• Mycobacterium abscessus species
• lymphangioleiomyomatosis
• nontuberculous mycobacterial pulmonary disease
• sirolimus

• Humans
• Female
• Middle Aged
• Lymphangioleiomyomatosis/drug therapy
• Lymphangioleiomyomatosis/diagnosis
• Mycobacterium Infections, Nontuberculous/drug therapy
• Mycobacterium Infections, Nontuberculous/diagnosis
• Mycobacterium Infections, Nontuberculous/etiology
• Sirolimus/adverse effects
• Sirolimus/therapeutic use
• Mycobacterium abscessus/isolation & purification
• Anti-Bacterial Agents/therapeutic use
• Anti-Bacterial Agents/adverse effects
• Lung Transplantation/adverse effects

• Crohn’s disease (CD)
• Johne’s disease (JD)
• Mycobacterium avium subspecies paratuberculosis (MAP)

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.

• Alzheimer’s disease
• Crohn’s disease
• Johne’s disease
• MAP
• Mycobacterium avium ss. paratuberculosis
• autophagy
• insulin resistance
• rifampin

Pathogenic mycobacteria species may subvert the innate immune mechanisms and can modulate the activation of cells that cause disease in the skin. Cutaneous mycobacterial infection may present different clinical presentations and it is associated with stigma, deformity, and disability. The understanding of the immunopathogenic mechanisms related to mycobacterial infection in human skin is of pivotal importance to identify targets for new therapeutic strategies. The occurrence of reactional episodes and relapse in leprosy patients, the emergence of resistant mycobacteria strains, and the absence of effective drugs to treat mycobacterial cutaneous infection increased the interest in the development of therapies based on repurposed drugs against mycobacteria. The mechanism of action of many of these therapies evaluated is linked to the activation of autophagy. Autophagy is an evolutionary conserved lysosomal degradation pathway that has been associated with the control of the mycobacterial bacillary load. Here, we review the role of autophagy in the pathogenesis of cutaneous mycobacterial infection and discuss the perspectives of autophagy as a target for drug development and repurposing against cutaneous mycobacterial infection.

• autophagy
• drug development
• mycobacteria
• skin
• skin cells

• autophagy
• host-directed therapies
• host–microbe interactions
• mycobacteria
• non-tuberculous mycobacteria
• vaccines

• R01 AI127711 NIAID NIH HHS
• R01 AI127715 NIAID NIH HHS

Crohn’s disease (CD) is rising in incidence and has a high morbidity and increased mortality. Current treatment use immunosuppressives but efficacy is suboptimal, and relapse is common. It has been shown that there is an imbalance present in the gut microbiome (dysbiosis) in CD with a possible infective aetiology—Mycobacterium avium subsp. paratuberculosis (MAP) being the most proposed. Antibacterial therapy and Faecal Microbiota Transplantation (FMT) are emerging treatments which can result in clinical and endoscopic remission, if employed correctly. The objective of this study was to report on the treatment and clinical outcomes of patients with CD in prolonged remission.

Ten patients were identified to have achieved prolonged remission for 3–23 years (median 8.5 years). Of these, 7/10 took targeted Anti-MAP therapy (AMAT) for a median 36 months and then ceased AMAT treatment. After stopping AMAT five patients underwent Faecal Microbiota Transplantation (FMT) (average four infusions). In 4/7, AMAT was combined with infliximab (mean of six infusions) that was withdrawn within 6 months after fistulae resolution. One patient achieved deep mucosal healing with AMAT alone. Of the 3/10 patients not prescribed AMAT, one had a combination of anti-inflammatory agents and a single antibiotic (metronidazole) followed by FMT. The other two received only FMT for Clostridioides difficile Infection.

Prolonged remission has been achieved for 3–23 years with individualised treatments, with the majority using AMAT ± infliximab and FMT. Treatment with antibiotics and/or FMT provides a potential new avenue for treatment of CD. These findings should stimulate thinking, investigations and better therapy against MAP and the dysbiosis of the gut flora, to enable higher rates of prolonged remission.

