Rifaximin reduces gut-derived inflammation in severe acute pancreatitis: an experimental animal model and randomized controlled trial

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Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
URI Uniform resource identifier for web resources.
Authors
Zou Y-y, Yu B-j, He C, Ding L, Xu X, Wan J-h, Lei Y-p, Huang X, Xiong H-f, He W-h, Luo L-y, Xia L, Lv N-h, Zhu Y
Journal
Microbiology spectrum
Year
2025
Keywords:
acute pancreatitis, gut microbiota, rifaximin, systemic inflammatory response syndrome
UNLABELLED: Severe acute pancreatitis (SAP) is characterized by systemic inflammation and intestinal barrier dysfunction and is often associated with gut microbiota dysbiosis. Rifaximin, a gut-specific non-absorbable antibiotic, is known to modulate the gut microbiota. Here, we investigated rifaximin's effects and mechanisms in SAP using murine models and a single-center, open-label, randomized controlled trial (Chinese Clinical Trial Registry: ChiCTR2100049794). In mice, rifaximin attenuated pancreatic injury and systemic inflammation and altered gut microbiota composition by decreasing mucin-degrading genera such as Akkermansia (P < 0.05). These protective effects persisted in antibiotic-treated and germ-free mice, suggesting mechanisms not solely dependent on gut microbiota modulation. In patients with predicted SAP (n  =  60), rifaximin significantly reduced systemic inflammation compared with controls. WBC decreased from a median of 11.50 × 10⁹/L (IQR 8.76-15.68) to 8.49 × 10⁹/L (6.93-10.20; P = 0.04) and TNF-α from 15.05 pg/mL (12.73-19.75) to 11.00 pg/mL (8.74-15.40; P = 0.009). However, the incidence of culture-confirmed infection did not differ between the rifaximin and control groups (13.3% vs. 13.3%; RR, 1.00; 95% CI, 0.28-3.63). Adverse events were comparable between groups. Metagenomic analyses revealed suppression of mucin-degrading bacteria (e.g., Akkermansia, Bacteroides fragilis, and Hungatella hathewayi) (P < 0.05) and reductions in mucin-degrading carbohydrate-active enzymes, including sialidases and fucosidases. In conclusion, among patients with predicted SAP, rifaximin did not reduce culture-confirmed infectious complications within 90 days after randomization compared with standard care, despite significant improvements in systemic inflammatory markers and selected fecal microbiome features. Larger randomized controlled trials are warranted to validate these findings. IMPORTANCE: Although rifaximin has been used to target gut-derived inflammation in other contexts, its role in SAP remains largely unexplored. In this study, rifaximin treatment was associated with reduced pancreatic injury and systemic inflammation in both murine models and patients with predicted SAP. Treatment also led to changes in gut microbial composition, notably a decrease in mucin-degrading taxa. Importantly, similar protective effects were also observed in antibiotic-treated and germ-free mice, indicating that rifaximin may act via microbiota-dependent and host-directed pathways. These findings offer novel insights into the gut-pancreas axis and suggest that rifaximin holds therapeutic potential by modulating gut microbial composition and host inflammatory responses in SAP.

Experiment 1


Needs review

Curated date: 2025/09/28

Curator: SheikhAlMamun

Revision editor(s): SheikhAlMamun

Subjects

Location of subjects
China
Host species Species from which microbiome was sampled. Contact us to have more species added.
Mus musculus
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
Acute pancreatitis acute necrotizing pancreatitis,acute pancreatic necrosis,acute pancreatitis,acute pancreatitis (disorder) [ambiguous],pancreatitis necrotizing,pancreatitis, acute,Acute pancreatitis
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Control (Con)
Group 1 name Corresponds to the case (exposed) group for case-control studies
Rifaximin (Rif)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Mice/patients with SAP receiving rifaximin intervention
Group 0 sample size Number of subjects in the control (unexposed) group
30
Group 1 sample size Number of subjects in the case (exposed) group
60
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
16S
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
Not specified
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
Mann-Whitney (Wilcoxon)
Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
0.05


Signature 1

Needs review

Curated date: 2025/09/28

Curator: SheikhAlMamun

Revision editor(s): SheikhAlMamun

Source: Figure 2E & 2F

Description: (E) Wilcoxon rank-sum test identified the most differentially abundant phyla and genera between Con group and Rif group. (F) Wilcoxon rank-sum test identified the most differentially abundant phyla and genera between Cer + Bom group and Cer + Bom + Rif group. *P < 0.05, **P < 0.01, and ***P < 0.001. Rif, rifaximin; Cer, caerulein; Bom, bombesin; Con, control; PCoA, principal coordinate analysis.

