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Immunostimulant, hepatoprotective, and nephroprotective potential of Bacillus subtilis (NMCC-path-14) in comparison to dexamethasone in alleviating CFA-induced arthritis

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Abstract

To investigate and compare efficacy as well as safety of Bacillus subtilis and dexamethasone (Dexa) in complete Freund’s adjuvant (CFA)-induced arthritis, we used glucocorticoid monotherapy (Dexa 5 mg/kg/day) and B. subtilis (1 × 108 CFU/animal/day p.o) as pre-treatment and concurrent treatment for a duration of 35 days. Specific emphasis was on chronic aspect of this study since long-term use of Dexa is known to produce undesirable side effects. Treatment with Dexa significantly attenuated the arthritic symptoms but produced severe side effects like weight loss, increased mortality, immunosuppression, and altered histology of liver, kidney, and spleen. Oxidative stress was also elevated by Dexa in these organs which contributed to the damage. Treatment with B. subtilis improved symptoms of arthritis without producing any deleterious side effects as seen with Dexa therapy. Immunohistochemistry (IHC) profile revealed decreased expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), and increased nuclear factor erythroid 2–related factor 2 (Nrf-2) expression by B. subtilis and Dexa treatment in ankle joint of arthritic mice. Radiological scores were also improved by both treatments. This study concludes that B. subtilis could be an effective alternative for treating arthritis than Dexa since it does not produce life-threatening side effects on prolong treatment.

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Data availability

The datasets generated and analyzed in the present study are available from the corresponding author upon reasonable request.

Abbreviations

RA:

Rheumatoid arthritis

MAPK:

Mitogen-activated protein kinase

ERK:

Extracellular signal-regulated kinase

ROS:

Reactive oxygen species

Dexa:

Dexamethasone

GC:

Glucocorticoids

CFU:

Colony-forming unit

CFA:

Complete Freund’s adjuvant

NC:

Normal control

AC:

Arthritic control

PBT:

Probiotics

BS-PT:

Bacillus subtilis Pre-treatment

BS-CT:

Bacillus subtilis Concurrent treatment

IL:

Interleukin

TNF-α:

Tumor necrosis factor alpha

N/S:

Normal saline

Nrf-2:

Nuclear factor erythroid 2–related factor 2

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

ABC:

Avidin-biotin–peroxidase complex

DAB:

3,3-Diaminobenzidine

H2O2 :

Hydrogen peroxide

GSH:

Reduced glutathione

GST:

Glutathione S-transferase

CAT:

Catalase

MDA:

Malonaldehyde

NO:

Nitric oxide

RBC:

Red blood cells

WBC:

White blood cells

Hb:

Hemoglobin

Hct:

Hematocrit

ALT:

Alanine transaminase

AST:

Aspartate aminotransferase

ALP:

Alkaline phosphatase

H & E:

Hematoxylin and eosin

HI:

Heme-agglutination inhibition

anti-NDV:

Anti-Newcastle disease vaccine

MDA:

Malonaldehyde

NO:

Nitric oxide

IHC:

Immunohistochemistry

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Acknowledgements

The authors would like to express special gratitude to Dr. Muhammad Mazhar Hussain, Dr. Shahzad Azam, and Dr. Muhammad Nafees (Fazaia Medical College, Air University, Islamabad), and Dr. Ihsan ul Haq and Dr. Salman Khan (Department of Pharmacy, QAU, Islamabad) for all their help and guidance without which this study would not have been possible.

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Authors and Affiliations

  1. Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

    Muhammad Usama Mazhar, Sadaf Naz, Tayyaba Zulfiqar, Jehan Zeb Khan & Muhammad Khalid Tipu

  2. National Institute for Genomics and Advanced Biotechnology (NIGAB), National Agricultural Research Centre (NARC), Islamabad, Pakistan

    Shakira Ghazanfar

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  1. Muhammad Usama Mazhar
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  2. Sadaf Naz
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  3. Tayyaba Zulfiqar
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Contributions

MUM, SN, TZ, and JK designed and performed research including behavioral and biochemical assays. SG was responsible for isolation, identification, and confirmation of the strain and provision of dose preparation of probiotic used in this study. MKT and MUM analyzed the data and drafted the manuscript. MKT supervised the project. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Muhammad Khalid Tipu.

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All animal studies were approved and performed according to the bioethical committee protocols of Quaid-i-Azam University, Islamabad, for the care and use of laboratory animals (Approval no. BEC-FBS-QAU2021-338).

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The authors declare no competing interests.

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Mazhar, M.U., Naz, S., Zulfiqar, T. et al. Immunostimulant, hepatoprotective, and nephroprotective potential of Bacillus subtilis (NMCC-path-14) in comparison to dexamethasone in alleviating CFA-induced arthritis. Naunyn-Schmiedeberg's Arch Pharmacol 397, 3275–3299 (2024). https://doi.org/10.1007/s00210-023-02814-w

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