• Anti-bacterial therapy
• Crohn disease
• Faecal microbiota transplant
• Inflammatory bowel disease
• Mycobacterium paratuberculosis

Prospective trials of anti-mycobacterial antibiotic therapy (AMAT) have proven efficacious in Crohn’s disease (CD) but use as first-line treatment in CD has not been evaluated. This paper reports the outcomes of patients with CD treated with first-line AMAT. This paper consists of a case series of treatment-naïve CD patients who received AMAT as first-line treatment between 2007 and 2014 at a single center. AMAT treatment consisted of rifabutin, clofazimine and clarithromycin, plus either ciprofloxacin, metronidazole or ethambutol. Symptoms, inflammatory blood markers, colonoscopy and histology results, in addition to, the Crohn’s Disease Activity Index (CDAI) were tabulated from patients’ clinical records, and descriptive statistics were conducted. A Wilcoxon signed-rank test assessed the difference in CDAI scores before and while on AMAT. The statistical significance was set at 5%. Clinical remission (CDAI < 150) with rapid improvement in clinical symptoms and inflammatory markers was seen in all eight patients receiving AMAT as sole therapy by 6 weeks. In all eight patients, the median CDAI score decreased significantly, from 289 prior to treatment to 62 at the 12-month follow-up (p < 0.001). Follow-up colonoscopies showed healing of CD ulcers, no visible mucosal inflammation, restoration of normal vascular patterns and complete mucosal healing on histology samples. AMAT as first-line therapy demonstrated a rapid improvement of Crohn’s disease (not previously seen when used as second-line therapy).

• Crohn’s disease
• Mycobacterium avium subspecies paratuberculosis
• anti-bacterial agents
• inflammatory bowel disease
• mucosal healing

• Blau syndrome
• CARD15
• Crohn’s
• HERV
• HSP65
• Hashimoto’s thyroiditis
• Johne’s
• MAP
• Mycobacterium avium ss. paratuberculosis
• Parkinson’s disease
• SLC11a1
• T1D
• TRIGR study
• ZnT8
• lupus
• molecular mimicry
• multiple sclerosis
• rheumatoid arthritis
• sarcoidosis
• type 1 diabetes mellitus
• zoonosis

• Assignment
• FKBP
• Mycobacterium tuberculosis
• NMR

• Carbon Isotopes
• Mycobacterium tuberculosis/enzymology
• Nitrogen Isotopes
• Nuclear Magnetic Resonance, Biomolecular
• Protein Structure, Secondary
• Protons
• Tacrolimus Binding Protein 1A/chemistry

• Johne’s disease
• Mycobacterium avium subsp. paratuberculosis
• mutant bank
• pathogenesis
• transposon mutagenesis

Mycobacterium avium subspecies paratuberculosis (MAP) is the causative agent of Johne’s disease in ruminants and is associated with Crohn’s disease (CD) in humans, although the latter remains controversial. In this study, we investigated the ability of MAP to adapt to anaerobic growth using the “Wayne” model of non-replicating persistence (NRP) developed for M. tuberculosis.

All strains adapted to anaerobiosis over time in a manner similar to that seen with MTB. Susceptibility to 12 antibiotics varied widely between strains under aerobic conditions. Under anaerobic conditions, no drugs caused significant growth inhibition (>0.5 log) except metronidazole, resulting in an average decrease of ~2 logs.

These results demonstrate that MAP is capable of adaptation to NRP similar to that observed for MTB with differential susceptibility to antibiotics under aerobic versus anaerobic conditions. Such findings have significant implications for our understanding of the pathogenesis of MAP in vivo and the treatment of CD should this organism be established as the causative agent.

• Anti-TNFα
• Crohn’s disease
• MAP
• RHB-104
• TNFα
• cytokines
• granuloma
• mycobacterium paratuberculosis

• Legionella
• amoeba
• antibiotics
• antivirulence
• calcineurin
• intracellular replication
• macrophage
• pathogen vacuole
• screen
• structure−activity relationship (SAR)
• type IV secretion

The possibility of an infectious origin in inflammatory bowel disease (IBD) has been postulated since the first description of Crohn’s disease (CD). Many observations implicate bacteria as a trigger for the development of CD: lesions occur in regions with higher bacterial concentrations; aphthous ulcers occur in Peyer’s patches; inflammation resolves when the fecal stream is diverted and is reactivated following reinfusion of bowel contents; severity of the disease is correlated with bacterial density in the mucosa; granulomas can contain bacteria; and susceptible mice raised in germ-free conditions develop inflammation when bacteria are introduced in the 1990’s, several studies sought to establish a relationship with viral infections and the onset of IBD, finally concluding that no direct link had been demonstrated. In the past fifteen years, evidence relating IBD pathogenesis to Mycobacterium avium paratuberculosis, salmonella, campylobacter, etc., has been found. The tendency now under discussion to regard microbiota as the primary catalyst has led to the latest studies on microbiota as pathogens, focusing on Escherichia coli, mainly in ileal CD. The present review discusses the literature available on these “bugs”.

