Accepted Manuscript Microbiota, Obesity and Malnutrition Didier Raoult PII:
S0882-4010(16)30052-3
DOI:
10.1016/j.micpath.2016.02.001
Reference:
YMPAT 1772
To appear in:
Microbial Pathogenesis
Received Date: 26 January 2016 Revised Date:
1 February 2016
Accepted Date: 1 February 2016
Please cite this article as: Raoult D, Microbiota, Obesity and Malnutrition, Microbial Pathogenesis (2016), doi: 10.1016/j.micpath.2016.02.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Microbiota, Obesity and Malnutrition
2
Editorial
3
Didier RAOULT*
RI PT
1
4 5
*URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, Aix Marseille Université,
7
Marseille, France
8
Phone: (+33) 491 32 43 75, Fax: (+33) 491 38 77 72
9
E-mail: [email protected]
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10
M AN U
SC
6
1
ACCEPTED MANUSCRIPT
11
Introduction
12 The putative role of microbiota in obesity and malnutrition is a growing issue. There are, in
14
this area, controversies, major industrial interests (probiotics industry) and methodological
15
difficulties that result in a very significant discrepancy between the different works and
16
different results [1, 2].
17
Clinically, the tangible link between gut microbiota manipulation and weight gain is
18
supported by several studies. [3]. Thus, M. Blaser, especially, is studying the role of
19
antibiotics in treatment of Helicobacter pylori caused gastroduodenal ulcers and in the
20
treatment of pneumonia in children showed that this causes weight gain [4]. In both cases, a
21
significant increase, relative to control, was noted [5]. We were able to report that
22
vancomycin prescribed for 6 weeks in patients with endocarditis, was also associated with
23
weight gain. It should be noted that the vancomycin structural analogue is avoparcin, used in
24
the farm industry for growing turkeys [4].
25
Antibiotics and probiotics, which manipulate the intestinal flora of the animals, have been
26
used for over 50 years, in farm industry, and lead, on average, in particular in poultry and
27
pigs, an increase of 8 to 10% of the weight of the body (muscles and fat) [3, 6]. Antibiotics,
28
most used were tetracyclines (first identified as a probiotic in Streptomyces aureofaciens), the
29
vancomycine and quinolones. Antibiotics were prescribed in young animals (mammals, fish
30
and poultry) to make them gain weight. It was suspected, by M. Blaser, the residual rate,
31
which could be found in the meat or milk, could cause weight gain in children [7]. These
32
antibiotics are banned as growth promotors in Europe since 2002 [7]. In contrast, the
33
prescription of probiotics is regulated by a European rating dating back to 1972 [3]. It is noted
34
that the assessment of the effect of probiotics, used to increase weight of animals, has not
AC C
EP
TE D
M AN U
SC
RI PT
13
2
ACCEPTED MANUSCRIPT
been extensively studied in humans to see if they produce the same effect [8]; yet what seems
36
logical. Two studies report the experience of growth promotors in this special issue [9, 10].
37
Microbiota studies have mostly used molecular biology techniques. Unfortunately, after a
38
very encouraging start, highlighting a particular profile in obese subjects in the USA,
39
numerous studies have been conducted, which found divergent results and not reproducible
40
from one study to another [1]. These elements highlight several points. The first is that the
41
extraction methods are very different from one study to the other and play an absolutely
42
critical role in metagenomics analysis. Furthermore, the primers, for PCR, are not always
43
identical. And finally, analysis of data uses different algorithms. In total, it is difficult at
44
present to have a very clear vision of role of the microbiota, in humans as different teams
45
have different results. Some do not even seeing significant differences between obese and
46
non-obese subjects [1, 11].
47
Culturomics studies, allowing a revival of culture techniques [12], are ongoing and could help
48
to highlight the presence of a number of microorganisms associated with obesity [13, 14]. It is
49
the same for severe malnutrition (kwashiorkor) or a restriction of heterogeneity was found
50
[15]. It should be noted that a restriction of heterogeneity was also found in obese subjects.
51
The role of bacteria, such as Faecalibacterium prausnitzii [16], or methanogenic archaea [11]
52
as have been proposed, which have not, so far, collected a consensus in the literature.
