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Cited by 92Gut microbiota and healthGastrointestinal motility and disordersProtease and Inhibitor Mechanisms

The emerging roles of bacterial proteases in intestinal diseases

Open access
Caminero, Alberto, Guzman, Mabel, Libertucci, Josie, Lomax, Alan E.·2023·Gut Microbes
DOI 10.1080/19490976.2023.2181922PMC PMC9980614
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Abstract

Proteases are an evolutionarily conserved family of enzymes that degrade peptide bonds and have been implicated in several common gastrointestinal (GI) diseases. Although luminal proteolytic activity is important for maintenance of homeostasis and health, the current review describes recent advances in our understanding of how overactivity of luminal proteases contributes to the pathophysiology of celiac disease, irritable bowel syndrome, inflammatory bowel disease and GI infections. Luminal proteases, many of which are produced by the microbiota, can modulate the immunogenicity of dietary antigens, reduce mucosal barrier function and activate pro-inflammatory and pro-nociceptive host signaling. Increased proteolytic activity has been ascribed to both increases in protease production and decreases in inhibitors of luminal proteases. With the identification of strains of bacteria that are important sources of proteases and their inhibitors, the stage is set to develop drug or microbial therapies to restore protease balance and alleviate disease.

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Written from the paper’s full text.

TL;DR

This narrative review synthesizes evidence that bacterial proteases from the gut microbiota contribute to the pathophysiology of inflammatory bowel disease (IBD), celiac disease (CeD), irritable bowel syndrome (IBS), and gastrointestinal (GI) infections by modulating dietary antigen immunogenicity, mucosal barrier function, and pro-inflammatory/pro-nociceptive host signaling. The authors argue that identifying bacterial sources of proteases and their inhibitors sets the stage for drug or microbial therapies that restore protease balance.

Key findings

  • Luminal proteolytic activity is elevated in IBD, IBS, and CeD, and this increase arises from both greater protease production and decreased inhibitors; fecal serine protease activity is increased in IBD, and increased fecal proteolytic activity was detected in UC patients even prior to disease onset, suggesting a potential early biomarker.
  • Bacterial proteases can either exacerbate or protect against disease depending on substrate specificity: *Pseudomonas aeruginosa* LasB degrades gluten into more immunogenic peptides and activates PAR-2, whereas *Rothia* strains, *Lactobacillus*, and prolyl endopeptidases from *Flavobacterium meningosepticum*, *Sphingomonas capsulate*, and *Myxococcus xanthus* degrade gluten/ATI and reduce immunogenicity.
  • Proteases disrupt barrier function by degrading mucus (e.g., ZmpB from *Clostridium perfringens*, Pic, vibriolysin, StcE, SslE, M60-like proteases) and inter-enterocyte junctions (e.g., GelE from *Enterococcus faecalis* degrades E-cadherin; SP-1 from *Clostridium* spp. impairs the epithelial barrier and exacerbates DSS colitis in mice).
  • PAR activation modulates pain bidirectionally: PAR-2 activation is pro-nociceptive, while PAR-4 activation suppresses colonic nociceptor excitability; *Faecalibacterium prausnitzii* media suppressed dorsal root ganglion neuron excitability via a cathepsin G-like serine protease activating PAR-4, and reversed visceral hyperalgesia in rodent IBS models.
  • Classification context: proteases represent up to 2% of the human genome with over 500 described; serine (35.1%) and metalloproteases (29.5%) dominate in humans, while bacterial proteolytic enzymes are mostly serine (39.2%), metalloproteases (35.9%), and cysteine (16.5%) proteases. CeD has a worldwide prevalence of 1.4%.

Methods

  • Design: narrative review of the literature on bacterial proteases in GI diseases, covering protease classification, disease associations (IBD, CeD, IBS, GI infections), and mechanisms (diet–microbiota interactions, mucosal barrier, immune signaling, abdominal pain).
  • Data: no primary data; the review cites published human cohort studies, preclinical mouse/rat models, in vitro work, and omics studies (shotgun metagenomics, proteomics, metabolomics), summarized in Table 1 and Figure 2.
  • Analysis: thematic synthesis of cited findings; no systematic search strategy, inclusion criteria, or quantitative meta-analysis is described.

