Figure 1: Reduction in the amount of F. prausnitzii in Inflammatory Bowel Diseases (IBD) patients. Sokol et al. IBD 2009

Figure 2: F. prausnitzii proportions at time of surgery according to the endoscopic recurrence status at 6 months (Sokol & al. 2008)

Figure 3: F. prausnitzii level at Infliximab discontinuation in CD patients Vs Relapse free survival rate (Rajca et al. IBD 2014)

Figure 4: Correlation F. prausnitzii and number of years to intestinal resection or colectomy (Shapiro et al. Cell Host & Microbe 2020)

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Faecalibacterium Prausnitzii IN INFLAMMATORY BOWEL DISEASES

Faecalibacterium prausnitzii (F. prau) to Fight Crohn’s Disease

A key intestinal bacterium associated with targeted modulating effects on the host’s immune system.

In 2008, Exeliom Bioscience co-founders were the first to demonstrate and publish the anti-inflammatory properties of F. prausnitzii (Sokol H, et al.). Since this discovery, the therapeutic potential of F. prau has been widely confirmed by both researchers and their peers globally. Here are the conclusions we can draw:
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Low levels of F. prausnitzii are a sign of illness: (1) The F. prausnitzii concentration level is decreased in patients suffering from inflammatory bowel diseases (Figure 1). (2) A reduction in the intestinal concentration of F. prausnitzii is associated with a higher risk of the postoperative recurrence of Crohn’s disease. (3) Low F. prausnitzii levels have also been associated with higher relapse risks.
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Good levels of F. prausnitzii are a sign of wellness. (1) For Crohn’s disease patients in remission, a high level of F. prausnitzii is associated with remission maintenance, while a low level is associated with a higher risk of clinical flare-ups (Figure 2). (2) A high level of F. prausnitzii is associated with a better response to current treatments (Figure 3). (3) A high level of F. prausnitzii is associated with a lower need for surgery (Figure 4). (4) A high abundance of F. prausnitzii has never been associated with any infections or any other disease in humans.

F. prausnitzii is therefore a unique bacterial species that plays a critical role in inflammatory bowel diseases.
As they are lacking this bacterium, Crohn’s disease patients do not have a fair chance to improve their condition. Increasing the level of F. prausnitzii in patients, by administering EXL01 for instance, could possibly lead to longer remission periods, a lower need for surgery, and an overall improved quality of life.
In other words, our lead candidate EXL01, a single F. prausnitzii strain drug-product, aims at giving patients a fair chance to fight.

Learn more about how EXL01 is being used in Crohn’s disease

Learn more about F. prau

Figure 1: Published F. prausnitzii's mechanisms of action.

Anti-inflammatory properties attributed to the F. prausnitzii species, include (1-3):

Induction of a tolerogenic cytokine profile on immune cells, in particular antigen presenting cells (dendritic cells, macrophages) and CD4CD8aa+ regulatory T cells, with elevated secretion of the anti-inflammatory cytokine IL10 and very low secretion of pro-inflammatory cytokines like IL12 and IFNγ-.
Butyrate production: Butyrate (a short chain fatty acid) can reduce intestinal mucosa inflammation through inhibiting nuclear factor-κB transcription factor activation, up-regulating peroxisome proliferator-activated receptor-γ, inhibiting IFN-γ, and promoting Foxp3+ regulatory T cells.
Production of the MAM protein which exhibits anti-inflammatory signalling in intestinal epithelial cells.

Furthermore, F. prausnitzii cells have been reported to reduce the severity of acute (4-6), chronic (7) and low grade (8) chemically induced inflammation in murine models.

In murine models of TNBS and DNBS induced colitis, intragastric administration of F. prausnitzii decreased the colitis severity in both severe and moderate chronic colitis models. The lower severity of colitis was associated with down regulation of myeloperoxidase, proinflammatory cytokines (IL12, IL6, and IFNγ) and effector T cell levels (5, 7).