53
The other problem of the majority of studies is that they use the faeces [17]. Unquestionably,
54
feces are not a good sample to study the microbiota associated with digestion. Digestion is in
55
the upper part of the intestine, especially the small intestine; 99.9% of the bacteria found in
56
fecal matter are these that grow and multiply within the colon. It is clear that the colon is not
57
associated with weight loss or obesity. Several million peoples have to undergo colonic
58
resection without associated metabolic disorders, if not a loss of water. Furthermore, the
59
determinations carried out of nutrients in the last loop of the small intestine, show that there
AC C
EP
TE D
M AN U
SC
RI PT
35
3
ACCEPTED MANUSCRIPT
retain only long sugars of vegetable origin, which are probably partly digested by the colon,
61
but that do not represent a significant factor in obesity. Preliminary studies show that there are
62
in the small intestine, bacteria specifically associated with obesity [18]. In all, some bacteria
63
seem to be more commonly associated with weight gain in animals and in men, including
64
Lactobacillus [9]. However, it can be at the strain level, the activity of Lactobacillus strains
65
may be neutral, promote obesity or otherwise prevent it. The hypothesis that we have, for the
66
role of Lactobacillus, is that those associated with obesity seem to allow early digestion of
67
lipids, that would promote their early absorption, and those associated with protection appear
68
to be better equipped to digest short sugar, so competing with the intestine to the recruitment
69
of calories. These data, made from analyzes of genome or metagenome, need to be confirmed
70
[19]. Moreover, the gut microbiota composition may be related to the wasting syndrome of
71
patients with HIV infection and their susceptibility to mucosal infection [20].
72
In the future, it is clear that there are still elements to be clarified. Some experimental models,
73
especially those developed by JF Gordon [16] show that transplantation of microbiota from
74
obese or malnourished children lead to changes in the xenobiotic mouse, and there is
75
sufficient evidence to suggest that manipulation of the microbiota plays a role in weight gain
76
or otherwise in its protection [3]. It is clear, for example, that the combination of antibiotics,
77
to resupply in malnourished subjects, plays a significant role in weight regain. Studies, more
78
systematic, carried out on the microbiota of the upper part of the intestine, combining
79
culturomics and deep metagenomic, probably will have a clearer landscape of
80
microorganisms associated with weight gain or protection. Furthermore, prospective
81
epidemiological studies, assessing the role of probiotics and antibiotics for children in weight
82
gain or protection, seem necessary.
83
Finally, the emergence of fields (microbiota, microbiota manipulation, metabolic modification
AC C
EP
TE D
M AN U
SC
RI PT
60
4
ACCEPTED MANUSCRIPT
84
and weight change) is a field of primary importance, but which require standardization and
85
different methodological approach to make truly useful findings to public health.
87
References
88
(1) Angelakis E, Armougom F, Million M, Raoult D. The relationship between gut
SC
89
RI PT
86
microbiota and weight gain in humans. Future Microbiol 2012 Jan; 7(1):91-109.
91
(2) Raoult D. Human microbiome: take-home lesson on growth promoters? Nature 2008
92
Aug 7; 454(7205):690-1.
M AN U
90
(3) Angelakis E, Merhej V, Raoult D. Related actions of probiotics and antibiotics on gut
94
microbiota and weight modification. Lancet Infect Dis 2013 Oct; 13(10):889-99.
95
TE D
93
(4) Thuny F, Richet H, Casalta JP, Angelakis E, Habib G, Raoult D. Vancomycin treatment of infective endocarditis is linked with recently acquired obesity. PLoS One
97
2010; 5(2):e9074.
99 100 101 102
(5) Cox LM, Yamanishi S, Sohn J, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 2014 Aug 14;
AC C
98
EP
96
158(4):705-21.
(6) Cromwell GL. Why and how antibiotics are used in swine production. Anim Biotechnol 2002 May; 13(1):7-27.
5
ACCEPTED MANUSCRIPT
103
(7) Phillips I, Casewell M, Cox T, et al. Does the use of antibiotics in food animals pose a
104
risk to human health? A critical review of published data. J Antimicrob Chemother
105
2004 Jan; 53(1):28-52.
110 111 112 113 114 115
RI PT
109
(9) Drissi F, Raoult D, Merhej V. Metabolic role of Lactobacilli in weight modification in humans and animals. Microb Pathog 2016; submitted.
SC
108
Microb Pathog 2016 Jan 11.
