Background/Purpose: Neuropsychiatric lupus (NPSLE) is a common and prognostically significant manifestation of SLE, affecting 20-40% of lupus patients. The ACR identified 19 clinical syndromes associated with NPSLE, which range from severe manifestations such as psychosis and transverse myelitis to milder involvement in the form of headaches, mood disorders, and cognitive deficits.The gut microbiota has been implicated in the pathogenesis of autoimmune diseases, including SLE. Microbes significantly influence mammalian metabolism, the immune system, and behavior. The gut-brain axis is a communication network connecting the CNS with the gut’s enteric nervous system, facilitating information exchange between the brain and digestive functions. Recent studies emphasize the gut microbiota’s crucial role in this relationship.Our goal was to examine whether modulation of the gut-brain axis using a short course of antibiotic treatment would affect the development, progression, and severity of neuropsychiatric disease in the MRL/lpr strain.

Methods: Antibiotic Treatment: 6-week-old MRL/MpJ and MRL/lpr mice were given vancomycin 0.5 g/L in drinking water for 2 weeks, with the water being refreshed every 3 days. Control mice of these strains received regular water with no additives. Behavioral Testing: After 2 weeks of treatment, the mice were given 4 weeks for gut microbiome recovery. Behavioral testing began at 12 weeks of age, and included standard tests for depressive-like behavior (Porsolt swim test), thermal hypersensitivity (hot plate), anxiety (elevated plus maze (EPM)), and cognition/memory (novel object location (NOL)), with rest periods of 1-3 days between the tests.

Results: Porsolt swim test: MRL/lpr showed significantly worse depressive-like (despair) behavior as shown by increased immobility in the Porsolt swim test (75.1+/-2.2 seconds) as compared to the MRL/MpJ group (65.3+/-4.7; P < 0.0001). Moreover, antibiotic-treated MRL/lpr showed significant attenuation of this phenotype (less immobility), as compared to non-treated MRL/lpr mice (Figure 1A). Hot plate: Antibiotic treated MRL/lpr mice showed significantly increased latency until hind paw licking (114.5+/-10.7 vs 98+/-7.4 in the untreated group, p=0.029), indicating decreased thermal hypersensitivity and improved nociception. No significant change was observed in thermal hypersensitivity with antibiotic treatment in the MRL/MpJ strain (Figure 1B). EPM: Untreated MRL/MpJ mice displayed less anxiety as compared to MRL/lpr mice, as reflected by significantly more time spent in the open arms (15.5+/- 9.9 vs 1.9+/-1.2, p=0.018). Notably, antibiotic treated MRL/lpr mice trended to less anxiety compared to the untreated MRL/lpr group (Figure 2A). Novel Object Location: Although untreated MRL/lpr mice did appear to have the worst performance on this cognitive test of spatial memory, no significant differences were observed between the groups (Figure 2B).

Conclusion: A short term course of intestinal decontamination with oral vancomycin attenuates several key features of neuropsychiatric disease in MRL/lpr lupus mice. Studies to determine the effects on other disease features and elucidate the mechanisms of protection are in progress.

Figure 1: A. In the Porsolt swim test, the mouse is placed in a water filled cylinder for 10 minutes. Mobility time was measured, and immobility is calculated based on the ratio of time that the mice were immobile (i.e. displaying despair, or depressive-like behavior) over the total time. B. To test thermal hypersensitivity, mice are placed on a plate heated to a temperature of 40°C and increasing to 52°C within three minutes. The latency, or response time, for the mice to lick their hind paws was measured for analysis.

Figure 2: A. To assess for anxiety, the elevated plus maze test was employed. The maze was placed in a dark infra-red lit room and the mouse placed on the maze for 5 minutes. Time spent in open arms compared to the total time was recorded and analyzed using Ethovision software. B. In assessing memory with the novel object location test, each mouse was first placed in an arena with two similar objects for 5 minutes. After an interval of 60-90 minutes, the mouse is put in the same arena in which one of the objects was moved to a new location. The preference index (normal >50%) was calculated by dividing the time spent in the area of the newly moved object by the total time spent in both object zones.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/short-term-antibiotic-treatment-improves-the-neurobehavioral-phenotype-of-mrl-lpr-mice/