Macaque Matters: A veterinary perspective on refinement of group-housed macaques

Abstract

Non-human primates (NHPs), such as macaques species, are used in biomedical research because of their biological and physiological similarities to human. These similarities make them invaluable models for studying diseases, disorders and the development of preventative and therapeutic interventions that benefit human medicine. Despite its scientific importance, the use of NHPs raises significant ethical concerns. The ethical guidelines require adherence to the principles of the 3Rs—Replacement, Reduction, and Refinement. Although macaques are well established as research models, knowledge of their species-specific health and welfare needs remains incomplete. Continued refinement of housing, husbandry, and veterinary care is necessary to improve their wellbeing. This thesis investigates refinement areas in the daily care of socially housed macaques in a research facility from a veterinary perspective. The first refinement was linked to the indoor air quality (IAQ) in the animal enclosures. Therefore, to refine housing, the indoor air flow, and air quality were assessed. While measured values stayed within human threshold limit values, the impact of chronic low-level exposure on macaques is unknown. Species-specific thresholds could improve and sustain IAQ in NHP housing. Secondly, chronic intermittent diarrhea poses a common welfare challenge in captive rhesus macaques, yet its etiology is often unclear. Nutritional factors are suspected contributors. A longitudinal crossover diet study compared several pelleted diets differing mainly in fiber and lactose content. The results showed that lactose-free diets reduced diarrhea incidence, supported by a microbiome signature consistent with lactose intolerance. Microbiome analysis proved to be a valuable diagnostic tool. However, traditional sequencing can be costly. Therefore, this thesis also developed an AI model capable of predicting key microbial markers directly from fecal-smear images. Thirdly, there are very few medications with scientifically tested dosages for macaques. As a result, treatments are often based on dosages used in other animals, without proven effectiveness for macaques. Therefore, to refine the veterinary care for macaques, dosage and effectivity of two different medicines were evaluated. We evaluated subdermal etonogestrel (ENG) implants as a contraceptive method for group-housed macaques. ENG proved effective, reversible, and long-acting in both rhesus and cynomolgus macaques. In addition, the pharmacokinetics, microbiome, and resistome effects of long-acting ampicillin (Albipen® LA) were assessed. A dose of 25 mg/kg IM maintained therapeutic plasma levels for 48 hours, reducing handling frequency. Single-dose treatment caused short-term microbiome disturbance and increased beta-lactam resistance genes, underscoring the need for judicious antibiotic use. This thesis shows that significant refinement opportunities remain in the care of macaques. Improvements in housing, dietary management, and veterinary treatment, as well as innovative tools such as AI-driven microbiome assessment, can meaningfully improve health and welfare. These efforts demonstrate the ongoing commitment to the 3Rs principles, ensuring that the care for macaques in biomedical research meets high standards of care.