(10) Angelakis E, Raoult D. Weight gain by gut microbiota manipulation in productive
M AN U
107
(8) Dror T, Dickstein Y, Dubourg G, Paul M. Microbiota manipulation for weight change.
animals. Microb Pathog 2016; submitted.
(11) Derrien M, Belzer C, de Vos WM. Akkermansia muciniphila and its role in regulating host functions. Microb Pathog 2016; submitted.
(12) Hugon P, Lagier JC, Colson P, Bittar F, Raoult D. Repertoire of Human Gut
TE D
106
Microbes. Microb Pathog 2016; submitted. (13) Lagier JC, Armougom F, Million M, et al. Microbial culturomics: paradigm shift in
117
the human gut microbiome study. Clin Microbiol Infect 2012 Dec; 18(12):1185-93.
119 120 121 122
(14) Lagier JC, Hugon P, Khelaifia S, Fournier PE, La SB, Raoult D. The rebirth of culture
AC C
118
EP
116
in microbiology through the example of culturomics to study human gut microbiota. Clin Microbiol Rev 2015 Jan; 28(1):237-64.
(15) Million M, Diallo A, Raoult D. Gut Microbiota and Malnutrition. Microb Pathog 2016; submitted.
6
ACCEPTED MANUSCRIPT
123
(16) Faith JJ, Colombel JF, Gordon JI. Identifying strains that contribute to complex
124
diseases through the study of microbial inheritance. Proc Natl Acad Sci U S A 2015
125
Jan 20; 112(3):633-40.
129 130
RI PT
128
2015 Sep 5.
(18) Angelakis E, Armougom F, Carriere F, et al. A Metagenomic Investigation of the
Duodenal Microbiota Reveals Links with Obesity. PLoS ONE 2015; 10(9):e0137784.
SC
127
(17) Raoult D. Obesity and stools, the "emperor's new clothing" paradigm. Eur J Epidemiol
(19) Drissi F, Merhej V, Angelakis E, et al. Comparative genomics analysis of
M AN U
126
131
Lactobacillus species associated with weight gain or weight protection. Nutr Diabetes
132
2014; 4:e109.
136
TE D
135
people. Microb Pathog 2016; submitted.
EP
134
(20) Dubourg G, Surenaud M, Levy PY, Hüe S, Raoult D. Microbiome of HIV-infected
AC C
133
7
S0882-4010(16)30052-3
DOI:
10.1016/j.micpath.2016.02.001
Reference:
YMPAT 1772
To appear in:
Microbial Pathogenesis
Received Date: 26 January 2016 Revised Date:
1 February 2016
Accepted Date: 1 February 2016
Please cite this article as: Raoult D, Microbiota, Obesity and Malnutrition, Microbial Pathogenesis (2016), doi: 10.1016/j.micpath.2016.02.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Microbiota, Obesity and Malnutrition
2
Editorial
3
Didier RAOULT*
RI PT
1
4 5
*URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, Aix Marseille Université,
7
Marseille, France
8
Phone: (+33) 491 32 43 75, Fax: (+33) 491 38 77 72
9
E-mail: [email protected]
AC C
EP
TE D
10
M AN U
SC
6
1
ACCEPTED MANUSCRIPT
11
Introduction
12 The putative role of microbiota in obesity and malnutrition is a growing issue. There are, in
14
this area, controversies, major industrial interests (probiotics industry) and methodological
15
difficulties that result in a very significant discrepancy between the different works and
16
different results [1, 2].
17
Clinically, the tangible link between gut microbiota manipulation and weight gain is
18
supported by several studies. [3]. Thus, M. Blaser, especially, is studying the role of
19
antibiotics in treatment of Helicobacter pylori caused gastroduodenal ulcers and in the
20
treatment of pneumonia in children showed that this causes weight gain [4]. In both cases, a
21
significant increase, relative to control, was noted [5]. We were able to report that
22
vancomycin prescribed for 6 weeks in patients with endocarditis, was also associated with
23
weight gain. It should be noted that the vancomycin structural analogue is avoparcin, used in
24
the farm industry for growing turkeys [4].
