Microbiota and Probiotics on Immunity

and Infection Protection

Pedro Gutiérrez-Castrellón MD, PhD

pedro.gutierrez@councilforprobiotics.org
L
A
S
M e x ic a n C o n s o rtiu m P
F o r th e S tu d y o f G
M ic ro b io m e H
N
Conflict of Interests
Scientific Advisor, External Researcher & Speaker for:

• Abbott Nutrition (1999 to date)

• BioGaia (2009 to date)
• Nestlé (2014 to date)
Agenda

1.Microbióta and role on Health & Disease

2.Microbiota and Interaction to Respiratory
Immunity
3.Probiotics and Mode of Action on
Immunity
4.Probiotics and Respiratory Tract Infections
Impacto de la Microbiota en las Etapas de la Vida

Bendetta Raspini et al. Ital J Pediatr 2020; doi.org/10.1186/s13052-020-0794-8

Microbiota and Windows of Opportunity

BMC Microbiology 2019; DOI 10.1186/s12866-016-0708-5c

Early Modifiers of Human Microbiota

Farzana Yazmin et al. Frontiers in Pediatrics 2019; doi: 10.3389/fped.2017.00200 

Microbiota and Respiratory Infections

Matthew S. Kelly et al. Pediatr Infect Dis J. 2017;36:e211-e218. 

Microbiota and Respiratory Syncitial Virus

Jeffrey N. Harding et al. BMC Microbiology 2020; doi.org/10.1186/s12866-020-01816-5

Microbiota and Immune Modulation

Carolina Maldonado Galdeano et al. Ann Nutr Metab 2019;74:115–124

Probiotics and Immune Modulation

Sarah E Clark et al. Curr Opin Immunol 2020;66:42-49

Probiotics and Respiratory Infections

Tanvi Shinde et al. Microorganisms 2020, 8, 921; doi:10.3390/microorganisms8060921

Inmunidad, SARS-CoV-2 & Covid-19

Eakachai Prompetchara et al. Asian Pacif J Allerrg Immunol 2020

Probiotics & Prevention of Infectious
Diseases in Children

Katja Hatakka. Br J Nutr 2001;322:1-5

Probiotics & Prevention of Infectious
Diseases in Children (L. GG & BB-12)

1x1010 CFU

Samuli Rautava et al. Br J Nutr 2009;101:1722-1726

Lactobacillus GG for risk reduction of Respiratory Infections
in children: Meta-Analysis

Shan Liu. Indian Pediatr 2013;50:377-381

Limosilactobacillus reuteri

Jinshui Zheng et al. Int. J. Syst. Evol. Microbiol 2020;DOI 10.1099/ijsem.0.004107

Limosilactobacillus reuteri and immunity

Yuying Liu. Am J Gastroint and Liver Physiol 2010;299: G1087–G1096

17
Limosilactobacillus reuteri and immunity

18
Yuying Liu. Am J Gastroint and Liver Physiol 2010;299: G1087–G1096
Limosilactobacillus reuteri and immunity

19
Krisztian P Benne. Front Microbiol 2017
Limosilactobacillus reuteri and immunity

Jennifer K Spinler et al. Genome Biol Evol 2014;6:1772-1789

Limosilactobacillus reuteri and immunity

Hongbin Liu Nutrients 2017; doi:10.3390/nu9060559

Limosilactobacillus reuteri and immunity

James Versalovick. Ann Nutr Metabol 2013;63:42-52

Limosilactobacillus reuteri and Microfilm

Steven A Frese Plos Genetics 2017

Limosilactobacillus reuteri and Microvesicles

Rosella Grande et al. Frontiers in Microbiology 2017; doi: 10.3389/fmicb.2017.01040

Limosilactobacillus reuteri and Histamine Cascade

Carissa M. Thomas. Plos One 2012;7:e31951:1-15

Lactobacillus reuteri and Infection Protection

Weizzman et al. Pediatrics 2005;115:5-9

Lactobacillus reuteri and Infection Protection

Gutiérrez-Castrellón P et al. Pediatrics 2014;133:904-909

Lactobacillus reuteri and Infection Protection
42 vs. 69 episodes

* *
*

Gutiérrez-Castrellón P et al. Pediatrics 2014;133:904-909

Lactobacillus reuteri DSM 17938 and Preventive Medicine
Follow-up

1x108 CFU
L. reuteri Protectis Follow-up

Inclusion
(16 months) 12 weeks 12 weeks

Placebo Follow-up

Gutiérrez-Castrellón P et al. Pediatrics 2014;133:904-909

 Lactobacillus reuteri and Infection Protection

93 vs. 204 episodes

* *

*
*

Gutiérrez-Castrellón P et al. Pediatrics 2014;133:904-909

Lactobacillus reuteri and Infection Protection

* *
*
*

Gutiérrez-Castrellón P et al. Pediatrics 2014;133:904-909

 Lactobacillus reuteri and Infection Protection
Author, Year SMD (CI95%) Weight (%)

z 10.6, p 0.0001

Gutiérrez-Castrellón P et al. 2018

Probiotics to Prevent or Reduce the Risk for Respiratory Infections in healthy Children

Fig. 2 Network Meta-Analysis on the efficacy of probiotics to reduce the ocurrence of

upper respiratory infections in ambulatory children

L a c t o b a c illu s r h a m n o s u s G G

P la c e b o

L . r h a m n o s u s G G + L . a c id o p h illu s + B B 1 2

Gutierrez-Castrellon P; Weizzman S; Cruchet S et al 2019 (submitted)

 Table 3. Quality Analysis of Included studies
Author Random Allocation Blinding of Blinding of Incomplete Selective Other
Sequence Concealment participants outcome outcome data reporting bias
Generation and personnel assessment
11
Hatakka, 2001
+ + ? ? ? + +
Weizman-A,
2005
33