Limitations

  • Stated by the paper: mechanistic characterization of specific bacterial proteases in gut disorders "still represent an enormous challenge"; deciphering whether fecal proteases are of host or bacterial origin "remains a challenge"; the extent to which bacterial proteases drive UC disease severity and whether a similar phenomenon occurs in CD "remain to be determined"; additional work is required to determine the importance of microbial protease contributions to PAR-dependent enterocyte effects; and study of commensal proteases "is still in its infancy."
  • Evident from the text: as a narrative review without a stated systematic search strategy, it may not comprehensively capture the literature; many cited mechanistic findings derive from preclinical rodent models or in vitro systems rather than human causal evidence; and several entries in Table 1 are marked "ND" (not determined), reflecting gaps in protease characterization.

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Integrity signals

Registry

Crossref · 10.1080/19490976.2023.2181922

Cites

167 of 167 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 155 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Serine proteases from a consortium of gut bacteria modulate the excitability of nociceptors via activation of protease-activated receptor 4.

    “serine proteases from a consortium of gut bacteria modulate the excitability of nociceptors via activation of protease-activated receptor 4 (PAR-4).19”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Sessenwein JL, Baker CC, Pradhananga S, Maitland ME, Petrof EO, Allen-Vercoe E, Noordhof C, Reed DE, Vanner SJ, Lomax AE, et al. Protease-Mediated suppression of DRG neuron excitability by commensal bacteria. J Neurosci. 2017; 37(48): 11758– 11768. doi: 10.1523/JNEUROSCI.1672-17.2017. 29089436 PMC5707769 source

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  • Premisecitation

    Cathepsin G and thrombin are overactive in supernatants of colonic tissues from inflammatory bowel disease patients compared to healthy controls.

    “Proteases such as cathepsin G and thrombin are overactive in supernatants of colonic tissues from IBD patients compared to healthy controls.8”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Denadai-Souza A, Bonnart C, Tapias NS, Marcellin M, Gilmore B, Alric L, Bonnet D, Burlet-Schiltz O, Hollenberg MD, Vergnolle N, et al. Functional proteomic profiling of secreted serine proteases in health and inflammatory bowel disease. Sci Rep. 2018; 8: 7834. doi: 10.1038/s41598-018-26282-y. 29777136 PMC5959920 source

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  • Premisecitation

    Elevated proteolytic activity is observed in stool supernatants from inflammatory bowel disease and irritable bowel syndrome patients compared to healthy subjects.

    “Elevated PA was also observed in stool supernatants from IBD and IBS patients compared to samples from healthy subjects, suggesting that enhanced PA in IBD and IBS may be due to elevations in PA from both host and microbial origin.12,13”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Jablaoui A, Kriaa A, Mkaouar H, Akermi N, Soussou S, Wysocka M, Wołoszyn D, Amouri A, Gargouri A, Maguin E, et al. Fecal Serine Protease Profiling in Inflammatory Bowel Diseases. Front Cell Infect Microbiol. 2020; 10: 21. doi: 10.3389/fcimb.2020.00021. 32117798 PMC7011180 source

      Not checked in the free run.

    • cites [13] Edogawa S, Edwinson AL, Peters SA, Chikkamenahalli LL, Sundt W, Graves S, Gurunathan SV, Breen-Lyles M, Johnson S, Dyer R, et al. Serine proteases as luminal mediators of intestinal barrier dysfunction and symptom severity in IBS. Gut. 2020; 69: 62– 73. doi: 10.1136/gutjnl-2018-317416. 30923071 PMC6765451 source

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  • Premisecitation

    In Crohn's disease and ulcerative colitis patients, increased host serine protease production from colonic tissue has been reported.

    “In both CD and UC patients, increased host serine protease production from colonic tissue have been reported.27,28”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Motta JP, Bermudez-Humaran LG, Deraison C, Martin L, Rolland C, Rousset P, Boue J, Dietrich G, Chapman K, Kharrat P, et al. Food-grade bacteria expressing elafin protect against inflammation and restore colon homeostasis. Sci Transl Med. 2012; 4: 158ra44. doi: 10.1126/scitranslmed.3004212. 23115353 source

      Not checked in the free run.

