Altered Gut Microbiome Composition and Function Are Associated With Gut Barrier Dysfunction in Healthy Relatives of Patients With Crohn’s Disease

Jul 19, 2022Gastroenterology

Changes in Gut Bacteria and Their Activity Linked to Gut Lining Problems in Healthy Family Members of Crohn's Disease Patients

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Abstract

Individuals with impaired gut barrier function (lactulose-to-mannitol ratio >0.025) had reduced alpha-diversity and altered beta-diversity in their gut microbiome.

Reduced alpha-diversity was indicated by the Chao1 index (P = 4.0e-4).
Altered beta-diversity was measured using the Bray-Curtis dissimilarity index (R = 0.001, P = 1.0e-3).
Eight genera and 52 microbial pathways were associated with an impaired gut barrier function (q < 0.05).
Specifically, four genera showed decreased prevalence or increased abundance linked to impaired barrier function.
Eight microbial pathways related to amino acid biosynthesis were also associated with changes in gut barrier function.
The random forest analysis suggested a bacterial community association with gut barrier function (area under the curve, 0.63; P = 1.4e-6).

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BACKGROUND & AIMS: The gut microbiome has been suggested to play a role in gut barrier hemostasis, but data are scarce and limited to animal studies. We therefore aimed to assess whether alterations in gut microbial composition and functional pathways are associated with gut barrier function in a cohort of healthy first-degree relatives of patients with Crohn's disease.

METHODS: We used the Crohn's and Colitis Canada Genetic Environmental Microbial (CCC-GEM) cohort of healthy first-degree relatives of patients with Crohn's disease. