PARADIGMAS DEL USO DE PROBI TICOS EN PEDIATR A

1. 1 PARADIGMAS DEL USO DE PROBI�TICOS EN PEDIATR�A Nenna Lung de Mart�nez MD. Pediatra Nutri�loga Pontificia U. Javeriana � U. El Bosque

2. 2 How does the intestinal flora develop? The aseptic gastro-intestinal tract of the fetus is inoculated during birth by the mother�s intestinal and vaginal flora. This leads to a diverse flora of bifidobacteria, enterobacteria, bacteroides, clostridia and gram-positive cocci. After this first inoculation, the flora changes rapidly, presumably under the influence of the diet. In entirely breast-fed infants, the flora is predominantly bifidobacteria, which is possibly caused by selective components that are present in human milk. In contrast, the flora of formula-fed infants is more diverse and does not show the predominance of bifidobacteria. The introduction of solid food leads to the bifidobacteria becoming less predominant in breast-fed infants. At 12 months of age, the anaerobic bacterial population of the large bowel of breast-fed and formula-fed infants begin to resemble the microflora of adults in both number and composition. References: Stark PL, Lee A. J Med Microbiol 1982; 15(2):189-203 Orrhage K, Nord CE. Acta Paediatr 1999; suppl. 430:47-57 Harmsen H et al. J Pediatr Gastroenterol Nutr 2000; 30:61-67 How does the intestinal flora develop? The aseptic gastro-intestinal tract of the fetus is inoculated during birth by the mother�s intestinal and vaginal flora. This leads to a diverse flora of bifidobacteria, enterobacteria, bacteroides, clostridia and gram-positive cocci. After this first inoculation, the flora changes rapidly, presumably under the influence of the diet. In entirely breast-fed infants, the flora is predominantly bifidobacteria, which is possibly caused by selective components that are present in human milk. In contrast, the flora of formula-fed infants is more diverse and does not show the predominance of bifidobacteria. The introduction of solid food leads to the bifidobacteria becoming less predominant in breast-fed infants. At 12 months of age, the anaerobic bacterial population of the large bowel of breast-fed and formula-fed infants begin to resemble the microflora of adults in both number and composition. References: Stark PL, Lee A. J Med Microbiol 1982; 15(2):189-203 Orrhage K, Nord CE. Acta Paediatr 1999; suppl. 430:47-57 Harmsen H et al. J Pediatr Gastroenterol Nutr 2000; 30:61-67

3. 3 Undigested components of the diet, such as resistant starch, pectin and non-digestible oligosaccharides, provide substrate for the colonic microflora. These substances stimulate the growth and metabolism of the bacteria present, giving rise to several beneficial effects:- synthesis of acids and a resultant reduction in pH, promotion of enterocyte growth which strengthens the gut barrier, stimulation of maturation of the immune system. The overall beneficial effect of these changes is a reduction in colonisation of the colon by pathogenic microorganisms.Undigested components of the diet, such as resistant starch, pectin and non-digestible oligosaccharides, provide substrate for the colonic microflora. These substances stimulate the growth and metabolism of the bacteria present, giving rise to several beneficial effects:- synthesis of acids and a resultant reduction in pH, promotion of enterocyte growth which strengthens the gut barrier, stimulation of maturation of the immune system. The overall beneficial effect of these changes is a reduction in colonisation of the colon by pathogenic microorganisms.