    • cites [28] Dabek M, Ferrier L, Roka R, Gecse K, Annahazi A, Moreau J, Escourrou J, Cartier C, Chaumaz G, Leveque M, et al. Luminal cathepsin g and protease-activated receptor 4: a duet involved in alterations of the colonic epithelial barrier in ulcerative colitis. Am J Pathol. 2009; 175: 207– 214. doi: 10.2353/ajpath.2009.080986. 19528350 PMC2708807 source

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  • Interpretationnone given

    Luminal proteases can modulate the immunogenicity of dietary antigens.

    “Luminal proteases, many of which are produced by the microbiota, can modulate the immunogenicity of dietary antigens, reduce mucosal barrier function and activate pro-inflammatory and pro-nociceptive host signaling.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 23
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Premisecitation

    Colonic epithelial cells are a major source of elastase-like activity and this activity is markedly increased in inflammatory bowel disease patients.

    “Motta et al.29 showed that colonic epithelial cells are a major source of elastase-like activity and this activity is markedly increased in IBD patients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Motta JP, Rolland C, Edir A, Florence AC, Sagnat D, Bonnart C, Rousset P, Guiraud L, Quaranta-Nicaise M, Mas E, et al. Epithelial production of elastase is increased in inflammatory bowel disease and causes mucosal inflammation. Mucosal Immunol. 2021; 14: 667– 678. doi: 10.1038/s41385-021-00375-w. 33674762 PMC8075934 source

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  • May combine two claims.

    Interpretationreasoning

    Some proteases protect against celiac disease and others exacerbate the disease, depending on the substrate specificity of the protease and its ability to reduce or increase the immunogenicity of gluten catabolic products.

    “Taken together, the evidence to date suggests that some proteases protect against CeD and other exacerbate the disease, depending on the substrate specificity of the protease in question and its ability to reduce or increase the immunogenicity of gluten catabolic products.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Trypsin-like activity and tryptase release are increased in colonic biopsies from irritable bowel syndrome patients.

    “For example, Trypsin-like activity and tryptase release are increased in colonic biopsies from IBS patients.7,58”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Rolland-Fourcade C, Denadai-Souza A, Cirillo C, Lopez C, Jaramillo JO, Desormeaux C, Cenac N, Motta J-P, Larauche M, Taché Y, et al. Epithelial expression and function of trypsin-3 in irritable bowel syndrome. Gut. 2017; 66: 1767– 1778. doi: 10.1136/gutjnl-2016-312094. 28096305 PMC5595105 source

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    • cites [58] Cenac N, Andrews CN, Holzhausen M, Chapman K, Cottrell G, Andrade-Gordon P, Steinhoff M, Barbara G, Beck P, Bunnett NW, et al. Role for protease activity in visceral pain in irritable bowel syndrome. J Clin Invest. 2007; 117(3): 636– 647. doi: 10.1172/JCI29255. 17304351 PMC1794118 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transfer of fecal microbiota from ulcerative colitis patients prior to disease onset into mice increased fecal proteolytic activity in the colon and activation of host inflammatory responses.

    “Importantly, transfer of fecal microbiota from UC patients prior to disease onset into mice increased fecal proteolytic activity in the colon and activation of host inflammatory responses.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Galipeau HJ, Caminero A, Turpin W, Bermudez-Brito M, Santiago A, Libertucci J, Constante M, Raygoza Garay JA, Rueda G, Armstrong S, et al. Novel fecal biomarkers that precede clinical diagnosis of ulcerative colitis. Gastroenterology. 2021; 160: 1532– 1545. doi: 10.1053/j.gastro.2020.12.004. 33310084 source

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    • Rests on an assumption: Findings from preclinical mouse models of gastrointestinal disease translate to human disease.

  • May combine two claims.

    Premisenone given

    Class-2 serine protease autotransporters from enterobacteriaceae disrupt mucosal barriers and modulate the immune response by targeting host glycoproteins.

    “On the other hand, class-2 SPATEs seem to disrupt mucosal barriers and modulate the immune response by targeting host glycoproteins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Some proteases correlated with ulcerative colitis include serine and metalloproteases that largely function in the extracellular space and may exacerbate disease activity.

    “Some of the correlated proteases included serine and metalloproteases that largely function in the extracellular space and may exacerbate disease activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Mills RH, Dulai PS, Vazquez-Baeza Y, Sauceda C, Daniel N, Gerner RR, Batachari LE, Malfavon M, Zhu Q, Weldon K, et al. Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity. Nat Microbiol. 2022; 7(2): 262– 276. doi: 10.1038/s41564-021-01050-3. 35087228 PMC8852248 source

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    Premisecitation

    Metagenomic analysis of faecal samples from patients with post-infectious irritable bowel syndrome revealed an altered gut microbiota composition and high gut proteolytic activity driven by specific host serine proteases compared with controls.