• Inflammatory bowel disease
• Crohn’s disease
• Ulcerative colitis
• Bacteria
• Virus
• Pathogenesis

• Crohn’s disease
• Helicobacter pylori
• Inflammatory bowel disease
• Johne’s disease
• Mycobacterium avium subspecies paratuberculosis
• prevention
• treatment trials

The origin of inflammatory bowel disease is unknown. Attempts have been made to isolate a microorganism that could explain the onset of inflammation, but no pathological agent has ever been identified. Johne’s disease is a granulomatous chronic enteritis of cattle and sheep caused by Mycobacterium avium subspecies paratuberculosis (MAP) and shows some analogies with Crohn’s disease (CD). Several studies have tried to clarify if MAP has a role in the etiology of CD. The present article provides an overview of the evidence in favor and against the “MAP-hypothesis”, analyzing the methods commonly adopted to detect MAP and the role of antimycobacterial therapy in patients with inflammatory bowel disease. Studies were identified through the electronic database, MEDLINE, and were selected based on their relevance to the objective of the review. The presence of MAP was investigated using multiple diagnostic methods for MAP detection and in different tissue samples from patients affected by CD or ulcerative colitis and in healthy controls. On the basis of their studies, several authors support a close relationship between MAP and CD. Although increasing evidence of MAP detection in CD patients is unquestionable, a clear etiological link still needs to be proven.

• Mycobacterium avium paratuberculosis
• Crohn’s disease
• Inflammatory bowel disease
• Johne’s disease
• Mycobacterial protein tyrosine phosphatase

• Animals
• Anti-Bacterial Agents/therapeutic use
• Bacteriological Techniques
• Crohn Disease/diagnosis
• Crohn Disease/drug therapy
• Crohn Disease/epidemiology
• Crohn Disease/microbiology
• Humans
• Intestines/drug effects
• Intestines/microbiology
• Mycobacterium avium subsp. paratuberculosis/drug effects
• Mycobacterium avium subsp. paratuberculosis/pathogenicity
• Paratuberculosis/diagnosis
• Paratuberculosis/drug therapy
• Paratuberculosis/epidemiology
• Paratuberculosis/microbiology
• Predictive Value of Tests
• Risk Factors
• Treatment Outcome

• Clofazimine
• Mycobacterium avium subspecies paratuberculosis
• Thioguanine
• Tuberculosis
• Vitamin A
• Vitamin D

• Animals
• Cell Survival/drug effects
• Cells, Cultured
• Chronic Disease
• Disease Models, Animal
• Female
• Glaucoma/pathology
• Glaucoma/physiopathology
• Neuroprotective Agents/pharmacology
• Ocular Hypertension/pathology
• Ocular Hypertension/physiopathology
• Rats
• Rats, Sprague-Dawley
• Retinal Ganglion Cells/drug effects
• Retinal Ganglion Cells/pathology
• Retinal Ganglion Cells/physiology
• Sirolimus/pharmacology

Autophagy is a cellular response to intracellular pathogens including mycobacteria and is induced by the direct inhibitors of mammalian target of Rapamycin (mTOR), a major negative regulator of autophagy. Autophagy induction by mTOR inhibition (mTOR dependent autophagy), through chemical means or starvation, leads to mycobacterial killing in infected cells. However, previous work by our group has shown that mycobacterial infection of macrophages naturally induces both autophagy and mammalian target of Rapamycin (mTOR) activity (mTOR independent autophagy). In the current work, we further explore the relationship between mTOR activity and mycobacterial killing in macrophages.

While low concentrations of the mTOR inhibitors, Rapamycin, Torin 1, and Torin 2, can effectively reduce or block mTOR activity in response to lipopolysaccharides (LPS) or mycobacteria, higher concentrations (10 uM) are required to observe Mycobacterium smegmatis killing. The growth of M. smegmatis was also inhibited by high concentrations of Rapamycin in LC3B and ATG5 deficient bone marrow derived macrophages, suggesting that non-autophagic mechanisms might contribute to killing at high doses. Since mycobacterial killing could be observed only at fairly high concentrations of the mTOR inhibitors, exceeding doses necessary to inhibit mTOR, we hypothesized that high doses of Rapamycin, the most commonly utilized mTOR inhibitor for inducing autophagic killing, may exert a direct bactericidal effect on the mycobacteria. Although a short-term treatment of mycobacteria with Rapamycin did not substantially affect mycobacterial growth, a long-term exposure to Rapamycin could impact mycobacterial growth in vitro in select species.

This data, coupled with previous work from our laboratory, further indicates that autophagy induction by mTOR inhibition is an artificial means to increase mycobacterial killing and masks more relevant endogenous autophagic biochemistry that needs to be understood.