Abundance in Group 1: increased abundance in Rifaximin (Rif)

NCBI Quality ControlLinks
Akkermansia
Alistipes
Alloprevotella
Atopostipes
Bifidobacterium
Candidatus Saccharimonas
Citrobacter
Colidextribacter
Enterococcus
Faecalibaculum
Helicobacter
Lachnoclostridium
Lactobacillus
Parasutterella
Sporosarcina
Staphylococcus
Verrucomicrobiota

Revision editor(s): SheikhAlMamun

Signature 2

Needs review

Curated date: 2025/09/28

Curator: SheikhAlMamun

Revision editor(s): SheikhAlMamun

Source: Figure 2E & 2F

Description: (E) Wilcoxon rank-sum test identified the most differentially abundant phyla and genera between Con group and Rif group. (F) Wilcoxon rank-sum test identified the most differentially decreased phyla and genera between Cer + Bom group and Cer + Bom + Rif group. *P < 0.05, **P < 0.01, and ***P < 0.001. Rif, rifaximin; Cer, caerulein; Bom, bombesin; Con, control; PCoA, principal coordinate analysis.

Abundance in Group 1: decreased abundance in Rifaximin (Rif)

NCBI Quality ControlLinks
ActinobacteriotaActinobacteriota
DesulfobacterotaDesulfobacterota
ProteobacteriaProteobacteria
PatescibacteriaPatescibacteria
CampilobacterotaCampilobacterota
Lachnospiraceae_UCG001Lachnospiraceae_UCG001
Lachnospiraceae_NK4A136_groupLachnospiraceae_NK4A136_group
Klebsiella
Facklamia
Clostridium_innocuum_groupClostridium_innocuum_group

Revision editor(s): SheikhAlMamun

Experiment 2


Needs review

Curated date: 2025/09/28

Curator: SheikhAlMamun

Revision editor(s): SheikhAlMamun

Differences from previous experiment shown

Subjects

Lab analysis

Statistical Analysis

Signature 1

Needs review

Curated date: 2025/09/28

Curator: SheikhAlMamun

Revision editor(s): SheikhAlMamun

Source: Figure 7A & 7B

Description: Rifaximin induces specific alterations in the abundance and function of the gut microbiota in patients predicted to SAP. (A) The top 30 differentially abundant bacterial species before and after treatment in the control group. (B) The top 30 differentially abundant bacterial species before and after treatment in the rifaximin group.

Abundance in Group 1: increased abundance in Rifaximin (Rif)

NCBI Quality ControlLinks
Alistipes
Anaerostipes
Bacteroidaceae
Bacteroides
Butyricimonas
Clostridium
Enterococcus
Escherichia coli
Faecalibacterium
Fusobacterium
Lachnospiraceae
Megamonas
Odoribacter
Odoribacter sp.
Oscillibacter
Parabacteroides
Prevotella
Roseburia
Ruminococcus
Streptococcus
Sutterella
Tannerella

Revision editor(s): SheikhAlMamun

Signature 2

Needs review

Curated date: 2025/09/28

Curator: SheikhAlMamun

Revision editor(s): SheikhAlMamun

Source: Figure 7A & 7B

Description: Rifaximin induces specific alterations in the decrease and function of the gut microbiota in patients predicted to SAP. (A) The top 30 differentially abundant bacterial species before and after treatment in the control group. (B) The top 30 differentially abundant bacterial species before and after treatment in the rifaximin group.

Abundance in Group 1: decreased abundance in Rifaximin (Rif)