25
Antibiotics and probiotics, which manipulate the intestinal flora of the animals, have been
26
used for over 50 years, in farm industry, and lead, on average, in particular in poultry and
27
pigs, an increase of 8 to 10% of the weight of the body (muscles and fat) [3, 6]. Antibiotics,
28
most used were tetracyclines (first identified as a probiotic in Streptomyces aureofaciens), the
29
vancomycine and quinolones. Antibiotics were prescribed in young animals (mammals, fish
30
and poultry) to make them gain weight. It was suspected, by M. Blaser, the residual rate,
31
which could be found in the meat or milk, could cause weight gain in children [7]. These
32
antibiotics are banned as growth promotors in Europe since 2002 [7]. In contrast, the
33
prescription of probiotics is regulated by a European rating dating back to 1972 [3]. It is noted
34
that the assessment of the effect of probiotics, used to increase weight of animals, has not
AC C
EP
TE D
M AN U
SC
RI PT
13
2
ACCEPTED MANUSCRIPT
been extensively studied in humans to see if they produce the same effect [8]; yet what seems
36
logical. Two studies report the experience of growth promotors in this special issue [9, 10].
37
Microbiota studies have mostly used molecular biology techniques. Unfortunately, after a
38
very encouraging start, highlighting a particular profile in obese subjects in the USA,
39
numerous studies have been conducted, which found divergent results and not reproducible
40
from one study to another [1]. These elements highlight several points. The first is that the
41
extraction methods are very different from one study to the other and play an absolutely
42
critical role in metagenomics analysis. Furthermore, the primers, for PCR, are not always
43
identical. And finally, analysis of data uses different algorithms. In total, it is difficult at
44
present to have a very clear vision of role of the microbiota, in humans as different teams
45
have different results. Some do not even seeing significant differences between obese and
46
non-obese subjects [1, 11].
47
Culturomics studies, allowing a revival of culture techniques [12], are ongoing and could help
48
to highlight the presence of a number of microorganisms associated with obesity [13, 14]. It is
49
the same for severe malnutrition (kwashiorkor) or a restriction of heterogeneity was found
50
[15]. It should be noted that a restriction of heterogeneity was also found in obese subjects.
51
The role of bacteria, such as Faecalibacterium prausnitzii [16], or methanogenic archaea [11]
52
as have been proposed, which have not, so far, collected a consensus in the literature.
53
The other problem of the majority of studies is that they use the faeces [17]. Unquestionably,
54
feces are not a good sample to study the microbiota associated with digestion. Digestion is in
55
the upper part of the intestine, especially the small intestine; 99.9% of the bacteria found in
56
fecal matter are these that grow and multiply within the colon. It is clear that the colon is not
57
associated with weight loss or obesity. Several million peoples have to undergo colonic
58
resection without associated metabolic disorders, if not a loss of water. Furthermore, the
59
determinations carried out of nutrients in the last loop of the small intestine, show that there
AC C
EP
TE D
M AN U
SC
RI PT
35
3
ACCEPTED MANUSCRIPT
retain only long sugars of vegetable origin, which are probably partly digested by the colon,
61
but that do not represent a significant factor in obesity. Preliminary studies show that there are
62
in the small intestine, bacteria specifically associated with obesity [18]. In all, some bacteria
63
seem to be more commonly associated with weight gain in animals and in men, including
64
Lactobacillus [9]. However, it can be at the strain level, the activity of Lactobacillus strains
65
may be neutral, promote obesity or otherwise prevent it. The hypothesis that we have, for the
66
role of Lactobacillus, is that those associated with obesity seem to allow early digestion of
67
lipids, that would promote their early absorption, and those associated with protection appear
68
to be better equipped to digest short sugar, so competing with the intestine to the recruitment
69
of calories. These data, made from analyzes of genome or metagenome, need to be confirmed
70
[19]. Moreover, the gut microbiota composition may be related to the wasting syndrome of
71
patients with HIV infection and their susceptibility to mucosal infection [20].
72
In the future, it is clear that there are still elements to be clarified. Some experimental models,
73
especially those developed by JF Gordon [16] show that transplantation of microbiota from
74
obese or malnourished children lead to changes in the xenobiotic mouse, and there is
75
sufficient evidence to suggest that manipulation of the microbiota plays a role in weight gain
76
or otherwise in its protection [3]. It is clear, for example, that the combination of antibiotics,
77
to resupply in malnourished subjects, plays a significant role in weight regain. Studies, more
78
systematic, carried out on the microbiota of the upper part of the intestine, combining
79
culturomics and deep metagenomic, probably will have a clearer landscape of
80
microorganisms associated with weight gain or protection. Furthermore, prospective
81
epidemiological studies, assessing the role of probiotics and antibiotics for children in weight
82
gain or protection, seem necessary.