• Culture Techniques/methods
• Dose-Response Relationship, Drug
• Humans
• Mycobacterium avium/drug effects
• Mycobacterium avium/growth & development
• Mycobacterium tuberculosis/drug effects
• Mycobacterium tuberculosis/growth & development
• Radiometry
• Vitamin A/metabolism
• Vitamin A/pharmacology
• Vitamin D/pharmacology
• beta Carotene/pharmacology

• Crohn's disease
• IS900
• Johne's disease
• Mycobacterium avium subsp. paratuberculosis
• mycobacterium
• paratuberculosis

• Colitis, Ulcerative/physiopathology
• Crohn Disease/microbiology
• Crohn Disease/physiopathology
• Culture Media
• Humans
• Mycobacterium avium subsp. paratuberculosis/drug effects
• Mycobacterium avium subsp. paratuberculosis/growth & development
• NAD/chemistry
• NAD/pharmacology
• Niacin/chemistry
• Niacin/pharmacology
• Niacinamide/chemistry
• Niacinamide/pharmacology
• Nicotiana/chemistry

Thyrotoxicosis is conceptualized as an “autoimmune” disease with no accepted infectious etiology. There are increasingly compelling data that another “autoimmune” affliction, Crohn disease, may be caused by Mycobacterium avium subspecies paratuberculosis (MAP). Like M. tb, MAP is systemic. We hypothesized that some cases of thyrotoxicosis may be initiated by a MAP infection. Because other thioamides treat tuberculosis, leprosy and M. avium complex, we hypothesized that a mode of action of some thioamide anti-thyrotoxicosis medications may include MAP growth inhibition.

The effect of the thioamides, thiourea, methimazole and 6-propo-2-thiouracil (6-PTU) were studied in radiometric Bactec® culture, on ten strains of three mycobacterial species (six of MAP, two of M. avium and two of M. tb. complex). Data are presented as “cumulative growth index,” (cGI) or “percent decrease in cumulative GI” (%-ΔcGI).

Methimazole was the most effective thioamide at inhibiting MAP growth. At 128µg/ml: MAP UCF-4; 65%-ΔcGI & MAP ATCC 19698; 90%-ΔcGI. Thiourea inhibited MAP “Ben” maximally; 70%-ΔcGI. Neither methimazole nor thiourea inhibited M. avium or M. tb. at the doses tested. 6-PTU has no inhibition on any strain studied, although a structurally analogous control, 5-PTU, was the most inhibitory thioamide tested.

We show inhibition of MAP growth by the thioamides, thiourea and methimazole in culture. These data are compatible with the hypothesis that these thioamides may have anti-prokaryotic in addition to their well-established eukaryotic actions in thyrotoxic individuals.

• Anti-Bacterial Agents/pharmacology
• Methimazole/pharmacology
• Mycobacterium avium/drug effects
• Mycobacterium avium/growth & development
• Thiourea/pharmacology

• Crohn Disease/microbiology
• Crohn Disease/pathology
• Humans
• Mycobacterium avium subsp. paratuberculosis
• Paratuberculosis/complications

Mycobacterium avium subspecies paratuberculosis (MAP) causes a chronic wasting diarrheal disease in ruminants called Johne's disease, that is evocative of human inflammatory bowel disease (IBD). Agents used to treat IBD, called "anti-inflammatories", immuno-modulators" and "immuno-suppressants" inhibit MAP growth in culture. We concluded that, unknowingly, the medical profession has been treating MAP since sulfasalazine's introduction in 1942. Monensin, called a "Growth Enhancer" in cattle, ameliorates Johne's disease without a documented mechanism of action. We hypothesized that Monensin would inhibit MAP in culture.

Using the radiometric ¹⁴CO₂ Bactec^® system, that expresses mycobacterial growth in arbitrary growth index (GI) units, we studied the effect of Monensin on the growth kinetic of MAP isolated from humans with IBD ("Dominic", "Ben" & UCF-4) and cattle with Johne's disease (303 & ATCC 19698.) Results are expressed as percent inhibition of cumulative GI (%–ΔcGI).

The positive control Clofazimine inhibits every strain tested. The negative controls Cycloheximide & Phthalimide, have no inhibition on any MAP strain. Monensin has dose dependent inhibition on every MAP strain tested. The most susceptible human isolate was UCF-4 (73% – ΔcGI at 1 μg/ml) and bovine isolate was 303 (73% – ΔcGI at 4 μg/ml.) Monensin additionally inhibits M. avium ATCC 25291 (87% – ΔcGI at 64 μg/ml) & BCG (92% – ΔcGI at 16 μg/ml).

We show that in radiometric culture the "Growth Enhancer" Monensin causes dose dependent inhibition of mycobacteria including MAP. We posit that the "Growth Enhancer" effect of Monensin may, at least in part, be due to inhibition of MAP in clinical or sub-clinical Johne's disease.