Together, these findings indicate that F. prausnitzii plays a crucial role in maintaining gut physiology and host wellbeing. Due to the importance of the microbiota in the development of IBD, there is increasing interest in the development of microbiota modulating therapies, and F. prausnitzii represents an ideal candidate. It is a well characterised, extremely oxygen-sensitive, commensal, anti-inflammatory bacteria, which colonises the area of the gastro-intestinal tract in healthy individuals and is affected by inflammation in Crohn’s disease.

References:

Godefroy E, Alameddine J, Montassier E, et al. Expression of CCR6 and CXCR6 by Gut-Derived CD4(+)/CD8alpha(+) T-Regulatory Cells, Which Are Decreased in Blood Samples From Patients With Inflammatory Bowel Diseases. Gastroenterology. 2018;155(4):1205-17.
Lopez-Siles M, Duncan SH, Garcia-Gil LJ, et al. Faecalibacterium prausnitzii: from microbiology to diagnostics and prognostics. ISME J. 2017;11(4):841-52.
Sarrabayrouse G, Bossard C, Chauvin JM, et al. CD4CD8alphaalpha lymphocytes, a novel human regulatory T cell subset induced by colonic bacteria and deficient in patients with inflammatory bowel disease. PLoS Biol. 2014;12(4):e1001833.
Huang XL, Zhang X, Fei XY, et al. Faecalibacterium prausnitzii supernatant ameliorates dextran sulfate sodium induced colitis by regulating Th17 cell differentiation. World J Gastroenterol. 2016;22(22):5201-10.
Qiu X, Zhang M, Yang X, et al. Faecalibacterium prausnitzii upregulates regulatory T cells and anti-inflammatory cytokines in treating TNBS-induced colitis. J Crohns Colitis. 2013;7(11):e558-68.
Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105(43):16731-6.
Zhang M, Qiu X, Zhang H, et al. Faecalibacterium prausnitzii inhibits interleukin-17 to ameliorate colorectal colitis in rats. PLoS One. 2014;9(10):e109146.
Martin R, Chain F, Miquel S, et al. The commensal bacterium Faecalibacterium prausnitzii is protective in DNBS-induced chronic moderate and severe colitis models. Inflamm Bowel Dis. 2014;20(3):417-30.
Martin R, Miquel S, Benevides L, et al. Functional Characterization of Novel Faecalibacterium prausnitzii Strains Isolated from Healthy Volunteers: A Step Forward in the Use of F. prausnitzii as a Next-Generation Probiotic. Front Microbiol. 2017;8:1226.

LEARN MORE ABOUT CROHN’s DISEASE

The human gut microbiota is estimated to contain as many as 500 to 1000 different bacterial species, totalling 10¹³ bacterial cells. The gut microbiota concentration increases along the gastro-intestinal tract, reaching its maximum in the distal colon (10¹¹ bacteria/g of content). It has an important relationship with the host in maintaining human health (1-2). F. prausnitzii, a member of the Firmicutes phylum, is the most abundant species in the human intestinal microbiota of healthy adults and represents approximately 5% of the total faecal microbiota healthy adults (3-4), which extrapolates to 5 . 10¹¹ bacteria.The abundance and ubiquity of F. prausnitzii suggests that it is a major contributor to microbiota functions in healthy individuals, and the modulation of F. prausnitzii populations may be useful in preventive or therapeutic treatments (5).Alterations or imbalances in the microbial composition in the gastro-intestinal tract have been reported in Inflammatory Bowel Disease (IBD), most notably in Crohn’s disease. Accumulating evidence has revealed a diminished prevalence and abundance of the anti-inflammatory bacterium F. prausnitzii in the faecal samples of patients with Crohn’s disease (6); low abundance of F. prausnitzii has been associated with a higher risk of postoperative endoscopic recurrence (6-8) and a higher relapse risk (9-10). Furthermore, recovery of F. prausnitzii counts has been associated with the maintenance of remission in patients with Ulcerative Colitis and Crohn’s disease (11-12). Based on the lack of specific blood markers in IBD and the complexity of performing an endoscopy or biopsy, the proportion of F. prausnitzii, alone or in association with other gut microbiota features, has been proposed as a biomarker of disease activity and a predictor of clinical relapse (13-14).
Finally, a high level of F. prausnitzii is associated with a better response to treatment (15).