4. 4

5. 5 COLONIZACI�N CUANTITATIVA DEL TRACTO GI. What does the quantitative colonisation of the GI-tract look like? Due to the acidic pH in the stomach its colonisation with bacteria is low with numbers of 0 to 103 CFU per ml. The small intestine constitutes a zone of transition between the sparsely populated stomach and the luxuriant bacterial flora of the colon. The main factors limiting bacterial growth in the upper parts of the small bowel are rapid transit of the contents and the secretion of bile and pancreatic juice. The highest bacterial counts are found in the colon with up to 1013 colony forming units (cfu) per ml gut content. Reference: Simon GL & Gorbach SL. Gastroenterol 1984; 86:174-193 What does the quantitative colonisation of the GI-tract look like? Due to the acidic pH in the stomach its colonisation with bacteria is low with numbers of 0 to 103 CFU per ml. The small intestine constitutes a zone of transition between the sparsely populated stomach and the luxuriant bacterial flora of the colon. The main factors limiting bacterial growth in the upper parts of the small bowel are rapid transit of the contents and the secretion of bile and pancreatic juice. The highest bacterial counts are found in the colon with up to 1013 colony forming units (cfu) per ml gut content. Reference: Simon GL & Gorbach SL. Gastroenterol 1984; 86:174-193

6. 6 Absorci�n de Nutrientes

7. 7 COMPOSICI�N DE LA MICROBIOTA INTESTINAL The large intestine can be described as a complex microbial eco-system. It has been recognised for many years that the different species of the intestinal flora may exert beneficial as well as harmful effects on health. The potentially harmful effects comprise the production of pathogenic or toxic substances, potentially resulting in diarrhoea, constipation, liver damage, cancer, encephalopathy and gastro-intestinal putrefaction. The beneficial effects include inhibiting the growth of exogenous and harmful bacteria, stimulation of immune functions, aiding the digestion and absorption of food ingredients and minerals, and the synthesis of vitamins. Whereas some species might exert only harmful effects such as pseudomonas or clostridia, others may have harmful as well as beneficial effects such as E. coli and bacteroides. However, there are also some groups which only have beneficial effects such as lactobacilli and bifidobacteria. The central vertical axis indicates the approximate bacterial counts of different species in adults. Bacteroides and bifidobacteria are the most common species. Reference: Gibson GR, Roberfroid MB. J Nutr 1995; 125:1401-1412The large intestine can be described as a complex microbial eco-system. It has been recognised for many years that the different species of the intestinal flora may exert beneficial as well as harmful effects on health. The potentially harmful effects comprise the production of pathogenic or toxic substances, potentially resulting in diarrhoea, constipation, liver damage, cancer, encephalopathy and gastro-intestinal putrefaction. The beneficial effects include inhibiting the growth of exogenous and harmful bacteria, stimulation of immune functions, aiding the digestion and absorption of food ingredients and minerals, and the synthesis of vitamins. Whereas some species might exert only harmful effects such as pseudomonas or clostridia, others may have harmful as well as beneficial effects such as E. coli and bacteroides. However, there are also some groups which only have beneficial effects such as lactobacilli and bifidobacteria. The central vertical axis indicates the approximate bacterial counts of different species in adults. Bacteroides and bifidobacteria are the most common species. Reference: Gibson GR, Roberfroid MB. J Nutr 1995; 125:1401-1412

8. 8 ECOSISTEMA INTESTINAL Depende de: Medio ambiente Alimentaci�n Patrimonio gen�tico

9. 9 FACTORES QUE AFECTAN LA MICROBIOTA INTESTINAL Extr�nsecos: Carga microbiana del medio ambiente H�bitos alimentarios Tipo de alimentos Composici�n de la microflora materna

10. 10 MODULACI�N NUTRICIONAL DE LA MICROBIOTA INTESTINAL Prebi�tico: aumentando el aporte de substratos utilizables por poblaciones end�genas. Probi�tico: aumentando el aporte de microorganismos ex�genos.