Weizman-B,
+ + + + + + +
Fig. 10 Best Treatment Analysis for Probiotics to reduce duration of upperrespiratory infections
2005
33 + + + + + + +
? ?
34
Cobo Sanz, 2006 + + + + +
Marseglia, 2007
35
_
Kloster Smerud,
2008
36
+
?
-
?
?
?
+
?
+
?
+
+
+
+ 10
37
Leyer-A, 2009
+ + + + + + +

9
37
Leyer-B, 2009
+ + + + + + +
38
Rautava, 2009
+ + + + + + +
Song Lin-A,
39 + ? + ? + + +
2009
+ + + + +
8
39
Song Lin-B, 2009
? ?
39
Song Lin-C, 2009
+ ? + ? + + +
Caceres, 2010
40
? _ L. reuteri
+ + + + +
L. rhamnosus GG
-
7

Prob. Best Treatment*

41
Hojsak, 2010
+ + + + + + +
Bifibobacterium lactis BB12
42
Merestein, 2010 + + + ? ? + +
43
Taipale, 2011
+ + + + + + +
Agustina-A,
2012
44 + + ? + + ? + 6
Agustina-B,
44
+ + ? + + ? +
2012
Kumpu, 2012
45
+ + + ? ? + +
Maldonado,
2012
46
+ + ? + + + + 5
Rerksuppaphol, + + + + + + +
2012
47
L. casei
Gutierrez-
Castrellon, 2014
Hojsak, 2016
49
48 +
+
+
+
+
?
+
+
+
+
+
+
+
+
4
50
Prodeus, 2016 + + ? + + + +

3
51
Taipale, 2016
+ + + + + + +

2
L. rhamnosus**
1
0
100 90 80 70 60 50 40 30 20 10 0
Sucra Values
* Sucra analysis include only probiotic with at least 2 studies on the topic
** Include rhamnosus strain different than GG

Gutierrez-Castrellon P; Weizzman S; Cruchet S et al 2019 (submitted)

 L. reuteri ATCC PTA 5289 & L. reuteri DSM 17938 (4x108 UFC) en el
tratamiento de Infecciones Respiratorias
Table 1. Baseline characteristics at study entry
Parameter L. reuteri group Placebo group
n=35 n=35
Age in years (mean ± s.d) 2.1± 0.8 2.4±1.1
Number of girls [n, (%)] 19 (55) 18 (52)
Days with respiratory symptoms before 0.8± 0.2 1.0± 0.3
recruitment (mean ± s.d)
Days with fever (mean ± s.d) 0.7±0.4 0.9±0.6
Severity of sore throat (FLACC Score) (mean ± s.d) 8±5 9±4
Rhinorrea [n, (%)] 25 (71) 24 (68)
Cough episodes [n, (%)] 20 (58) 21 (60)
Nasal congestion [n, (%)] 11 (32) 10 (29)
Snoring episodes [n, (%)] 10 (29) 11 (32)
Sleep disturbances [n, (%)] 11 (32) 10 (29)
* p <0.05, ** p <0.01, otherwise non-significant

●
Gutierrez-Castrellon et al. Submited 2020
L. reuteri ATCC PTA 5289 & L. reuteri DSM 17938 (4x108 UFC) en el
tratamiento de Infecciones Respiratorias

Table 2. Aetiology for Upper Respiratory Infections

Microorganism L. reuteri Placebo
group group
n=35 n=35
(%) (%)
Rhinovirus 30 32
Adenovirus 28 31
Influenza A 12 16
Influenza V 18 12
Syncytial Respiratory 7 6
Virus
Coronavirus 3 2
Moraxella Catarralis 2 3
Streptococcus 6 4
pneumonie
* p <0.05, ** p <0.01, otherwise non-significant
** It is not 100% because there were mixed infections

Gutierrez-Castrellon et al. Submited 2020

L. reuteri ATCC PTA 5289 & L. reuteri DSM 17938 (4x108 UFC) en el
tratamiento de Infecciones Respiratorias

Figure 2. L. reuteri and evolution of fever in children with Pharyngitis/ Tonsillitis

39
Temperature (oC) (x± s.d.)

38.5

38
*
37.5 *
*
37

36.5

36
0 1 2 3 4 5 6 7 8 9 10
Days after Intervention
* < p 0.05; ** p < 0.01
L. reuteri Group Placebo Group

Gutierrez-Castrellon et al. Submited 2020

L. reuteri ATCC PTA 5289 & L. reuteri DSM 17938 (4x108 UFC) en el
tratamiento de Infecciones Respiratorias

Table 3. Outcome Analysis at Day 10

Parameter L. reuteri group Placebo group
n=35 n=35
Primary outcomes
Duration of symptoms (days) (mean ± s.d) 3.1±0.8 5.2±1.4*
Severity of sore throat (FLACC Score) (mean ± s.d) 5.0±1.2 8.0±3.4*
Rhinorrea [n, (%)] 6 (17) 15 (43)*
Cough episodes [n, (%)] 6 (17) 7 (21)
Nasal congestion [n, (%)] 3 (8) 10 (28)*
Snoring episodes [n, (%)] 4 (12) 5 (14)
Sleep disturbances [n, (%)] 3 (8) 4 (11)
The Pragmatic Scoring System for Pharyngitis 0.7±0.2 1.1±0.4
(mean ± s.d)
* p <0.05, ** p <0.01, otherwise non-significant
Gutierrez-Castrellon et al. Submited 2020
 Thank you¡¡

Pedro Gutiérrez-Castrellón
pedro.gutierrez@councilforprobiotics.org