Successful treatment of asymptomatic or clinically terminal bovine Mycobacterium avium subspecies paratuberculosis infection (Johne's disease) with the bacterium Dietzia used as a probiotic alone or in combination with dexamethasone

Abstract

A naturally occurring gastrointestinal disease, primarily of ruminants (Johne disease), is a chronic debilitating disease that is caused by Mycobacterium avium subspecies paratuberculosis (MAP). MAP infection occurs primarily in utero and in newborns. Outside our Dietzia probiotic treatment, there are no preventive/curative therapies for bovine paratuberculosis. Interestingly, MAP is at the center of controversy as to its role in (cause of) Crohn disease (CD) and more recently, its role in diabetes, ulcerative colitis, and irritable bowel syndrome (IBS); the latter two, like CD, are considered to be a result of chronic intestinal inflammation. Treatments, both conventional and biologic agents, which induce and maintain remission are directed at curtailing processes that are an intricate part of inflammation. Most possess side effects of varying severity, lose therapeutic value, and more importantly, none routinely result in prevention and/or cures. Based on (a) similarities of Johne disease and Crohn disease, (b) a report that Dietzia inhibited growth of MAP under specific culture conditions, and (c) findings that Dietzia when used as a probiotic, (i) was therapeutic for adult bovine paratuberculosis, and (ii) prevented development of disease in MAP-infected calves, the goal of the present investigations was to design protocols that have applicability for IBD patients. Dietzia was found safe for cattle of all ages and for normal and immunodeficient mice. The results strongly warrant clinical evaluation as a probiotic, in combination with/without dexamethasone..

Acknowledgements

This research was funded, in part, by NIH Grant R01AI027331 (prior to retirement from Univ. WI-RF) and by Altick Associates, River Falls, WI. I thank William D. Richards for the initial ICON 6 isolate (Dietzia) and Dr. Craig Van Kampen for statistical analysis and editorial assistance. The sponsors, outside their funding, had no involvement in any part of the study.

Conflict of Interest

The author is a partner in Altick Associates, in SCVF, as well as a member of Paralab, LLC, which is the assignee of a patent application covering the Dietzia technology presented in this paper.

Figures and Tables

Figure 1 Photographs of Stage IV, end-stage, diseased cow, Green-4, before and after Dietzia treatment. Photo on the left is prior to treatment and photo on the right is four months post-treatment: note increase in body mass and improved coat appearance.

Figure 2 Longitudinal changes in body weight, milk production, ELISA values and fecal MAP for Stage IV cow, Green-4. (A) Dashed line is body weight and solid line is official DHIA weight of milk produced/day. (B) Solid line is ELISA OD405 nm values and dashed line is fecal MAP. Symbol (+) signifies a positive AGID. (C) Dose (viable colony forming units, cfu) of Dietzia.

Figure 3 Longitudinal ELISA values for seven individual Stage II or III cows considered cured after Dietzia treatment. Vertical lines with animal's identification number indicate the time at which Dietzia treatment was terminated. Thin dashed lines denote best-fit of ELISA OD405 nm values. BL is 1.4 ELISA-positive/negative cutoff. As discussed in the text, during the initial months of treatment, the best-linear-fit curves declined to negative values (<1.4), suggesting the absence of systemic MAP (animal was cured)

Figure 4 Longitudinal ELISA values for cow with Stage II, then Stage I and finally Stage IV disease (biphasic ELISA changes) at different doses of Dietzia. Thin dashed lines are best-fit for ELISA OD405 nm values. BL is 1.4 ELISA-positive/negative cutoff.

Figure 5 Longitudinal ELISA and fecal values for cow, April, with Stage II or IV disease at different doses of Dietzia and dexamethasone. Upper panel. Solid line is ELISA OD405 nm values and dashed line is fecal MAP. Symbol (+) signifies a positive AGID. BL is 1.4 ELISA-positive/negative cutoff. Lower panel. Dose of Dietzia and dexamethasone.

Figure 6 Longitudinal ELISA and fecal values for cow, 232, with initial Stage II and then Stage III disease at different doses of Dietzia and dexamethasone. Upper panel, solid line is ELISA OD405 nm values and dashed line is fecal MAP. Symbol (+) signifies a positive AGID. Thin dashed lines denote best-fit of ELISA values. BL is 1.4 ELISA-positive/negative cutoff. Lower panel, dose of Dietzia and dexamethasone.

Figure 7 Longitudinal ELISA and fecal values for cow, Trixie, with lifetime intermittent Stage II or III disease at different doses of Dietzia and dexamethasone. Upper panel. Solid line is ELISA OD405 nm values and dashed line is fecal MAP. Symbol (+) signifies a positive AGID. Thin dashed lines denote best-fit of ELISA values. BL is 1.4 ELISA-positive/negative cutoff. Lower panel. Dose of Dietzia and dexamethasone.

Figure 8 Longitudinal ELISA and fecal values for cow, 255, with initial Stage III disease at different doses of Dietzia and dexamethasone. Solid line is ELISA OD405 nm values and dashed line is fecal MAP. Symbol (+) signifies a positive AGID. BL is 1.4 ELISA-positive/negative cutoff. Start and stop Dietzia shown by vertical lines.

Table 1 Parameters of Dietzia-treated and non-treated Stage II or III paratuberculosis cows

Table 2 Dietzia plus dexamethasone treatment of Stage III or IV paratuberculosis cows