    “In a recent study, metagenomic analysis of faecal samples from patients with post-infectious IBS revealed an altered gut microbiota composition and high gut proteolytic activity driven by specific host serine proteases compared with controls.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Edwinson AL, Yang L, Peters S, Hanning N, Jeraldo P, Jagtap P, Simpson JB, Yang T-Y, Kumar P, Mehta S, et al. Gut microbial beta-glucuronidases regulate host luminal proteases and are depleted in irritable bowel syndrome. Nat Microbiol. 2022; 7: 680– 694. doi: 10.1038/s41564-022-01103-1. 35484230 PMC9081267 source

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    Premisecitation

    Intracellular and membrane proteases such as Clp, Lon or HtrA contribute to virulence through the timely degradation of virulence regulators and indirectly by providing tolerance to adverse conditions in the host.

    “Intracellular and membrane proteases such as Clp, Lon or HtrA contribute to virulence through the timely degradation of virulence regulators and indirectly by providing tolerance to adverse conditions in the host.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Frees D, Brondsted L, Ingmer H. Bacterial proteases and virulence. Subcell Biochem. 2013; 66: 161– 192. 23479441 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Proteases expressed by pathobionts impact gluten metabolism and immune activation in the small intestine of celiac disease patients.

    “These studies suggest that proteases expressed by pathobionts impact gluten metabolism and immune activation in the small intestine of CeD patients.43”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Caminero A, Galipeau HJ, McCarville JL, Johnston CW, Bernier SP, Russell AK, Jury J, Herran AR, Casqueiro J, Tye-Din JA, et al. Duodenal bacteria from patients with celiac disease and healthy subjects distinctly affect gluten breakdown and immunogenicity. Gastroenterology. 2016; 151: 670– 683. doi: 10.1053/j.gastro.2016.06.041. 27373514 source

      Not checked in the free run.

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    Premisecitation

    Oral administration of the bacterial serine protease SP-1, produced by Clostridium spp, resulted in impaired epithelial barrier, altered microbiota community composition, and exacerbated DSS-induced colitis.

    “Oral administration of the bacterial serine protease SP-1, produced by Clostridium spp resulted in impaired epithelial barrier, altered microbiota community compostion, and exacerbated DSS-induced colitis.129”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Kriaa A, Jablaoui A, Rhimi S, Soussou S, Mkaouar H, Mariaule V, et al. SP-1, a serine protease from the gut microbiota, influences colitis and drives intestinal dysbiosis in mice. In: Cells. 2021; 10:2658. doi: 10.3390/cells10102658. PMC8534766 34685638 source

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    Premisecitation

    It has been proposed to block specific proteases to prevent common gastrointestinal infections, but there are still no approved drugs with this mode of action.

    “it has been proposed to block specific proteases to prevent common gastrointestinal infections; however, there are still no approved drugs with this mode of action.25”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Culp E, Wright GD. Bacterial proteases, untapped antimicrobial drug targets. J Antibiot (Tokyo). 2017; 70: 366– 377. doi: 10.1038/ja.2016.138. 27899793 source

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  • May combine two claims.

    Premisecitation

    StcE and SslE, metalloproteases from diarrheagenic E. coli strains, cleave mucin glycoproteins, which may help the pathogen to reach the epithelium.

    “StcE and SslE, metalloproteases from diarrheagenic E. coli strains, also cleave mucin glycoproteins, which may help the pathogen to reach the epithelium.74–76”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [74] Hews CL, Tran SL, Wegmann U, Brett B, Walsham ADS, Kavanaugh D, et al. The StcE metalloprotease of enterohaemorrhagic Escherichia coli reduces the inner mucus layer and promotes adherence to human colonic epithelium ex vivo. Cell Microbiol. 2017; 19(6):e12717. doi: 10.1111/cmi.12717. PMC5434857 28054754 source

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    • cites [75] Grys TE, Siegel MB, Lathem WW, Welch RA. The StcE protease contributes to intimate adherence of enterohemorrhagic Escherichia coli O157: h7 to host cells. Infect Immun. 2005; 73: 1295– 1303. doi: 10.1128/IAI.73.3.1295-1303.2005. 15731026 PMC1064933 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Compromised intestinal barrier function has been associated with a number of disease states, both intestinal and systemic.

