Gut microbiome and serum metabolome alterations associated with lactose intolerance (LI): a case‒control study and paired-sample study based on the American Gut Project (AGP)

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Reviewed Marked as Reviewed by Svetlana up on 2024-11-27
study design
Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
Authors
Xue H, Wang Y, Mei C, Han L, Lu M, Li X, Chen T, Wang F, Tang X
Journal
mSystems
Year
2024
Keywords:
16S rRNA, fecal microbiota transplantation (FMT), gut microbiome, lactose intolerance, metagenomics, serum metabolome
UNLABELLED: Lactose intolerance (LI) is a prevalent condition characterized by gastrointestinal symptoms that arise following lactose consumption. Recent evidence suggests that the gut microbiome may influence lactose levels in the gut. However, there is limited understanding regarding the alterations in microbiota and metabolism between individuals with LI and non-LI. This study conducted a paired-sample investigation utilizing data from the American Gut Project (AGP) and performed metagenomic and untargeted metabolomic analyses in a Chinese cohort to explore the interaction between the gut microbiome and serum metabolites. In addition, fecal microbiota transplantation (FMT) experiments were conducted to further examine the impact of the LI-associated gut microbiome on inflammatory outcomes. We identified 14 microbial genera that significantly differed between LI and controls from AGP data. Using a machine learning approach, group separation was predicted based on seven species and nine metabolites in the Chinese cohort. Notably, increased levels of Escherichia coli in the LI group were negatively correlated with several metabolites, including PC (22:6/0:0), indole, and Lyso PC, while reduced levels of Faecalibacterium prausnitzii and Eubacterium rectale were positively correlated with indole and furazolidone. FMT-LI rats displayed visceral hypersensitivity and an altered gut microbiota composition compared to FMT-HC rats. Metagenomic and metabolomic analyses revealed an enrichment of MAPK signaling in LI, which was confirmed by FMT-LI rats showing higher expression of ERK and RAS, along with increased concentrations of proinflammatory cytokines. This study provides valuable insights into the disrupted microbial and metabolic traits associated with LI, emphasizing potential microbiome-based approaches for its prevention and treatment. IMPORTANCE: Lactose intolerance (LI) is a prevalent condition characterized by gastrointestinal symptoms after lactose consumption due to a deficiency of lactase. There is limited understanding regarding the microbiota and metabolic alterations between individuals with LI and non-LI. This study represents the first exploration to investigate metagenomic and metabolomic signatures among subjects with lactose intolerance as far as our knowledge. We identified 14 microbial genera in the Western cohort and 7 microbial species, along with 9 circulating metabolites in the Chinese cohort, which significantly differed in LI patients. Metagenomic and metabolomic analyses revealed an enrichment of MAPK signaling in LI patients. This finding was confirmed by FMT-LI rats, exhibiting increased expression of ERK and RAS, along with higher concentrations of pro-inflammatory cytokines. Our study provides insights into the disrupted functional and metabolic traits of the gut microbiome in LI, highlighting potential microbiome-based approaches for preventing and treating LI.

Experiment 1


Reviewed Marked as Reviewed by Svetlana up on 2024-11-27

Curated date: 2024/10/11

Curator: Nathcynthia

Revision editor(s): Nathcynthia, Tosin

Subjects

Location of subjects
Canada
United Kingdom
United States of America
Host species Species from which microbiome was sampled. Contact us to have more species added.
Homo sapiens
Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces
Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
Lactose intolerance lactase persistence,lactose intolerance,lactose intolerance (disease),LM - lactose malabsorption,Lactose intolerance
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Participants without Lactose Intolerance(Non-LI)
Group 1 name Corresponds to the case (exposed) group for case-control studies
Participants with Lactose Intolerance(LI)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Participants with condition, Lactose intolerance (LI) which is a prevalent condition characterized by gastrointestinal symptoms that arise following lactose consumption.
Group 0 sample size Number of subjects in the control (unexposed) group
562
Group 1 sample size Number of subjects in the case (exposed) group
562
Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
6 months.

Lab analysis

Sequencing type
16S
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
V4
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
relative abundances
Statistical test
LEfSe
Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
0.05
MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?
No
LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool
2
Matched on Factors on which subjects have been matched on in a case-control study
age, alcohol consumption measurement, body mass index, diet, geographic area, sex

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
unchanged
Chao1 Abundance-based estimator of species richness
decreased
Richness Number of species
decreased

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2024-11-27

Curated date: 2024/10/11

Curator: Nathcynthia

Revision editor(s): Nathcynthia, Rahila, Tosin

Source: Fig 1c

Description: Gut microbiota alterations between LI cohort and non-LI cohort assessed using the linear discriminative analysis (LDA) effect size (LEfSe).