References:

Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science. 2005;308(5728):1635-8.
Sekirov I, Russell SL, Antunes LC, et al. Gut microbiota in health and disease. Physiol Rev. 2010;90(3):859-904.
Hold GL, Schwiertz A, Aminov RI, et al. Oligonucleotide probes that detect quantitatively significant groups of butyrate-producing bacteria in human feces. Appl Environ Microbiol. 2003;69(7):4320-4.
Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59-65.
Miquel S, Martin R, Bridonneau C, et al. Ecology and metabolism of the beneficial intestinal commensal bacterium Faecalibacterium prausnitzii. Gut Microbes. 2014;5(2):146-51.
Miquel S, Martin R, Rossi O, et al. Faecalibacterium prausnitzii and human intestinal health. Curr Opin Microbiol. 2013;16(3):255-61.
Mondot S, Lepage P, Seksik P, et al. Structural robustness of the gut mucosal microbiota is associated with Crohn's disease remission after surgery. Gut. 2016;65(6):954-62.
Sokol H, Lay C, Seksik P, et al. Analysis of bacterial bowel communities of IBD patients: what has it revealed? Inflamm Bowel Dis. 2008;14(6):858-67.
Wright EK, Kamm MA, Wagner J, et al. Microbial factors associated with postoperative Crohn's disease recurrence. J Crohns Colitis. 2017;11(2):191-203.
Busquets D, Mas-de-Xaxars T, Lopez-Siles M, et al. Anti-tumour necrosis factor treatment with adalimumab induces changes in the microbiota of Crohn's disease. J Crohns Colitis. 2015;9(10):899-906.
Rajca S, Grondin V, Louis E, et al. Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn's disease. Inflamm Bowel Dis. 2014;20(6):978-86.
Varela E, Manichanh C, Gallart M, et al. Colonisation by Faecalibacterium prausnitzii and maintenance of clinical remission in patients with ulcerative colitis. Aliment Pharmacol Ther. 2013;38(2):151-61.
Marlicz W, Skonieczna-Zydecka K, Dabos KJ, et al. Emerging concepts in non-invasive monitoring of Crohn's disease. Therap Adv Gastroenterol. 2018;11:1756284818769076.
Pascal V, Pozuelo M, Borruel N, et al. A microbial signature for Crohn's disease. Gut. 2017;66(5):813-22.
Magnusson MK, Strid H, Sapnara M, et al. Anti-TNF therapy response in patients with ulcerative colitis is associated with colonic antimicrobial peptide expression and microbiota composition. J Crohns Colitis. 2016;10(8):943-52.