83
Finally, the emergence of fields (microbiota, microbiota manipulation, metabolic modification
AC C
EP
TE D
M AN U
SC
RI PT
60
4
ACCEPTED MANUSCRIPT
84
and weight change) is a field of primary importance, but which require standardization and
85
different methodological approach to make truly useful findings to public health.
87
References
88
(1) Angelakis E, Armougom F, Million M, Raoult D. The relationship between gut
SC
89
RI PT
86
microbiota and weight gain in humans. Future Microbiol 2012 Jan; 7(1):91-109.
91
(2) Raoult D. Human microbiome: take-home lesson on growth promoters? Nature 2008
92
Aug 7; 454(7205):690-1.
M AN U
90
(3) Angelakis E, Merhej V, Raoult D. Related actions of probiotics and antibiotics on gut
94
microbiota and weight modification. Lancet Infect Dis 2013 Oct; 13(10):889-99.
95
TE D
93
(4) Thuny F, Richet H, Casalta JP, Angelakis E, Habib G, Raoult D. Vancomycin treatment of infective endocarditis is linked with recently acquired obesity. PLoS One
97
2010; 5(2):e9074.
99 100 101 102
(5) Cox LM, Yamanishi S, Sohn J, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 2014 Aug 14;
AC C
98
EP
96
158(4):705-21.
(6) Cromwell GL. Why and how antibiotics are used in swine production. Anim Biotechnol 2002 May; 13(1):7-27.
5
ACCEPTED MANUSCRIPT
103
(7) Phillips I, Casewell M, Cox T, et al. Does the use of antibiotics in food animals pose a
104
risk to human health? A critical review of published data. J Antimicrob Chemother
105
2004 Jan; 53(1):28-52.
110 111 112 113 114 115
RI PT
109
(9) Drissi F, Raoult D, Merhej V. Metabolic role of Lactobacilli in weight modification in humans and animals. Microb Pathog 2016; submitted.
SC
108
Microb Pathog 2016 Jan 11.
(10) Angelakis E, Raoult D. Weight gain by gut microbiota manipulation in productive
M AN U
107
(8) Dror T, Dickstein Y, Dubourg G, Paul M. Microbiota manipulation for weight change.
animals. Microb Pathog 2016; submitted.
(11) Derrien M, Belzer C, de Vos WM. Akkermansia muciniphila and its role in regulating host functions. Microb Pathog 2016; submitted.
(12) Hugon P, Lagier JC, Colson P, Bittar F, Raoult D. Repertoire of Human Gut
TE D
106
Microbes. Microb Pathog 2016; submitted. (13) Lagier JC, Armougom F, Million M, et al. Microbial culturomics: paradigm shift in
117
the human gut microbiome study. Clin Microbiol Infect 2012 Dec; 18(12):1185-93.
119 120 121 122
(14) Lagier JC, Hugon P, Khelaifia S, Fournier PE, La SB, Raoult D. The rebirth of culture
AC C
118
EP
116
in microbiology through the example of culturomics to study human gut microbiota. Clin Microbiol Rev 2015 Jan; 28(1):237-64.
(15) Million M, Diallo A, Raoult D. Gut Microbiota and Malnutrition. Microb Pathog 2016; submitted.
6
ACCEPTED MANUSCRIPT
123
(16) Faith JJ, Colombel JF, Gordon JI. Identifying strains that contribute to complex
124
diseases through the study of microbial inheritance. Proc Natl Acad Sci U S A 2015
125
Jan 20; 112(3):633-40.
129 130
RI PT
128
2015 Sep 5.
(18) Angelakis E, Armougom F, Carriere F, et al. A Metagenomic Investigation of the
Duodenal Microbiota Reveals Links with Obesity. PLoS ONE 2015; 10(9):e0137784.
SC
127
(17) Raoult D. Obesity and stools, the "emperor's new clothing" paradigm. Eur J Epidemiol
(19) Drissi F, Merhej V, Angelakis E, et al. Comparative genomics analysis of
M AN U
126
131
Lactobacillus species associated with weight gain or weight protection. Nutr Diabetes
132
2014; 4:e109.
136
TE D
135
people. Microb Pathog 2016; submitted.
EP
134
(20) Dubourg G, Surenaud M, Levy PY, Hüe S, Raoult D. Microbiome of HIV-infected
AC C
133
7
