Pica is far more than an odd behavioral quirk. In sheep production systems it manifests as the persistent ingestion of non-feed substances: geophagia, trichophagia, urine drinking, fence licking, and even plastic chewing. Beyond disrupting normal feeding, it raises the risk of gastrointestinal injury, impaired nutrient absorption, parasitic infection, and lost productivity. Although the full etiology remains unresolved, researchers have long considered pica a multifactorial disorder rooted in nutritional imbalance, metabolic disturbance, and environmental stress, with mineral deficiency or imbalance widely recognized as a major driver. Shortages of elements such as phosphorus, copper, iron, zinc, and selenium can undermine antioxidant defenses and metabolic homeostasis, potentially pushing animals into the abnormal oral behaviors that define the syndrome.

Simple mineral supplementation has shown promise before—earlier work on wool-eating lambs found that dosing with iron, copper, and zinc sulfate salts raised blood mineral levels and produced complete recovery within eight weeks. But the picture is complicated by the fact that pica may also involve oxidative stress, endocrine dysregulation, and metabolic dysfunction. Moreover, whether supplemented minerals actually reach the bloodstream depends on their chemical form, antagonistic interactions among minerals, the rumen environment, and the intricacies of gastrointestinal absorption. This is where the new study departs from convention: instead of relying on minerals alone, the researchers combined them with Shariga-5, a traditional Mongolian multi-herb formula derived from local ethnoveterinary practice and rich in bioactive flavonoids and phenolic acids.

The Mongolian herbal–mineral supplement, or MHMS, was manufactured into solid 5-kilogram lick blocks containing target concentrations of calcium, phosphorus, copper, iron, manganese, zinc, selenium, and cobalt, along with vitamins D3 and E. Embedded within the mineral matrix were five medicinal herbs of the Mongolian Plateau: turmeric rhizome (Shariga), forsythia fruit (Saolong-Jimusi), clove flower buds (Gaoletu-Baori), chebulic myrobalan fruit (Arula), and gardenia fruit (Zhurula). Widely targeted metabolomic profiling of the individual herbs identified 1,427 metabolite annotation records, with phenolic acids accounting for nearly 39 percent and flavonoids another 32 percent—two chemical classes renowned for free-radical scavenging, metal-ion chelation, and anti-inflammatory activity. The design logic was synergy: trace elements supply the cofactors for antioxidant enzymes, while plant secondary metabolites provide complementary redox support.

To test the formula, the team screened East Friesian rams over seven consecutive days, enrolling only animals that showed five to ten instances of pica behaviors per observation day. Twenty rams, averaging about 1.5 years of age and 42.6 kilograms, were randomly split into two groups of ten, each housed in its own pen. The control group received only a basal diet of corn silage, oat hay, alfalfa, and Leymus chinensis hay; the treatment group received the same diet plus continuous free-choice access to an MHMS lick block. After a 14-day adaptation and a 60-day experimental period, blood was drawn before morning feeding, and serum from six animals per group underwent mineral, biochemical, antioxidant, hormonal, and untargeted metabolomic analyses.

The mineral results were strikingly selective. Serum copper roughly doubled, rising from 4.86 to 9.55 micromoles per liter, while zinc climbed from 10.62 to 15.29 and selenium from 0.43 to 0.59 micromoles per liter. Yet calcium, phosphorus, magnesium, sodium, potassium, iron, and manganese remained unchanged. This selectivity, the authors argue, suggests the supplement primarily restored the trace elements most closely tied to redox defense, metalloenzyme activity, immune regulation, and metabolic homeostasis. Copper underpins mitochondrial respiration and iron metabolism, zinc is a structural and catalytic factor for countless enzymes and supports epithelial barriers, and selenium is an essential component of glutathione peroxidase, a key peroxide-removing selenoprotein. The pattern also echoes previous work showing that mineral responses in ruminants are shaped not just by dose but by body reserves, absorption efficiency, and antagonistic interactions among elements.