11. 11 PROPIEDADES PROTECTORAS DEUNA MICROBIOTA DOMINADA POR BACILLUS CLAUSSI What is the relevance of the bifido-dominant flora in breast-fed infants? Several health-promoting and protective properties have been attributed to bifidobacteria such as: lowering the pH by production of acids such as acetic and lactic acids, leading to an antibacterial environment, the inhibition of pathogens by the secretion of substances which directly inhibit many other bacteria, activation of the immune system, as described before, production of digestive enzymes such as casein phosphatase and lysozyme, the production of vitamins, largely of the B-group. The overall benefit of these effects is to protect infants from the growth of pathogenic micro-organisms in the intestine during a phase of insufficient immune response. For these reasons, it seems very desirable to also increase the numbers of bifidobacteria in the intestinal flora of formula-fed infants. References: Gibson GR, Roberfroid M. J Nutr 1995; 1256:1401-1412 Koletzko B et al. Br J Nutr 1998; 80 (suppl1):S5-S45 Salminen S et al. Br J Nutr. 1998; 80 (suppl1):S147-S171 Kalliom�ki M et al. J Allergy Clin Immunol 2001; 107:129-34 Bj�rksten B et al. J Allergy Clin Immunol 2001; 108: 516-20What is the relevance of the bifido-dominant flora in breast-fed infants? Several health-promoting and protective properties have been attributed to bifidobacteria such as: lowering the pH by production of acids such as acetic and lactic acids, leading to an antibacterial environment, the inhibition of pathogens by the secretion of substances which directly inhibit many other bacteria, activation of the immune system, as described before, production of digestive enzymes such as casein phosphatase and lysozyme, the production of vitamins, largely of the B-group. The overall benefit of these effects is to protect infants from the growth of pathogenic micro-organisms in the intestine during a phase of insufficient immune response. For these reasons, it seems very desirable to also increase the numbers of bifidobacteria in the intestinal flora of formula-fed infants. References: Gibson GR, Roberfroid M. J Nutr 1995; 1256:1401-1412 Koletzko B et al. Br J Nutr 1998; 80 (suppl1):S5-S45 Salminen S et al. Br J Nutr. 1998; 80 (suppl1):S147-S171 Kalliom�ki M et al. J Allergy Clin Immunol 2001; 107:129-34 Bj�rksten B et al. J Allergy Clin Immunol 2001; 108: 516-20

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13. 13  PROBI�TICOS Pre- and probiotic supplements are the only efficient methods available to increase the bifidogenicity of infant formulas. What kind of substances are described as pro- and prebiotics? A probiotic is defined as a live microbial food supplement, including fermented milk and over-the counter preparations that contain lyophilised bacteria, that beneficially affect the host by improving its intestinal microbial balance. In other words, live beneficial microorganisms are administered, they remain in a viable form during transit through the gastrointestinal tract and become active on reaching the colon, where appropriate physiochemical conditions for their growth occur. References: Collins MD et al. Probiotics, prebiotics, and synbiotics: approaches for modulating the microbial ecology of the gut. Am J Clin Nutr 1999; 69:1052S-1057S Fuller R. A review: probiotics in man and animals. J Appl Bacteriol 1989; 66:365-738  Pre- and probiotic supplements are the only efficient methods available to increase the bifidogenicity of infant formulas. What kind of substances are described as pro- and prebiotics? A probiotic is defined as a live microbial food supplement, including fermented milk and over-the counter preparations that contain lyophilised bacteria, that beneficially affect the host by improving its intestinal microbial balance. In other words, live beneficial microorganisms are administered, they remain in a viable form during transit through the gastrointestinal tract and become active on reaching the colon, where appropriate physiochemical conditions for their growth occur. References: Collins MD et al. Probiotics, prebiotics, and synbiotics: approaches for modulating the microbial ecology of the gut. Am J Clin Nutr 1999; 69:1052S-1057S Fuller R. A review: probiotics in man and animals. J Appl Bacteriol 1989; 66:365-738

14. 14 PROBI�TICOS: REQUISITOS (I) De origen humano No ser pat�gena No ser sensible a enzimas proteol�ticas Ser capaz de vivir en tr�nsito g�strico No conjugarse con sales biliares Capacidad de adhesi�n y colonizaci�n Adherencia a c�lulas epiteliales

15. 15 PROBI�TICOS: REQUISITOS (II) Sobre vivencia en el ecosistema intestinal Producci�n de componentes antimicrobianos Permanencia prolongada y estable Inmunoestimulaci�n

16. 16 INMUNOMODULACI�N Se basa en tres principios: Reconocimiento del ant�geno Destrucci�n del mismo Regulaci�n del material destruido

