Exocrine pancreatic insufficiency (EPI) is a malabsorptive syndrome resulting from insufficient secretion of pancreatic digestive enzymes. EPI is treated with pancreatic enzyme replacement therapy (PERT), but the persistence of clinical signs, especially diarrhea, is common after treatment. We used untargeted metabolomics of serum to identify metabolic disturbances associated with EPI and generate novel hypotheses related to its pathophysiology. Fasted serum samples were collected from dogs with EPI (n = 20) and healthy controls (n = 10), all receiving PERT. Serum metabolomes were generated using UPLC-MS/MS, and differences in relative metabolite abundances were compared between the groups. Of the 759 serum metabolites detected, 114 varied significantly (p < 0.05, q < 0.2) between dogs with EPI and healthy controls. Differences in amino acids (arginate, homoarginine, 2-oxoarginine, N-acetyl-cadaverine, and α-ketoglutaramate) and lipids (free fatty acids and docosahexaenoylcarnitine) were consistent with increased proteolysis and lipolysis, indicating a persistent catabolic state in dogs with EPI. Relative abundances of gut microbial metabolites (phenyllactate, 4-hydroxyphenylacetate, phenylacetyl-amino acids, catechol sulfates, and o-cresol-sulfate) were altered in dogs with EPI, consistent with disruptions in gut microbial communities. Increased kynurenine is consistent with the presence of intestinal inflammation in dogs with EPI. Whether these metabolic disturbances participate in the pathophysiology of EPI or contribute to the persistence of clinical signs after treatment is unknown, but they are targets for future investigations.

Chronic inflammatory enteropathy (CIE) and low-grade intestinal T-cell lymphoma (LGITL) are common chronic enteropathies (CE) in cats. Enteric microbiota dysbiosis is implicated in the pathogenesis of CE; however, the mechanisms of host–microbiome interactions are poorly understood in cats. Microbial indole catabolites of tryptophan (MICT) are gut bacterial catabolites of tryptophan that are hypothesized to regulate intestinal inflammation and mucosal barrier function. MICTs are decreased in the sera of humans with inflammatory bowel disease and previous studies identified altered tryptophan metabolism in cats with CE. We sought to determine whether MICTs were decreased in cats with CE using archived serum samples from cats with CIE (n = 44) or LGITL (n = 31) and healthy controls (n = 26). Quantitative LC-MS/MS was used to measure serum concentrations of tryptophan, its endogenous catabolites (kynurenine, kynurenate, serotonin) and MICTs (indolepyruvate, indolealdehyde, indoleacrylate, indoleacetamide, indoleacetate, indolelactate, indolepropionate, tryptamine). Serum concentrations of tryptophan, indolepropionate, indoleacrylate, indolealdehyde, indolepyruvate, indolelactate were significantly decreased in the CIE and LGITL groups compared to those in healthy controls. Indolelactate concentrations were significantly lower in cats with LGITL compared to CIE (p = 0.006). Significant correlations were detected among serum MICTs and cobalamin, folate, fPLI, and fTLI. Our findings suggest that MICTs are promising biomarkers to investigate the role of gut bacteria in the pathobiology of chronic enteropathies in cats.

Enteric microbial dysbiosis can contribute to the pathobiology of canine diabetes mellitus (DM) by interfering with host metabolism, promoting inflammation, and altering incretin hormone responses. Enriching and diversifying an unbalanced gastrointestinal microbiome with microbiome-based interventions such as lyophilized fecal preparations (LFP) can help improve gut function and glycemic control of diabetic dogs. This study aimed to determine the differences in the serum metabolomes, levels of interstitial glucose (IG), and 24-hour water intake of diabetic dogs treated with daily administration of LFP or placebo. A prospective, randomized, double-masked, placebo-controlled clinical trial was conducted using six DM dogs in the LFP group and six DM dogs in the placebo group. Dogs had physical examinations and 24-hour water intake assessments at admission, 2, 4, 6, and 8 weeks, with continuous IG monitoring performed throughout the study. Serum samples were collected longitudinally at baseline and during follow-up for untargeted metabolomic analysis. The marginal mean of IG after 8 weeks was lower in the LFP group (286 ± 22 mg/dL vs. 309 ± 22 mg/dL; p = 0.468), with the LFP group showing lower marginal mean IG at each time point except week five. Marginal mean log 24-hour water intake was significantly lower in the LFP group compared to placebo (mean difference − 0.24 ± 0.10, p = 0.024). Treatment groups significantly differed in metabolites with important roles in carbohydrate, protein, and lipid metabolism. Overall, our results show that LFP induced measurable metabolic alterations, with patterns generally consistent with a more favorable metabolic profile, but only minimal improvement in glycemic control.