The downstream physiological shifts extended well beyond minerals. Total antioxidant capacity in serum rose significantly, even though the individual enzyme activities of superoxide dismutase, glutathione peroxidase, and catalase did not change—an indication that the improvement came from the composite, largely non-enzymatic antioxidant pool, plausibly driven by the herbal polyphenols. Biochemical markers told a similar story of de-escalation: serum glucose fell from 4.44 millimoles per liter, sitting at the upper edge of the ovine reference range, to 3.60, a healthier mid-range value, and aspartate aminotransferase activity dropped from 160.70 to 125.35 units per liter, returning from above the normal range to within it. Because AST reflects hepatic metabolic burden and tissue injury—and pica-affected calves have previously shown elevated transaminases linked to copper deficiency—this normalization suggests the supplement eased tissue metabolic stress in the treated animals.

Perhaps the most dramatic changes appeared in the endocrine panel. Serum triiodothyronine, thyroxine, insulin-like growth factor 1, and growth hormone all rose significantly, signaling enhanced metabolic rate and activated anabolic growth signaling, while cortisol—the primary stress hormone of the hypothalamic–pituitary–adrenal axis—fell markedly, from 943 to 746 picograms per milliliter. The authors note that the supplement’s selenium, copper, zinc, and vitamin E all carry antioxidant functions that could plausibly dampen the HPA axis burden imposed by chronic nutritional stress and oxidative pressure. Previous studies lend support to the mechanism: curcumin supplementation has raised thyroid hormones and lowered cortisol in goats, and vitamin E and selenium combinations have reduced cortisol in transportation-stressed dairy heifers.

The untargeted metabolomics added an exploratory molecular layer. Out of 1,062 putatively annotated serum metabolites, 112 differed significantly between groups—51 higher and 61 lower in the supplemented rams. Pathway analysis ranked porphyrin metabolism, the biochemical route for heme synthesis, as the top candidate pathway, with glycine abundance more than doubled and porphobilinogen reduced to less than half of control levels. Because glycine is the starting substrate for heme biosynthesis and also a precursor for glutathione, the body’s master intracellular antioxidant, its rise fits a scenario of improved antioxidant substrate supply. The drop in porphobilinogen, an early heme precursor that can accumulate abnormally when the pathway falters, correlated positively with serum AST, hinting that reduced accumulation of this intermediate accompanied the easing of tissue metabolic pressure. The authors are careful to flag that this pathway enrichment did not survive multiple-testing correction and the metabolites lack validation against authentic standards, so these findings are hypothesis-generating rather than definitive.

The study also candidly acknowledges its limits: individual lick-block intake was not recorded, the composite design cannot separate the effects of minerals from herbs or their synergy, the sample was modest, and rumen fluid and microbiota were not examined. Even so, the overall picture is compelling—a traditional Mongolian herbal formula fused with trace-element nutrition appears to shift pica-affected rams from a stress-laden, oxidatively burdened metabolic state toward physiological balance, with elevated thyroid and growth hormones, subdued cortisol, stronger antioxidant capacity, and a metabolome inching back toward order. For a condition as old as animal husbandry itself, the remedy may lie partly in knowledge herders on the Mongolian Plateau have carried for generations, now given rigorous, molecule-by-molecule confirmation.

Subject of Research: Effects of a Mongolian herbal–mineral supplement on serum minerals, antioxidants, hormones, and metabolomics in rams with pica

Article Title: Free-choice Mongolian herbal-mineral supplementation improves serum mineral, antioxidant, endocrine, and metabolic indices in rams with pica

Article References: Man, D., Chen, L., Ao, X., Zhang, W., & Na, R. (2026). Free-choice Mongolian herbal-mineral supplementation improves serum mineral, antioxidant, endocrine, and metabolic indices in rams with pica. Frontiers in Veterinary Science, 13, Article 1946016. https://doi.org/10.3389/fvets.2026.1946016

Image Credits: AI Generated

DOI: 10.3389/fvets.2026.1946016

Keywords: pica, sheep, herbal-mineral supplement, trace minerals, antioxidant capacity, cortisol, thyroid hormones, serum metabolomics, porphyrin metabolism, Mongolian ethnoveterinary medicine, ruminant nutrition, oxidative stress

An international team of researchers from Italy and Brazil, led by Gabriele Rocchetti of the Università Cattolica del Sacro Cuore, used an untargeted metabolomic approach based on ultra-high-performance liquid chromatography coupled to high-resolution Orbitrap mass spectrometry. Rather than testing a pre-selected list of compounds, untargeted metabolomics casts a wide analytical net, capturing and tentatively identifying as many small molecules as possible in a biological sample. In this case, the platform putatively annotated 1,412 metabolites in whole blood, cross-referenced against the comprehensive Bovine Metabolome Database. Amino acids, peptides and their analogues dominated the detectable metabolome with 281 compounds, followed by carbohydrates and their conjugates with 90, and fatty acids and conjugates with 63.

The experimental design took advantage of a long-running field study at São Paulo State University’s experimental station in Araçatuba, Brazil. Twenty-five Nellore and 25 Angus young bulls, half-sibs within each breed to minimize genetic variation, were reared under identical conditions. After an adaptation period with access to shade, half of the animals in each breed were exposed to direct sunlight and high temperature-humidity conditions for 56 days during the height of the southern summer, from early December 2015 to early February 2016. Shading was then restored and the animals entered a recovery phase. Blood was drawn from five sun-exposed animals per breed at the peak of heat stress and again in the cooler season, allowing the researchers to compare each animal against its own baseline. Notably, these were the same animals whose DNA methylation patterns the team had characterized in an earlier study, providing an unusual opportunity to link epigenetic regulation with metabolic chemistry.

When the researchers applied supervised statistical modeling to the metabolomic profiles collected during the challenge period, the two breeds separated cleanly, with a prediction ability of Q² = 0.917. Twenty metabolites showed outstanding discriminating power, each achieving a perfect area under the receiver operating characteristic curve. The single most predictive compound was the steroid 4-hydroxyestrone, which accumulated far more in the blood of heat-stressed Angus than in Nellore, with a log2 fold-change of 3.79. Steroid metabolism is known to be highly responsive to environmental stressors, and this finding points to breed-specific endocrine regulation under thermal load. Other top discriminators included lysine, the membrane lipid LysoPC(16:0), and citric acid, all previously implicated in heat-related metabolic adjustments and consistent with the known effects of heat stress on mitochondrial metabolism, substrate use, and membrane lipid turnover.

The most striking results, however, emerged from the longitudinal comparison of each breed between the heat challenge and the recovery period. Because repeated measurements from the same animals can inflate apparent significance, the team used linear mixed models that accounted for individual identity and then applied stringent false discovery rate correction. Under this rigorous framework, the contrast between the breeds was dramatic. Nellore cattle showed 114 metabolites whose phase-dependent changes remained statistically significant, spanning amino acids and peptides, carbohydrates, purine and pyrimidine derivatives, acyl-carnitines, steroids, and tetrapyrrole-related compounds. Angus, by comparison, retained only three significant metabolites: urobilin, deoxycitidine, and D-1-piperideine-2-carboxylic acid.

Interpreting this asymmetry requires care, the authors caution. The scarcity of significant metabolites in Angus does not mean the breed was unaffected by heat. Multivariate modeling still identified 264 metabolites contributing to class discrimination in Angus, but their univariate changes were modest and variable across animals. The researchers suggest two non-exclusive explanations: either Angus responses are more biologically variable between individuals, or the breed lacks the systemic metabolic plasticity that characterizes its zebu cousin. In Nellore, the large and coherent set of regulated metabolites points to a tightly controlled, network-level reprogramming, precisely the kind of coordinated response one would expect from a breed evolutionarily shaped by tropical climates.