17. 17 FUNCI�N INMUNOL�GICA Aumenta actividad fagoc�tica Aumenta producci�n de linfocitos Aumenta actividad de c�lulas NK Reduce producci�n de citoquinas Aumenta producci�n de Interleuquinas Inhibici�n de agentes carcinog�nicos Incremento de IgA total y espec�fica

18. 18 FACTORES QUE DISMINUYEN LA POBLACI�N DE PROBI�TICOS Estr�s Envejecimiento Antibioticoterapia Quimioterapia y radioterapia Anticonceptivos Alcohol Diarrea intermitente Desnutrici�n

19. 19  PREBI�TICOS The definition of a prebiotic has recently been redefined by Gibson and Probert as a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microflora, that confers benefits upon host well-being and health. This definition is broader than the previous one by Gibson and Roberfroid (1995) which referred only to the specific effects of prebiotics on colonic bacteria. In other words, a prebiotic is a food ingredient which is undigested and serves as a growth substrate for beneficial bacteria in the GI tract, thereby providing one or more health benefits. References: Gibson GR et al. J Nutr, submitted 2003 Gibson GR, Roberfroid MB. J Nutr 1995; 125:1401-1412 The definition of a prebiotic has recently been redefined by Gibson and Probert as a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microflora, that confers benefits upon host well-being and health. This definition is broader than the previous one by Gibson and Roberfroid (1995) which referred only to the specific effects of prebiotics on colonic bacteria. In other words, a prebiotic is a food ingredient which is undigested and serves as a growth substrate for beneficial bacteria in the GI tract, thereby providing one or more health benefits. References: Gibson GR et al. J Nutr, submitted 2003 Gibson GR, Roberfroid MB. J Nutr 1995; 125:1401-1412

20. 20 SIMBI�TICOS(ALIMENTOS FUNCIONALES) PROBI�TICOS + PREBI�TICOS

21. 21 PROBI�TICOS (1.965) PREBI�TICOS (1.995) SIMBI�TICOS (2.001)

22. 22 The first component comprises galacto-oligosaccharides. These are carbohydrates which are built up from galactose and glucose. This fraction consists of a mixture of linear molecules with a chain length of two to six sugar molecules. The first component comprises galacto-oligosaccharides. These are carbohydrates which are built up from galactose and glucose. This fraction consists of a mixture of linear molecules with a chain length of two to six sugar molecules.

23. 23 Galacto-oligosaccharides are consumed by infants in several naturally occurring forms. They are components of human milk and are also by products of lactose hydrolysis in fermented milk and milk products. Therefore, they are a natural part of the human infant diet. Galacto-oligosaccharides are consumed by infants in several naturally occurring forms. They are components of human milk and are also by products of lactose hydrolysis in fermented milk and milk products. Therefore, they are a natural part of the human infant diet.

24. 24 Fructo-oligosaccharides are natural storage carbohydrates present in many plants such as chicory, banana, wheat and leeks. These oligosaccharides are therefore natural food components.Fructo-oligosaccharides are natural storage carbohydrates present in many plants such as chicory, banana, wheat and leeks. These oligosaccharides are therefore natural food components.

25. 25 TR�FICAS Control de la proliferaci�n y diferenciaci�n de c�lulas epiteliales; desarrollo y homeostasis del sistema inmunitario. PROTECTORAS Protecci�n contra pat�genos (el Efecto Barrera). METAB�LICAS Fermentaci�n de los residuos alimentarios no digeridos y moco end�geno: recuperaci�n de energ�a en forma de �cidos grasos de cadena corta, producci�n de vitamina K, absorci�n de iones. PRINCIPALES FUNCIONES DE LA MICROBIOTA INTESTINAL