Induction of remission
Aside from mild Ulcerative Colitis, which is usually treated with Mesalamine, the standard treatment for acute Crohn’s disease flares consists of the administration of the systemic corticosteroids Budesonide or Prednisone (orally or intravenously), according to disease severity and topography. Once symptoms have subsided, the dose is tapered and finally stopped. Other agents are then introduced to maintain remission, as outlined below (1-2).
If systemic steroid therapy does not induce remission, anti-TNF-α antibodies (infliximab, adalimumab, certolizumab pegol and golimumab), the anti-IL-12/23 antibody ustekinumab, the anti-integrin antibody vedolizumab, or a Janus kinase inhibitor (tofacitinib for UC only) can be used (1-2).
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Maintenance of remission
ECCO guidelines support the use of thiopurine immunomodulators (Azathioprine and Mercaptopurine) as effective maintenance therapy for both Crohn’s disease and Ulcerative Colitis (1,3). Amino salicylates can be used for maintenance in Ulcerative Colitis but are not effective in Crohn’s disease (2). Patients who easily become steroid dependent or who have frequent relapses, are recommended to receive immunosuppressive therapy; the first line of treatment is the administration of a thiopurine drug, such as Azathioprine or 6-Mercaptopurine. If poorly tolerated, Methotrexate is an alternative for the treatment of Crohn’s disease. If a relapse has been successfully treated with anti-TNF-α antibodies, the treatment can be continued to maintain remission (1, 2, 4).
For each major class of Inflammatory Bowel Disease (IBD), medications (5-aminosalicyclates, immunomodulators, biologic agents and small molecules), can be used alone or in combination, but there is a risk of relapse following the reduction or cessation of treatment (3). Treatment costs associated with indefinite maintenance therapy are considerable, and there may furthermore be some toxicity exposure due to the prolonged use of the treatment. On top of the increased risk of serious infection associated with the use of all immunosuppressants, there is also an increased risk of neoplasia (5). Indeed, risks associated with the long-term use of thiopurine in patients with IBD, include: elevated risk of lymphoproliferative disorders, nonmelanoma skin cancers, myeloid disorders and urinary tract cancers. The use of anti-TNF agents is associated with an increased risk of urinary tract cancers, melanoma and hepatosplenic T cell lymphoma (3,5).
A loss of response frequently leads to the incomplete control of the disease, and a need for frequent changes of therapeutics; intestinal damage accumulates, and most patients will ultimately require surgery; 50% of patients with Crohn’s disease undergo surgical treatment (removal of the entire colon and rectum, or in other cases the removal of damaged segments of the small bowel) within 10 years of receiving the diagnosis (2). Surgery, however, is not a cure. Disease typically recurs at the anastomosis or in the segments neighbouring the resected, diseased bowel segment in 10% to 60% of cases. 20% of patients who undergo surgical treatment, will need surgery again within 5 years (2). Thus, there is a large unmet medical need for new therapies with fewer side effects, to maintain patients with Crohn’s disease in remission for longer periods, while improving their overall quality of life and delaying or avoiding the need for invasive surgery.
There is no cure for Crohn’s disease. The main purpose of current treatments is to reduce inflammation to relieve symptoms by treating flare-ups to put the disease in remission and maintain remission. There is an urgent need to develop new, well tolerated treatments that maintain patients with Crohn’s disease in remission, without the serious side effects associated with some of the therapies in current use, while also improving the quality of life and delaying surgery. The isolation and manufacturing of a single F. prausnitzii strain (EXL01strain) from a healthy volunteer provides the opportunity to utilise the protective properties of F. prausnitzii on gut dysfunction mediated by inflammation. Based on the body of in vitro and in vivo data, it is anticipated that the delivery of a well characterised, nonmodified, single strain of F. prausnitzii to the site of inflammation in patients with Crohn’s disease, may provide a safe treatment to prolong maintenance of remission. The abundance of F. prausnitzii in healthy individuals suggests this approach is safe and may reduce the need for prolonged, conventional immunosuppressive therapy.

References:

Torres J, Bonovas S, Doherty G, et al. ECCO guidelines on therapeutics in Crohn's disease: medical treatment. J Crohns Colitis. 2020;14(1):4-22.
Wehkamp J, Gotz M, Herrlinger K, et al. Inflammatory Bowel Disease. Dtsch Arztebl Int. 2016;113(5):72-82.
Doherty G, Katsanos KH, Burisch J, et al. European Crohn's and Colitis Organisation Topical Review on Treatment Withdrawal ['Exit Strategies'] in Inflammatory Bowel Disease. Journal of Crohn's & colitis. 2018;12(1):17-31.
Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science. 2005;308(5728):1635-8.
Beaugerie L, Rahier JF, Kirchgesner J. Predicting, preventing, and managing treatment-related complications in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2020;18(6):1324-35 e2.

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