microbe-induced obesity. Cell Metab. 2013;17(6):883-894.
  15. Grummer-Strawn LM, Reinold C, Krebs NF; Centers for Disease Control and Prevention (CDC). Use of World Health Organization and CDC growth charts for children aged 0-59 months in the United States [published correction appears in MMWR Recomm Rep. 2010 Sep 17;59(36):1184]. MMWR Recomm Rep. 2010;59(RR-9):1-15.
  16. Food and Drug Administration. FDA Approves Treatment for Chronic Weight Management in Pediatric Patients Aged 12 Years and Older (accessed on 30 October 2022)]; 2022 June 27. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-chronic-weight-management-pediatric-patients-aged-12-years-and-older.
  17. Dhurandhar NV, Whigham LD, Abbott DH, et al. Human adenovirus Ad-36 promotes weight gain in male rhesus and marmoset monkeys. J Nutr. 2002;132(10):3155-3160.
  18. Dhurandhar NV, Bailey D, Thomas D. Interaction of obesity and infections. Obes Rev. 2015;16(12):1017-1029.
  19. Solans M, Barceló MA, Morales-Suárez-Varela M, Moya A, Saez M. Prenatal exposure to antibiotics and risk of childhood overweight or obesity: A systematic review and meta-analysis. Obes Rev. 2022;23 Suppl 1:e13382.
  20. Kobyliak N, Conte C, Cammarota G, et al. Probiotics in prevention and treatment of obesity: a critical view. Nutr Metab (Lond). 2016;13:14.

Articole din ediţiile anterioare

PAGINA REZIDENTULUI | Ediţia 1 45 / 2017

Polimiozita - caz clinic

Anca Adam, Prof. dr. Evelina Moraru

Polimiozita este o boală rară din grupul miopatiilor inflamatorii idiopatice, caracterizată prin apariţia la nivelul muşchiului scheletic a unui pr...

04 aprilie 2017
REVIEW | Ediţia 3 67 / 2022

Aspecte biochimice şi imunobiologice în malnutriţia protein-calorică la copil

Bogdan Marius Istrate, Steluţa Constanţa Boroghină

Malnutriţia protein-calorică se caracterizează prin greutatea mică a copilului faţă de greutatea pe care ar trebui să o aibă la vârsta respectivă ş...

31 octombrie 2022
STADIUL ACTUAL AL CUNOAȘTERII | Ediţia 1 / 2015

Antibioterapia în pneumonia comunitară

Paraschiva Cherecheș-Panța

Pneumonia comunitară rămâne o problemă de sănătate la copil. În lumina abordărilor actuale, e necesară o apreciere a severităţii pentru măsurile in...

12 martie 2015
ACTUALITĂŢI | Ediţia 2 54 / 2019

Imunoterapia modernă

Alice Azoicăi, Prof. dr. Evelina Moraru

Imunoterapia specifică (ITS), sau vaccinarea alergenică, este o variantă terapeutică utilizată de medicii alergologi pentru a reduce reactivitatea ...

28 mai 2019