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Polypeptide for use in the protection of oxygen sensitive gram-positive bacteria

Pending Publication Date: 2022-07-28
INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM) +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019]The inventors have shown that an increase in the concentration of the hReg3α lectin into the gastrointestinal tract (GIT) lumen of transgenic mice induced significant changes in the composition of the gut microbiota, and dramatically improved host resistance to intestinal inflammation. In fact, hReg3α-transgenic mice exposed to DSS (dextran sodium sulphate) exhibited very few signs of colitis, retained a tight mucosal barrier and achieved complete survival. hReg3α exerted a potent antioxidant activity on intestinal epithelial cells during colitis, and in particular the ROS scavenging activity of a recombinant human Reg3α (rcReg3α) acted on prokaryote cells, in particular, by promoting the survival of highly oxygen sensitive bacteria.
[0034]According to an embodiment, said Reg3α polypeptide allows the increase survival and growth of butyrate-producing bacteria, and of butyrate concentration which is an anti-inflammatory compound. Thus said Reg3α polypeptide permits the reduction of inflammation.
[0067]As used herein, the term “ex vivo viability and / or growth” includes the viability and / or growth in fermenter and / or in product, such as food product (for example dairy product). Indeed it is difficult to obtain high yield of oxygen sensitive gram-positive bacteria because of the apparition of Reactive Oxygen Species (ROS). Use of a polypeptide according to the invention permits to protect oxygen sensitive gram-positive bacteria from oxidative stress and thus permits to obtain higher production yield.

Problems solved by technology

Under abnormal circumstance such as inflammation for example, there is an imbalance in the microbiota and said microbiota can influence host defence and immunity, and in turn may become pathogenic and contribute to disorder and / or disease initiation or exacerbations.
Health problems begin when there is an imbalance (due to antibiotic treatment as an example) of the gut microbiota.
A wide range of factors, such as changes in dietary habits or antibiotic use, can influence the delicate microbial balance and thus, lead to dysbiosis.

Method used

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  • Polypeptide for use in the protection of oxygen sensitive gram-positive bacteria
  • Polypeptide for use in the protection of oxygen sensitive gram-positive bacteria
  • Polypeptide for use in the protection of oxygen sensitive gram-positive bacteria

Examples

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example 1

3α Delivered into the Gut Lumen Shifts the Gut Microbiota Composition in Hepatocyte-Targeted Reg3α Transgenic Mice

[0093]We studied the effects of human Reg3α (hReg3α) on the composition of the gut microbiota and gut barrier integrity in mice transgenic for hReg3α under homeostatic and inflammatory conditions. Inflammation was induced by oral absorption of dextran sodium sulphate (DSS). To prevent degradation of the hReg3α protein by acid and luminal proteases in the upper GIT, we used previously generated homozygous transgenic C57BL / 6 mice expressing hReg3α in hepatocytes under the control of the mouse albumin gene promoter and showed that, in these mice, the hReg3α protein flowed into bile ducts and into the gastrointestinal tract (GIT) lumen. Transgenic hepatocytes secreted hReg3α into blood vessels through the basolateral membranes, and into bile canaliculi through the apical membranes.

[0094]The expression levels of endogenous Reg3β and Reg3γ in the blood and colon tissue were ne...

example 2

[0112]Intravenous Administration of rcReg3α Did not Improve DSS-Induced Colitis in WT Mice Contrary to hReg3α Transgenic Mice

[0113]We studied the effects of intravenous administration of 4.2 μg of recombinant human Reg3α (rcReg3α) per day in WT mice under inflammatory conditions. Inflammation was induced by oral absorption of dextran sodium sulphate (DSS). These results were compared with homozygous transgenic C57BL / 6 mice expressing hReg3α in hepatocytes under the control of the mouse albumin gene promoter. Transgenic hepatocytes secreted hReg3α into blood vessels through the basolateral membranes, and into bile canaliculi through the apical membranes.

[0114]Histological score, based on the evaluation of the mucosal architectural change, mononuclear cell infiltration, neutrophil infiltration epithelial defects and Goblet cell loss, was evaluated in colon and distal colon of both groups (results presented in FIG. 10). The severity of the inflammation was stronger in WT mice treated w...

example 3

[0116]hReg3α-Transgenic Mice Resist Better to DSS-Induced Colitis after Antibiotherapy

[0117]Degradation of the microbiota by antibiotics leads to a potentiation of inflammation and to numerous intestinal and extra-intestinal deleterious effects. We studied the effects of two antibiotics (named Abx), vancomycin and gentamicin, administered during three days on the following response to DSS-induced colitis on WT mice and hReg3α transgenic mice. Vancomycin is a tricyclic glycopeptide that kills most gram-positive organisms by binding to bacteria cell walls and altering cell membrane permeability. It also interferes with bacteria RNA synthesis. Gentamicin is a broad-spectrum aminoglycoside antibiotic that targets aerobic gram-negative bacilli.

[0118]In two independent experiments, we observed a diminished body weight loss and diarrhea score in Abx-transgenic (TG Abx) mice compared to Abx-wild-type mice (WT Abx) and even compare to WT mice which did not had antibiotherapy (WT) (see for ex...

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Abstract

The invention concerns a Reg3α polypeptide (also known as Hepatocarcinoma-Intestine-Pancreas / Pancreatitis Associated Protein (HIP / PAP)) for protecting oxygen sensitive gram-positive bacteria, compositions comprising the polypeptide, and their use. The inventors showed that increasing concentration of the hReg3α lectin into the gastrointestinal tract (GIT) lumen of hReg3α-transgenic mice induced significant changes in composition of gut microbiota, and dramatically improved host resistance to intestinal inflammation. hReg3α exerted a potent antioxidant activity on intestinal epithelial cells during colitis, and the ROS scavenging activity, by promoting the survival of highly oxygen sensitive bacteria. Inventors also showed that hReg3α-transgenic mice were better able to resist DSS-induced colitis after antibiotherapy. The Reg3α polypeptide may be used for preventing or treating microbiota-related diseases and / or disorders, including inflammatory bowel disease (IBD), colitis, gastrointestinal infections, irritable bowel syndrome and other gastrointestinal functional diseases, gastrointestinal tract cancer, metabolic syndrome and obesity, diabetes, liver diseases, allergic diseases, neurodegenerative diseases and psychological disorders.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a Divisional application of U.S. application Ser. No. 16 / 630,252, filed Jan. 10, 2020, which is a national stage entry under 35 USC § 371 of International Application PCT / EP2018 / 069133, filed Jul. 13, 2018, which is based on and claims a priority to European patent application 17305925.4, filed Jul. 13, 2017, all of said applications being incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention concerns a polypeptide for use in the protection of oxygen sensitive gram-positive bacteria, compositions comprising the polypeptide and their use, and the use of this polypeptide for promoting ex vivo growth of oxygen sensitive gram-positive bacteria.TECHNICAL BACKGROUND[0003]In mammals, and especially humans, the microbiota includes microorganisms such as bacteria, viruses, fungi and archaea (single-celled microorganisms) and can be found on skin including dermis and dermal adipose tissue, in the mou...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/17A23L33/19
CPCA61K38/1709A23L33/19A61P1/00A61P3/00A23L2/66A23L33/18A23C9/1322Y02A50/30
Inventor DORE, JOËLFAIVRE, JAMILAMONIAUX, NICOLASBRECHOT, CHRISTIANDARNAUD, MARION
Owner INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM)
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