Antimicrobial treatment with the fixed-dose antibiotic combination RHB-104 for <i>Mycobacterium avium</i> subspecies <i>paratuberculosis</i> in Crohn’s disease: pharmacological and clinical implications

Savarino, Edoardo; Bertani, Lorenzo; Ceccarelli, L.; Bodini, Giorgia; Zingone, Fabiana; Buda, Andrea; Facchin, Sonia; Lorenzon, Greta; Marchi, Santino; Marabotto, Elisa; Bortoli, Nicola de; Savarino, Vincenzo; Costa, Francesco; Blandizzi, Corrado

doi:10.1080/14712598.2019.1561852

Cited by 17 publications

(13 citation statements)

References 84 publications

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“…Besides recombinant anti-inflammatory cytokines and inhibitors, there are few existing drugs repurposed for treating IBD. For instance, an anti-mycobacterium drug RHB-104 (product of RedHill Biopharma Ltd based in Tel-Aviv, Israel) was repurposed for CD, and it is in phase III trial [169]. Adacolumn is another example of an emerging treatment for IBD, which is a safe, non-drug intervention.…”

Section: Biologicsmentioning

confidence: 99%

Revisiting Inflammatory Bowel Disease: Pathology, Treatments, Challenges and Emerging Therapeutics Including Drug Leads from Natural Products

Yeshi

Ruscher

Hunter

et al. 2020

JCM

119

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Inflammatory bowel disease (IBD) is a chronic and life-long disease characterized by gastrointestinal tract inflammation. It is caused by the interplay of the host’s genetic predisposition and immune responses, and various environmental factors. Despite many treatment options, there is no cure for IBD. The increasing incidence and prevalence of IBD and lack of effective long-term treatment options have resulted in a substantial economic burden to the healthcare system worldwide. Biologics targeting inflammatory cytokines initiated a shift from symptomatic control towards objective treatment goals such as mucosal healing. There are seven monoclonal antibody therapies excluding their biosimilars approved by the US Food and Drug Administration for induction and maintenance of clinical remission in IBD. Adverse side effects associated with almost all currently available drugs, especially biologics, is the main challenge in IBD management. Natural products have significant potential as therapeutic agents with an increasing role in health care. Given that natural products display great structural diversity and are relatively easy to modify chemically, they represent ideal scaffolds upon which to generate novel therapeutics. This review focuses on the pathology, currently available treatment options for IBD and associated challenges, and the roles played by natural products in health care. It discusses these natural products within the current biodiscovery research agenda, including the applications of drug discovery techniques and the search for next-generation drugs to treat a plethora of inflammatory diseases, with a major focus on IBD.

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Section: Biologicsmentioning

confidence: 99%

Revisiting Inflammatory Bowel Disease: Pathology, Treatments, Challenges and Emerging Therapeutics Including Drug Leads from Natural Products

Yeshi

Ruscher

Hunter

et al. 2020

JCM

119

View full text Add to dashboard Cite

show abstract

“…Though the link of MAP zoonosis to Crohn's disease has been controversial for over one hundred years (13), validation of this association has come from studies showing Crohn's disease resolution with anti-mycobacterial therapy targeted against MAP (72)(73)(74)(75). Moreover, MAP is now linked to an increasing list of inflammatory and autoimmune diseases (13,76).…”

Section: Map and Human Diseasementioning

confidence: 99%

Warm, Sweetened Milk at the Twilight of Immunity - Alzheimer’s Disease - Inflammaging, Insulin Resistance, M. paratuberculosis and Immunosenescence

Dow

2021

Front. Immunol.

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This article prosecutes a case against the zoonotic pathogen Mycobacterium avium ss. paratuberculosis (MAP) as a precipitant of Alzheimer’s disease (AD). Like the other major neurodegenerative diseases AD is, at its core, a proteinopathy. Aggregated extracellular amyloid protein plaques and intracellular tau protein tangles are the recognized protein pathologies of AD. Autophagy is the cellular housekeeping process that manages protein quality control and recycling, cellular metabolism, and pathogen elimination. Impaired autophagy and cerebral insulin resistance are invariant features of AD. With a backdrop of age-related low-grade inflammation (inflammaging) and heightened immune risk (immunosenescence), infection with MAP subverts glucose metabolism and further exhausts an already exhausted autophagic capacity. Increasingly, a variety of agents have been found to favorably impact AD; they are agents that promote autophagy and reduce insulin resistance. The potpourri of these therapeutic agents: mTOR inhibitors, SIRT1 activators and vaccines are seemingly random until one recognizes that all these agents also suppress intracellular mycobacterial infection. The zoonotic mycobacterial MAP causes a common fatal enteritis in ruminant animals. Humans are exposed to MAP from contaminated food products and from the environment. The enteritis in animals is called paratuberculosis or Johne’s disease; in humans, it is the putative cause of Crohn’s disease. Beyond Crohn’s, MAP is associated with an increasing number of inflammatory and autoimmune diseases: sarcoidosis, Blau syndrome, autoimmune diabetes, autoimmune thyroiditis, multiple sclerosis, and rheumatoid arthritis. Moreover, MAP has been associated with Parkinson’s disease. India is one county that has extensively studied the human bio-load of MAP; 30% of more than 28,000 tested individuals were found to harbor, or to have harbored, MAP. This article asserts an unfolding realization that MAP infection of humans 1) is widespread in its presence, 2) is wide-ranging in its zoonosis and 3) provides a plausible link connecting MAP to AD.