NCBI Quality ControlLinks
Branconicola_faeciumBranconicola_faecium
Bacteroides_caccaeBacteroides_caccae
Clostridium_butyricumClostridium_butyricum
Prevotella_copriPrevotella_copri
Bacteroides_fragilisBacteroides_fragilis
Bifidobacterium_longumBifidobacterium_longum
Ruminococcus_gnavusRuminococcus_gnavus
Fusobacterium_nucleatumFusobacterium_nucleatum
Prevotella_sp_CAG_520Prevotella_sp_CAG_520
Branconicola spBranconicola sp
Enterococcus_faecalisEnterococcus_faecalis
Faecalibacterium_prausnitziiFaecalibacterium_prausnitzii
Bacteroides_thetaiotaomicronBacteroides_thetaiotaomicron
Enterocloster_bolteaeEnterocloster_bolteae
Enterobacter_hormaecheiEnterobacter_hormaechei
Streptococcus_parasanguinisStreptococcus_parasanguinis
[Eubacterium]_rectale[Eubacterium]_rectale
Hungatella_hathewayiHungatella_hathewayi
Lachnospiraceae_bacteriumLachnospiraceae_bacterium
Tyzerella_nankisTyzerella_nankis
Faecalibacterium_spFaecalibacterium_sp
Roseburia_inulinivoransRoseburia_inulinivorans
Phascolarctobacterium_faeciumPhascolarctobacterium_faecium
Prevotella_stercoreaPrevotella_stercorea
Bacteroides_finegoldiiBacteroides_finegoldii
Parabacteroides_sp._AF18-52Parabacteroides_sp._AF18-52
Klebsiella_aerogenesKlebsiella_aerogenes
Dorea_longicatenaDorea_longicatena
[Ruminococcus]_torques[Ruminococcus]_torques
Alistipes_putredinisAlistipes_putredinis
Blautia_wexleraeBlautia_wexlerae
Bacteroides_eggerthiiBacteroides_eggerthii
uncultured_Clostridium_spuncultured_Clostridium_sp
uncultured_bacteriumuncultured_bacterium
Bacteroides_cellulosilyticusBacteroides_cellulosilyticus
Faecalibacterium_sp._AF28-13ACFaecalibacterium_sp._AF28-13AC
Enterococcus_faeciumEnterococcus_faecium
Escherichia_coliEscherichia_coli
Bacteroides_stercorisBacteroides_stercoris
Parabacteroides_merdaeParabacteroides_merdae
Bacteroidaceae_bacteriumBacteroidaceae_bacterium
Odoribacter_splachnicusOdoribacter_splachnicus
Ruminococcaceae_bacteriumRuminococcaceae_bacterium
Shigella_sp.Shigella_sp.
Megamonas_funiformisMegamonas_funiformis
Alistipes_onderdonkiiAlistipes_onderdonkii
Clostridia_bacteriumClostridia_bacterium
Fusobacterium_mortiferumFusobacterium_mortiferum
Clostridiales_bacteriumClostridiales_bacterium
Oscillibacter_sp.Oscillibacter_sp.
Butyricimonas_virosaButyricimonas_virosa
Enterobacter_asburiaeEnterobacter_asburiae
Tannerella_sp._AF04-6Tannerella_sp._AF04-6
Bacteroides_sp._ANT25-34Bacteroides_sp._ANT25-34
Anaerostipes_hadrusAnaerostipes_hadrus
Shigella_sonneiShigella_sonnei
Alistipes_shahiiAlistipes_shahii
Enterococcus_hiraeEnterococcus_hirae
Eubacterium_sp._CAG:180Eubacterium_sp._CAG:180
Sutterella_megalosphaeroidesSutterella_megalosphaeroides
Shigella_flexneriShigella_flexneri

Revision editor(s): SheikhAlMamun

Experiment 3


Needs review

Curated date: 2025/09/28

Curator: SheikhAlMamun

Revision editor(s): SheikhAlMamun

Differences from previous experiment shown

Subjects

Lab analysis

Statistical Analysis

Signature 1

Needs review

Curated date: 2025/09/28

Curator: SheikhAlMamun

Revision editor(s): SheikhAlMamun

Source: Table S7 & Table S8

Description: The abundance of gut microbiota had specific alterations at the phylum, genus, and species levels. At the phylum level, rifaximin decreased Verrucomicrobia and Fibrobacteres (P < 0.05) (Table S7). At the genus level, significant reductions in mucin-degrading genera, such as Akkermansia and Hungatella, were observed in the fecal samples (P < 0.05) (Table S8).

Abundance in Group 1: increased abundance in Rifaximin (Rif)

NCBI Quality ControlLinks
Aerococcus
Akkermansia
Anaerostipes
Bifidobacterium
Blautia
Catonella
Cellulomonas
Clostridium
Collinsella
Deferribacteres
Dialister
Dorea
Enterocloster
Faecalibacterium
Fusicatenibacter
Gemmiger
Hungatella
Lachnoclostridium
Mycobacteroides
Paraprevotella
Phascolarctobacterium
Prevotella
Roseburia
Ruminococcus
Staphylococcus
Subdoligranulum

Revision editor(s): SheikhAlMamun

Signature 2

Needs review

Curated date: 2025/09/28

Curator: SheikhAlMamun

Revision editor(s): SheikhAlMamun

Source: Table S7 & Table S8

Description: The decreased of gut microbiota had specific alterations at the phylum, genus, and species levels. At the phylum level, rifaximin decreased Verrucomicrobia and Fibrobacteres (P < 0.05) (Table S7). At the genus level, significant reductions in mucin-degrading genera, such as Akkermansia and Hungatella, were observed in the fecal samples (P < 0.05) (Table S8).

Abundance in Group 1: decreased abundance in Rifaximin (Rif)

NCBI Quality ControlLinks
Enterobacter
candidate_division_WOR-3candidate_division_WOR-3
Candidatus_BipolaricaulotaCandidatus_Bipolaricaulota
Candidatus_LevybacteriaCandidatus_Levybacteria
NitrospinaeNitrospinae
Candidatus_PeregrinibacteriaCandidatus_Peregrinibacteria
Candidatus_TectomicrobiaCandidatus_Tectomicrobia
TyzerellaTyzerella
VerrucomicrobiaVerrucomicrobia
FibrobacteresFibrobacteres
CoproccoccusCoproccoccus

Revision editor(s): SheikhAlMamun