26. 26 AGENTES BIOTERAP�UTICOS

27. 27 AGENTES BIOTERAP�UTICOS

28. 28

29. 29 AGENTES BIOTERAP�UTICOS

30. 30 AGENTES BIOTERAP�UTICOS

31. 31 EFICACIA DE LOS PROBI�TICOS RECOMENDACI�N DE GRADO A (Datos de nivel 1A) Tratamiento de la diarrea infecciosa aguda en ni�os Prevenci�n de la diarrea asociada a los antibi�ticos Prevenci�n de la diarrea nosocomial y adquirida en ni�os Diarrea en ni�os Tratamiento de la mal absorci�n de lactosa

32. 32 BACILLUS CLAUSII PRINCIPIO ACTIVO: Microorganismo gram positivo, aerobio estricto, con tolerancia alcalina (capacidad de crecer a un ph = 7 y superior), no pat�geno y ubicuo, encontr�ndose incluso en el intestino humano. Puede existir en forma de esporas resistente a condiciones f�sicas y qu�mica adversas. 80% de sujeto sanos (heces) 104107 x gr. de heces

33. 33 ESPORAS DE BACILLUS CLAUSII

34. 34 PROPIEDADES DEL BACILLUS CLAUSII Capaz de colonizar y sobrevivir en el tracto gastrointestinal. Produce inhibici�n en la adherencia de bacterias pat�genas. Produce sustancias antimicrobianas. Resistente a diversos antibi�ticos y al mismo tiempo no trasmite esta resistencia a g�rmenes pat�genos. Tiene efecto inmunomodulador.

35. 35 ESPORAS BACTERIANAS (BACILLUS CLAUSII) PROPIEDADES Resistencia al �cido: Sobrevive a la exposici�n de jugos g�stricos naturales y artificiales. Resistencias a sales biliares. Resistencia al calor.

36. 36 Entre 20�c- 45 �c en medio l�quido 50�c en medio s�lido �ptimo 35 �c- 40 �c No crecen = 55 �c

37. 37 BACILLUS CLAUSII CARACTER�STICAS GENERALES Cuatro cepas: O/C N/R T SIN

38. 38 INDICACIONES Diarrea infecciosa Diarrea del viajero Diarrea secundaria a antibi�ticos Trastorno inflamatorio intestinal Colon irritable Deficiencia de lactasa Reducci�n de colesterol Enfermedad Al�rgica Infecci�n por H. Pylori Pancreatitis ?

39. 39 Infecci�n por H. Pylori

40. 40 Evidencia basada en meta�nalisiscon B. Clausii

41. 41 Evidencia basada en meta�nalisiscon B. Clausii

42. 42 BACILLUS CLAUSII CONTRAINDICACI�N: HIPERSENSIBILIDAD CONOCIDA A SU COMPOSICI�N. PRECAUCI�N: DURANTE LA ANTIBIOTICOTERAPIA, ADMINISTRARLO EN EL INTERVALO DE DOS DOSIS.

43. 43 BACILLUS CLAUSII INTERACCI�N: NO SE CONOCEN. EMBARAZO Y LACTANCIA: NO EST� CONTRAINDICADO. CAPACIDAD DE CONDUCCI�N: NO INTERFIERE.

44. 44 BACILLUS CLAUSII EFECTOS INDESEADOS: NO SE HAN REPORTADO. SOBREDOSIS: NO SE HAN DESCRITO.

45. 45

46. 46 CONCLUSIONES Por sus caracter�sticas biol�gicas Bacillus Clausii es una alternativa eficaz y segura en el tratamiento o prevenci�n de la diarrea por antibi�ticos Las evidencias hasta ahora sugieren que Bacillus Clausii probablemente tenga una influencia positiva en todas aquellas entidades relacionadas con desequilibrio en la microflora intestinal: * sobrecrecimiento bacteriano (intestino irritable, s�ndrome intestino corto, trastornos en la motilidad intestinal)

47. 47 RECOMENDACI�N DE ESPGHAN ESPGHAN:European Society of Pediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. Agostoni C, Axelsson I, Bregger C, et al. Probiotic bacteria in dietetic products for infants: a commentary by the ESPGHAN Committee on Nutrition. J. Pediatr Gastroenterol Nutr 2004;38(4):365-74

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