    “Compromised intestinal barrier function has been associated with a number of disease states, both intestinal and systemic.128”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Tight junctions are targets of infectious agents such as Pseudomonas aeruginosa (through LasB), H. pylori (PqqE and HtrA), C. jejuni (HtrA), V. cholerae (vibrolysin), Shigella, Salmonella or pathogenic Escherichia coli (SepA).

    “Tight junctions are also targets of infectious agents such as Pseudomonas aeruginosa (through LasB),132 H. pylori (PqqE and HtrA),61–63 C. jejuni (HtrA), 79,80 V. cholerae (vibrolysin),10,83 Shigella, Salmonella or pathogenic Escherichia coli (SepA).72,133”
    Quote in the paperSubstantial claim0 of 6 sources checked
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  • May combine two claims.

    Premisenone given

    The inner mucus layer in the colon is firmly attached to the epithelium, impenetrable to bacteria and essential for inhibiting the interaction of microbes with host receptors on the epithelium.

    “The inner mucus layer is firmly attached to the epithelium, impenetrable to bacteria and essential for inhibiting the interaction of microbes with host receptors on the epithelium.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The outer mucus layer in the colon is expanded and serves as a habitat for the microbiota.

    “The outer mucus layer in the colon (secreted) is expanded and serves as a habitat for the microbiota.121”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Johansson ME, Hansson GC. Immunological aspects of intestinal mucus and mucins. Nat Rev Immunol. 2016; 16: 639– 649. doi: 10.1038/nri.2016.88. 27498766 PMC6435297 source

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  • May combine two claims.

    Premisecitation

    Activation of the different members of the PAR family is protease specific, tightly regulated and influences physiological functions in the gut such as motility, permeability and nociception.

    “The activation of the different members of the PAR family (PAR-1, 2,3 and 4) is protease specific, tightly regulated and influences a number of physiological functions in the gut such as motility, permeability and nociception.22”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Vergnolle N. Protease inhibition as new therapeutic strategy for GI diseases. Gut. 2016; 65: 1215– 1224. doi: 10.1136/gutjnl-2015-309147. 27196587 PMC4941139 source

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    Premisecitation

    Apical administration of PAR-2 activating ligands led to prostanoid and interferon release as well as an increase in paracellular permeability due to ZO-1 degradation.

    “Regarding the role of PARs in intestinal function, apical administration of PAR-2 activating ligands led to prostanoid and interferon release as well as an increase in paracellular permeability due to ZO-1 degradation.6,134”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Kong W, McConalogue K, Khitin LM, Hollenberg MD, Payan DG, Bohm SK, Bunnett NW. Luminal trypsin may regulate enterocytes through proteinase-activated receptor 2. Proc Natl Acad Sci U S A. 1997; 94(16): 8884– 8889. doi: 10.1073/pnas.94.16.8884. 9238072 PMC23180 source

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    • cites [134] Cenac N, Chin AC, Garcia-Villar R, Salvador-Cartier C, Ferrier L, Vergnolle N, Buret AG, Fioramonti J, Bueno L. PART 2 activation alters colonic paracellular permeability in mice via IFN-γ-dependent and -independent pathways. J Physiol. 2004; 558: 913– 925. doi: 10.1113/jphysiol.2004.061721. 15194744 PMC1665017 source

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    Premisecitation

    A Zn-metalloproteinase from Legionella pneumophila has the ability to degrade IL-2.

    “A Zn-metalloproteinase from Legionella pneumophila also has the ability to degrade IL-2.148”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • May combine two claims.

    Premisecitation

    PARs have been implicated in the pathogenesis of colorectal cancer and inflammatory and functional intestinal disorders.

    “PARs have been implicated in the pathogenesis of colorectal cancer138 and inflammatory and functional intestinal disorders.139–141”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [138] Darmoul D, Gratio V, Devaud H, Peiretti F, Laburthe M. Activation of proteinase-activated receptor 1 promotes human colon cancer cell proliferation through epidermal growth factor receptor transactivation. Mol Cancer Res. 2004; 2: 514– 522. doi: 10.1158/1541-7786.514.2.9. 15383630 source

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  • May combine two claims.