Abundance in Group 1: increased abundance in Participants with Lactose Intolerance(LI)

NCBI Quality ControlLinks
Alcaligenaceae
Betaproteobacteria
Blautia
Burkholderiales
Clostridium
Collinsella
Comamonas
Dialister
Haemophilus
Lachnospiraceae
Megasphaera
Pasteurellaceae
Pasteurellales
Porphyromonadaceae
Spirochaetaceae
Spirochaetales
Spirochaetota bacterium
Treponema
SR1.c.oSR1.c.o
SR1.cSR1.c
SR1SR1
SP1.c.o.fSP1.c.o.f
SR1.c.o.f.gSR1.c.o.f.g

Revision editor(s): Nathcynthia, Rahila, Tosin

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2024-11-27

Curated date: 2024/10/13

Curator: Nathcynthia

Revision editor(s): Nathcynthia, Rahila, Tosin

Source: Fig 1c

Description: Gut microbiota alterations between LI cohort and non-LI cohort assessed using the linear discriminative analysis (LDA) effect size (LEfSe)'.

Abundance in Group 1: decreased abundance in Participants with Lactose Intolerance(LI)

NCBI Quality ControlLinks
Alistipes
Butyrivibrio
Cyanobacteriota
Desulfovibrio
Eubacterium
Leuconostocaceae bacterium
Mollicutes
Mycoplasmatota
Oscillospiraceae
Prevotella
Prevotellaceae
Rikenellaceae
Ruminococcus
Succinivibrio
ML615J_28ML615J_28
RF39.f_g_RF39.f_g_
RF39RF39
RF39.f_RF39.f_
ML615J_28.f_ML615J_28.f_
ML615J_28_.f_.g_ML615J_28_.f_.g_
Clostridiales.f_.g_Clostridiales.f_.g_
Clostridiales.f_Clostridiales.f_

Revision editor(s): Nathcynthia, Rahila, Tosin

Experiment 2


Reviewed Marked as Reviewed by Svetlana up on 2024-11-27

Curated date: 2024/10/11

Curator: Nathcynthia

Revision editor(s): Nathcynthia, Tosin

Differences from previous experiment shown

Subjects

Location of subjects
China


Group 0 name Corresponds to the control (unexposed) group for case-control studies
Healthy controls (HC)
Group 0 sample size Number of subjects in the control (unexposed) group
41
Group 1 sample size Number of subjects in the case (exposed) group
41
Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
3 months

Lab analysis

Sequencing type
WMS
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
Not specified

Statistical Analysis

Matched on Factors on which subjects have been matched on in a case-control study
Not specified

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
unchanged
Chao1 Abundance-based estimator of species richness
unchanged
Simpson Estimator of species richness and species evenness: more weight on species evenness
unchanged
Richness Number of species
unchanged

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2024-11-27

Curated date: 2024/10/14

Curator: Nathcynthia

Revision editor(s): Nathcynthia, Rahila, Tosin

Source: Fig 3b

Description: LeFSe analysis reveals significant taxonomic differences between LI Patients and HCs.

Abundance in Group 1: increased abundance in Participants with Lactose Intolerance(LI)

NCBI Quality ControlLinks
Bacteroides fragilis
Burkholderiales
Enterobacter
Enterobacter hormaechei
Enterobacterales
Enterobacteriaceae
Escherichia
Escherichia coli
Firmicutes bacterium CAG:313
Gammaproteobacteria
Lachnospira
Leuconostoc
Parabacteroides sp. AF19-14
Pseudomonadota
Ruminococcus sp. AF12-5
Ruminococcus sp. CAG:177
Salmonella
Salmonella enterica
Shigella
unclassified Enterobacter
unclassified Enterobacteriaceae
unclassified Klebsiella
unclassified Parabacteroides
unclassified Pseudomonadota

Revision editor(s): Nathcynthia, Rahila, Tosin

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2024-11-27

Curated date: 2024/10/14

Curator: Nathcynthia

Revision editor(s): Nathcynthia, Rahila, Tosin

Source: Fig 3b

Description: LeFSe analysis reveals significant taxonomic differences between LI Patients and HCs.

Abundance in Group 1: decreased abundance in Participants with Lactose Intolerance(LI)

NCBI Quality ControlLinks
Clostridium sp. AF36-18BH
Eubacterium sp.
Faecalibacterium sp. CAG:82
Lachnospira eligens
unclassified Faecalibacterium
uncultured Ruminococcus sp.

Revision editor(s): Nathcynthia, Rahila, Tosin

Experiment 3


Reviewed Marked as Reviewed by Svetlana up on 2024-11-27

Curated date: 2024/10/18

Curator: Nathcynthia

Revision editor(s): Nathcynthia, Tosin

Differences from previous experiment shown

Subjects

Host species Species from which microbiome was sampled. Contact us to have more species added.
Rattus norvegicus


Group 0 name Corresponds to the control (unexposed) group for case-control studies
FMT-Healthy Controls group
Group 1 name Corresponds to the case (exposed) group for case-control studies
FMT-Lactose Intolerance group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Rats receiving gut microbiota from LI patients .
Group 0 sample size Number of subjects in the control (unexposed) group
6
Group 1 sample size Number of subjects in the case (exposed) group
6
Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
Not specified

Lab analysis

Sequencing type
16S
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
V3-V4

Statistical Analysis

Statistical test
Spearman Correlation
Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
Not specified
MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?
Yes
LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool
Not specified

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
unchanged
Chao1 Abundance-based estimator of species richness
decreased
Richness Number of species
decreased

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2024-11-27

Curated date: 2024/10/18

Curator: Nathcynthia

Revision editor(s): Nathcynthia, Tosin

Source: Figure 7D

Description: Heatmap based on the relative abundance of the genera between FMT-HC (FMT-Healthy control group) and FMT-LI (FMT-Lactose intolerance group).