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“…Consistent with their in vitro activity, the combination of clarithromycin, rifabutin and clofazimine, has shown efficacy as a primary treatment for Crohn’s disease [ 76 ]. Preliminary report from a multi-center, international open clinical trial of 331 participants with Crohn’s disease noted that adding anti- MAP therapy to standard therapy provided promising treatment effect [ [77] , [78] , [79] ].…”

Section: Countering Mycobacteria With Bcg And/or Antimicrobial Agentsmentioning

confidence: 99%

What is the evidence that mycobacteria are associated with the pathogenesis of Sjogren’s syndrome?

Dow

Chan

2021

Journal of Translational Autoimmunity

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Sjogren’s syndrome (SS) is a common, systemic autoimmune disorder primarily affecting the exocrine glands resulting in xerostomia and xerophthalmia. SS may also manifest with polyarthralgia, polyarthritis, polymyalgia, cutaneous/other organ vasculitis, interstitial lung disease, and/or various other disorders. The primary autoantibodies associated with SS and used as adjuncts to diagnosis are anti-Ro (SSA) and anti-La (SSB). The pathogenesis of SS is considered to involve genetic susceptibility and environmental triggers. An identified genetic susceptibility for SS lies in variants of the tumor necrosis factor alpha inducible protein 3 ( TNFAIP3 ) gene, the product of which is known as A20. Deficiency or dysfunction of A20 is known to induce macrophage inflammatory response to mycobacteria, potentially increasing the repertoire of mycobacterial antigens available and predisposing to autoimmunity via the paradigm of molecular mimicry; i.e. , providing a mechanistic link between genetic susceptibility to SS and exposure to environmental non-tuberculous mycobacteria (NTM). Mycobacterium avium ss. paratuberculosis ( MAP ) is an NTM that causes Johne’s disease, an enteritis of ruminant animals. Humans are broadly exposed to MAP or its antigens in the environment and in food products from infected animals. MAP has also been implicated as an environmental trigger for a number of autoimmune diseases via cross reactivity of its heat shock protein 65 (hsp65) with host-specific proteins. In the context of SS, mycobacterial hsp65 shares epitope homology with the Ro and La proteins. A recent study showed a strong association between SS and antibodies to mycobacterial hsp65. If and when this association is validated, it would be important to determine whether bacillus Calmette-Guerin (BCG) vaccination (known to be protective against NTM likely through epigenetic alteration of innate and adaptive immunity) and anti-mycobacterial drugs (to decrease mycobacterial antigenic load) may have a preventive or therapeutic role against SS. Evidence to support this concept is that BCG has shown benefit in type 1 diabetes mellitus and multiple sclerosis, autoimmune diseases that have been linked to MAP via hsp65 and disease-specific autoantibodies. In conclusion, a number of factors lend credence to the notion of a pathogenic link between environmental mycobacteria and SS, including the presence of antibodies to mycobacterial hsp65 in SS, the homology of hsp65 with SS autoantigens, and the beneficial effects seen with BCG vaccination against certain autoimmune diseases. Furthermore, given that BCG may protect against NTM, has immune modifying effects, and has a strong safety record of billions of doses given, BCG and/or anti-mycobacterial therapeutics should be studied in SS.

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Antimicrobial treatment with the fixed-dose antibiotic combination RHB-104 for Mycobacterium avium subspecies paratuberculosis in Crohn’s disease: pharmacological and clinical implications

Cited by 17 publications

References 84 publications

Revisiting Inflammatory Bowel Disease: Pathology, Treatments, Challenges and Emerging Therapeutics Including Drug Leads from Natural Products

Revisiting Inflammatory Bowel Disease: Pathology, Treatments, Challenges and Emerging Therapeutics Including Drug Leads from Natural Products

Warm, Sweetened Milk at the Twilight of Immunity - Alzheimer’s Disease - Inflammaging, Insulin Resistance, M. paratuberculosis and Immunosenescence

What is the evidence that mycobacteria are associated with the pathogenesis of Sjogren’s syndrome?

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