    Premisecitation

    The intestinal microbiota can degrade IgA, which plays a key role in mucosal immunology, and mice with documented degradation of secretory IgA are more susceptible to chemically-induced colitis.

    “It has been shown that the intestinal microbiota can degrade IgA, which plays a key role in mucosal immunology, and mice with documented degradation of secretory IgA are more susceptible to chemically-induced colitis.152”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Intracolonic administration of fecal supernatants from IBS-D and IBS-C patients increased the visceromotor response to distension, with evidence of both allodynia and hyperalgesia.

    “Intracolonic administration of fecal supernatants from IBS-D and IBS-C patients increased the visceromotor response to distension, with evidence of both allodynia and hyperalgesia.159,160”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [159] Annahazi A, Gecse K, Dabek M, Ait-Belgnaoui A, Rosztoczy A, Roka R, Molnár T, Theodorou V, Wittmann T, Bueno L, et al. Fecal proteases from diarrheic-IBS and ulcerative colitis patients exert opposite effect on visceral sensitivity in mice. Pain. 2009; 144(1): 209– 217. doi: 10.1016/j.pain.2009.04.017. 19450926 source

      Not checked in the free run.

    • cites [160] Annahazi A, Ferrier L, Bezirard V, Leveque M, Eutamene H, Ait-Belgnaoui A, Coëffier M, Ducrotté P, Róka R, Inczefi O, et al. Luminal cysteine-proteases degrade colonic tight junction structure and are responsible for abdominal pain in constipation-predominant IBS. Am J Gastroenterol. 2013; 108(8): 1322– 1331. doi: 10.1038/ajg.2013.152. 23711626 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Host proteases such as trypsin are capable of degrading IgA, and microbial commensals such as Paraprevotella can prevent its degradation in the gut.

    “Host proteases such as trypsin are capable of degrading IgA, and microbial commensals such as Paraprevotella can prevent its degradation in the gut.9”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Li Y, Watanabe E, Kawashima Y, Plichta DR, Wang Z, Ujike M, et al. Identification of trypsin-degrading commensals in the large intestine. Nature. 2022;609(7927):582-589. doi: 10.1038/s41586-022-05181-3. PMC9477747 36071157 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PAR-4 activation suppresses the excitability of colonic nociceptors in vitro and in vivo.

    “PAR-4 activation suppresses the excitability of colonic nociceptors in vitro,157 and in vivo.158”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [157] Karanjia R, Spreadbury I, Bautista-Cruz F, Tsang ME, Vanner S. Activation of protease-activated receptor-4 inhibits the intrinsic excitability of colonic dorsal root ganglia neurons. Neurogastroenterol Motil. 2009; 21: 1218– 1221. doi: 10.1111/j.1365-2982.2009.01353.x. 19566587 source

      Not checked in the free run.

    • cites [158] Auge C, Balz-Hara D, Steinhoff M, Vergnolle N, Cenac N. Protease-activated receptor-4 (PAR 4): a role as inhibitor of visceral pain and hypersensitivity. Neurogastroenterol Motil. 2009; 21:1189-e107. doi: 10.1111/j.1365-2982.2009.01310.x. 19413681 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intracolonic administration of cysteine proteases within IBS-C fecal supernatants to mice increased colonic permeability and led to degradation of occludin, which in turn led to increased visceral pain.

    “Instead, intracolonic administration of cysteine proteases within IBS-C fecal supernatants to mice increased colonic permeability and led to degradation of occluding, which in turn led to increased visceral pain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] Annahazi A, Ferrier L, Bezirard V, Leveque M, Eutamene H, Ait-Belgnaoui A, Coëffier M, Ducrotté P, Róka R, Inczefi O, et al. Luminal cysteine-proteases degrade colonic tight junction structure and are responsible for abdominal pain in constipation-predominant IBS. Am J Gastroenterol. 2013; 108(8): 1322– 1331. doi: 10.1038/ajg.2013.152. 23711626 source

      Not checked in the free run.

25 of 25

  • The paper relies on this without support.

    Findings from preclinical mouse models of gastrointestinal disease translate to human disease.