Within the Nellore response, each chemical class told a coherent physiological story. Amino acids and peptides formed the largest affected category, with 34 significant compounds showing a global reduction, consistent with heat-induced shifts in nitrogen metabolism, increased amino acid catabolism, and the redistribution of substrates toward energy production. Carbohydrate-related metabolites also declined, plausibly reflecting altered glucose utilization and gluconeogenic flux. Purine and pyrimidine derivatives were predominantly reduced during heat exposure, a pattern linked to energy balance, redox homeostasis, and stress signaling. Perhaps most intriguingly, acyl-carnitines, key intermediates in fatty acid transport and mitochondrial beta-oxidation, showed a strong cumulative increase, suggesting that heat-stressed Nellore cattle shift their metabolism toward lipid substrates. Steroids and steroid-conjugated metabolites were broadly reduced, while phenolic compounds of dietary origin, including quercetin and enterolactone, also fell during the challenge period.

The metabolic findings dovetail elegantly with the team’s earlier epigenetic work on the same animals. In the previous DNA methylation study, Nellore cattle exhibited hypo-methylation of stress-responsive genes during heat exposure, including ELOVL5 and FADS1, which govern fatty acid chain elongation and desaturation, and PDE5A, a regulator of vascular function and oxidative stress responses. The convergence of epigenetic loosening of lipid-metabolism genes with the observed remodeling of acyl-carnitines and membrane lipids supports the hypothesis that Nellore cattle possess a multi-layered adaptive framework: gene regulation and metabolite chemistry responding in concert to preserve membrane stability, optimize lipid turnover, and limit oxidative damage. Pathway analysis reinforced this picture, identifying porphyrin, purine, and pyrimidine metabolism as the routes most consistently modulated by heat, particularly in Nellore, with porphyrin metabolism standing out as a shared signature in both breeds.

That shared porphyrin signature is biologically telling. Urobilin, a downstream catabolite of heme breakdown, plummeted during heat exposure in both breeds, with log2 fold-changes of −6.08 in Angus and −5.97 in Nellore, and achieved maximal predictive power in the Angus model. Heme is central to oxygen transport, mitochondrial electron transfer, and cellular redox balance, and thermal stress is known to influence mitochondrial activity, oxygen utilization, and reactive oxygen species generation. The marked drop in urobilin thus suggests that heat stress perturbs heme turnover in both breeds, even as their broader metabolic responses diverge. In Angus, the rise of deoxycitidine hints at increased nucleotide turnover, possibly reflecting DNA and RNA damage and repair under oxidative stress, while the fall of D-1-piperideine-2-carboxylic acid, a lysine degradation intermediate, points to perturbed amino acid catabolism.

The study’s authors are careful to frame their conclusions within its limits. The cohort was small, with five animals per breed providing longitudinal samples, and data acquisition was performed exclusively in positive ionization mode, meaning that metabolites preferentially detected in negative mode, including several classes of organic acids, may be underrepresented. Larger cohorts and targeted validation will be needed to confirm the functional roles of the identified metabolites. Even so, the implications are considerable. If heat tolerance in cattle reflects the capacity for controlled, systemic metabolic reprogramming rather than the magnitude of any single molecular change, then breeding programs may eventually be able to use blood metabolite panels as biomarkers to select thermotolerant animals. In an era when climate change is squeezing livestock systems on every continent, the humble blood sample of a Nellore steer may hold a blueprint for building more resilient herds.

Subject of Research: Breed-specific blood metabolomic responses of Nellore and Angus cattle to heat stress

Article Title: Metabolomic profiling of blood from Nellore and Angus cattle under heat stress

Article References: Metabolomic profiling of blood from Nellore and Angus cattle under heat stress. (n.d.). https://doi.org/10.1007/s44154-026-00303-7

Image Credits: AI Generated

DOI: 10.1007/s44154-026-00303-7

Keywords: heat stress, cattle, metabolomics, Nellore, Angus, thermotolerance, porphyrin metabolism, purine metabolism, pyrimidine metabolism, acyl-carnitines, urobilin, livestock