Abundance in Group 1: increased abundance in FMT-Lactose Intolerance group

NCBI Quality ControlLinks
Coprobacillus
Dielma
Escherichia/Shigella sp.
Sutterella

Revision editor(s): Nathcynthia, Tosin

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2024-11-27

Curated date: 2024/10/18

Curator: Nathcynthia

Revision editor(s): Nathcynthia, Tosin

Source: Figure 7D

Description: Heatmap based on the relative abundance of the genera between FMT-HC (Healthy control group) and FMT-LI (Lactose intolerance group).

Abundance in Group 1: decreased abundance in FMT-Lactose Intolerance group

NCBI Quality ControlLinks
Anaerobutyricum hallii
Faecalibacterium
Fusicatenibacter

Revision editor(s): Nathcynthia, Tosin

Experiment 4


Reviewed Marked as Reviewed by Svetlana up on 2024-11-27

Curated date: 2024/10/19

Curator: Tosin

Revision editor(s): Tosin, Nathcynthia

Differences from previous experiment shown

Subjects

Host species Species from which microbiome was sampled. Contact us to have more species added.
Homo sapiens


Group 0 name Corresponds to the control (unexposed) group for case-control studies
Healthy Controls
Group 1 name Corresponds to the case (exposed) group for case-control studies
Participants with Lactose intolerance (LI)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Participants with condition, Lactose intolerance (LI) which is a prevalent condition characterized by gastrointestinal symptoms that arise following lactose consumption.
Group 0 sample size Number of subjects in the control (unexposed) group
41
Group 1 sample size Number of subjects in the case (exposed) group
41
Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
3 months

Lab analysis

Sequencing type
WMS
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
Not specified

Statistical Analysis

Statistical test
T-Test
Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
0.05
MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?
No

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
unchanged
Chao1 Abundance-based estimator of species richness
unchanged
Simpson Estimator of species richness and species evenness: more weight on species evenness
unchanged

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2024-11-27

Curated date: 2024/10/20

Curator: Tosin

Revision editor(s): Tosin, Nathcynthia

Source: Figure 3d-I.

Description: Comparison of the relative abundances at the species level according to metagenomic sequencing between the two groups.

Abundance in Group 1: increased abundance in Participants with Lactose intolerance (LI)

NCBI Quality ControlLinks
Bacteroides fragilis
Dialister massiliensis
Escherichia coli
Shigella flexneri
Streptococcus salivarius

Revision editor(s): Tosin, Nathcynthia

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2024-11-27

Curated date: 2024/10/20

Curator: Tosin

Revision editor(s): Tosin, Nathcynthia

Source: Figure 3d-I

Description: Comparison of the relative abundances at the species level according to metagenomic sequencing between the two groups.

Abundance in Group 1: decreased abundance in Participants with Lactose intolerance (LI)

NCBI Quality ControlLinks
Eubacterium sp.

Revision editor(s): Tosin, Nathcynthia

Experiment 5


Reviewed Marked as Reviewed by Svetlana up on 2024-11-27

Curated date: 2024/10/21

Curator: Nathcynthia

Revision editor(s): Nathcynthia, Tosin

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Participants with Lactose Intolerance
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Participants with condition, Lactose intolerance (LI) which is prevalent condition characterized by gastrointestinal symptoms that arise following lactose consumption.

Lab analysis

Statistical Analysis

Statistical test
Spearman Correlation
Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
Not specified
MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?
Yes

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
unchanged
Chao1 Abundance-based estimator of species richness
unchanged
Simpson Estimator of species richness and species evenness: more weight on species evenness
unchanged

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2024-11-27

Curated date: 2024/10/21

Curator: Tosin

Revision editor(s): Tosin, Nathcynthia

Source: Figure 3c

Description: Heatmap based on the relative abundance of the genera between Healthy control group and Lactose Intolerance group.

Abundance in Group 1: increased abundance in Participants with Lactose Intolerance

NCBI Quality ControlLinks
Escherichia

Revision editor(s): Tosin, Nathcynthia

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2024-11-27

Curated date: 2024/10/21

Curator: Tosin

Revision editor(s): Tosin, Nathcynthia

Source: Figure 3c

Description: Heatmap based on the relative abundance of the genera between Healthy control group and Lactose Intolerance group.

Abundance in Group 1: decreased abundance in Participants with Lactose Intolerance

NCBI Quality ControlLinks
Enterococcus
Thomasclavelia
Veillonella

Revision editor(s): Tosin, Nathcynthia