    “Elafin, a Lactobacillus-derived inhibitor of serine proteases reduced the severity of colitis in mice exposed to dextran sulfate sodium (DSS) or trinitro benzene sulphonic acid.27,30,31”

  • The paper relies on this without support.

    Increased proteolytic activity measured in fecal samples reflects luminal proteolytic activity relevant to disease pathogenesis.

    “Elevated PA was also observed in stool supernatants from IBD and IBS patients compared to samples from healthy subjects, suggesting that enhanced PA in IBD and IBS may be due to elevations in PA from both host and microbial origin.12,13”

  • The paper relies on this without support.

    Bacterial proteases can be selectively targeted to restore protease balance and alleviate disease without disrupting beneficial proteolytic functions.

    “With the identification of strains of bacteria that are important sources of proteases and their inhibitors, the stage is set to develop drug or microbial therapies to restore protease balance and alleviate disease.”

  • The paper relies on this without support.

    The implications of mucin-degrading proteases in specific chronic intestinal diseases are not yet well understood.

    “Although mucin degradative capacity is considered a virulence factor of many GI pathogens, the implications in specific chronic intestinal diseases are not yet well understood.”

  • The paper relies on this without support.

    The full implications of activating PARs by microbial proteases in the context of GI diseases are still being resolved.

    “However, the full implications of activating PARs by microbial proteases in the context of GI diseases are still being resolved.”

  • The paper relies on this without support.

    Much remains to be done to understand whether proteases released by commensals promote or neutralize the production of anti- and pro-inflammatory mediators.

    “However, much remains to be done to understand whether proteases released by commensals promote or neutralize the production of anti- and pro- inflammatory mediators, respectively.”

  • The paper relies on this without support.

    The study of proteases from commensal gut bacteria and their contribution to disease is still in its infancy.

    “Although recent findings have shown the importance of proteases from commensal gut bacteria in gut homeostasis, the study of these proteases and their contribution to disease is still in its infancy.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Other unique COGs are associated with host-immune interactions and osmotic and pH regulation.

    “Specifically, 25 unique COGs are implicated in the import and processing of human milk sugars [84] , while others are associated with host-immune interactions [85] and osmotic and pH regulation [86] , i.e., functions that support survival in the infant gut [23,87,88] .”

    From Genome-scale insights into the metabolic landscape and evolutionary development of Bifidobacterium bifidum (2026) · cites this paper as [85]

    The section “Bacterial protease effects on cell and immune signaling” (page unavailable) describes bacterial proteases affecting host cytokines and immunoglobulins, supporting the general host-immune interaction. It does not identify unique COGs or associate them with that function. Osmotic and pH regulation is attached to a different citation, [86], rather than this source [85]. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Protease classifications list different catalytic classes

    Minor

    The introduction presents a classification with six catalytic classes, but the later classification adds asparagine proteases as a seventh class. Both lists are presented as classifications by catalytic mechanism.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Sattar SBA, Bacterial Gastroenteritis SS. StatPearls. Treasure Island (FL). 2022

Cited by

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Related

Authors
Caminero, A., Guzman, M., Libertucci, J., & Lomax, A. E.
Affiliations
  • McMaster University (CA)
  • Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen’s University, Kingston, Ontario, Canada
  • Queen's University (CA)
Corresponding author
Lomax, Alan E.
ORCID
Venue
Gut Microbes
Publisher
Informa UK Limited
Published
2023-02-26
Volume
15
Issue
1
Pages
2181922-2181922
ISSN
  • 1949-0976 (ISSN-L)
  • 1949-0984
DOI
10.1080/19490976.2023.2181922
PMC
PMC9980614
OpenAlex
W4322216951
Semantic Scholar
f6c1f34ec0898bbe72939594826db4c9adbd4608
Cited by
92
References
166
Citations by year
2026: 20 · 2025: 43 · 2024: 20 · 2023: 9
FWCI
2.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Gut Microbes (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Canadian Institutes of Health Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords
bacterial proteases, intestinal diseases, celiac disease, irritable bowel syndrome, inflammatory bowel disease, gastrointestinal infections, gut microbiota, mucosal barrier function, protease inhibitors, pro-inflammatory signaling, nociception, microbial treatment
MeSH terms
Gastrointestinal Microbiome, Bacteria, Bacterial Proteins, Celiac Disease, Humans, Peptide Hydrolases, Endopeptidases, Inflammatory Bowel Diseases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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