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MT21-003: The role of microbial indole catabolites of tryptophan in host-microbiome cross-talk in cats with chronic enteropathies

Barko PC, Williams DA, Wu YA, Steiner JM, Suchodolski JS, Gal A, Marsilio S. Chronic Inflammatory Enteropathy and Low-Grade Intestinal T-Cell Lymphoma Are Associated with Altered Microbial Tryptophan Catabolism in Cats. Animals (Basel). 2023 Dec 23;14(1):67. doi: 10.3390/ani14010067. PMID: 38200798; PMCID: PMC10777963. (MT21-003: An EveryCat Funded Research Summary)

 

EveryCat Health Foundation has funded a number of health studies pursuing the identification of novel biomarkers in a variety of feline disease processes, including gastrointestinal conditions. The aim of this published study (funded under grant MT21-003) was to survey the presence of microbial indole catabolites of tryptophan (MICT) in the sera of cats with chronic inflammatory enteropathy (CIE) and low-grade intestinal T-cell lymphoma (LGITL). CIE and LGITL are common feline chronic intestinal diseases that have negative impacts on the quality of lives in cats. MICTs are gut bacterial catabolites of tryptophan that play a role in gastrointestinal immunity and barrier function. In humans and rodent studies, altered tryptophan metabolism has been correlated with intestinal inflammation and impairment. As modifications in the feline intestinal microbiota has been associated with the development of chronic enteropathies, this study sought to quantify seven different indoles and other tryptophan catabolites in cats with CIE and LGITL in comparison with controls.

Study Inclusion:
– All cats had active clinical signs of gastrointestinal dysfunction for more than 3 weeks, which included vomiting, diarrhea, weight loss, anorexia, or a combination of.
– All cats needed histopathologic findings consistent with CIE or LGITL based on a diagnosis from endoscopic or full-thickness surgical biopsies by a board-certified veterinary pathologist.
– For cats where CIE or LGITL could not be differentiated, testing with immunohistochemistry and PCR for antigen receptor rearrangement (PARR) was performed.
– Exclusions included antibiotics or immunomodulatory therapies within 4 weeks of biopsies, diagnosis of hyperthyroidism unless gastrointestinal symptoms persisted after successful treatment, and diagnoses of other neoplasms or exocrine pancreatic insufficiency (EPI).
– Archived serum samples had been collected over a 4-year period between 2015 and 2019 on client-owned animals that previously underwent comprehensive diagnostics for investigations unrelated to the study.
– 44 cats with CIE and 31 cats with LGTIL were enrolled.

Selection of Control Patients:
– Thorough medical histories included questions related to: attitude/activity, appetite, drinking, urination, chronic illnesses, weight loss, vomiting, and diarrhea.
– Exclusions included gastrointestinal signs within 6 months of enrollment, systemic and and/or chronic diseases, hypocobalaminemia, hypo or hyperfolatemia, EPI, and antibiotics or immunomodulatory drugs within 6 months of collection.
– Archived serum samples had been collected over a 6-year period between 2015 and 2021
– 26 healthy control cats met inclusion.

Serum Concentrations of Tryptophan Catabolites:
Quantitative (targeted) liquid chromatography–mass spectrometry (LC-MS) was used to measure: Tryptophan, Indolepyruvate acid, Indolealdehyde, Indoleacrylate, Indoleacetamide, Indoleacetate, Indolelactate, Indolepropionate, Kynurenine, Kynurenic acid, Tryptamine, and Serotonin.

Significant Results among the three groups:
– LGITL group was significantly older (median age 12 years) than control group (median age 10 years).
– Serum cobalamin was significantly lower in LGITL and CIE groups compared to control group.
– Serum fTLI (feline trypsin-like immunoreactivity) concentrations were significantly higher in LGITL group compared to CIE and control groups.
– Serum tryptophan concentrations were significantly lower in the CIE and LGITL groups compared to controls, but no difference between CIE and LGITL groups.
– Several MICTs (indolepropionate, indolepyruvate, indolelactate,
indolealdehyde, indoleacrylate) were significantly lower in cats with CIE and LGITL compared to control group.
– Statistically significant correlations among serum MICTs and serum biomarkers of gastrointestinal and pancreatic health (cobalamin, fPLI (feline pancreatic lipase immunoreactivity), and fTLI) were established.
– Median serum concentrations of kynurenine were higher in the CIE and LGITL groups than control group, though this was not statistically significant.

Conclusion:
These findings demonstrated altered tryptophan catabolism in cats with CIE and LGITL, which has been documented in humans with inflammatory bowel disease (IBD). Additionally, decreased concentrations of MICTs in cats with CIE and LGITL may be a result of altered microbial tryptophan catabolism and enteric microbiota dysbiosis. Limitations of the study included the use of archived frozen serum samples, non-uniform biopsy techniques (either full-thickness or endoscopic), no control for the diets of the cats, unknown significance of extra-intestinal comorbidities (such as chronic kidney disease) on tryptophan catabolites, and retrospective nature of data collection. Overall, this study may have ultimately discovered new biomarkers that could be therapeutic or diagnostic targets in the future for feline patients with CIE and LGITL.  ~BJP

For Further Reading:
Marsilio S, Freiche V, Johnson E, Leo C, Langerak AW, Peters I, Ackermann MR. ACVIM consensus statement guidelines on diagnosing and distinguishing low-grade neoplastic from inflammatory lymphocytic chronic enteropathies in cats. J Vet Intern Med. 2023 May-Jun;37(3):794-816. doi: 10.1111/jvim.16690. Epub 2023 May 2. PMID: 37130034; PMCID: PMC10229359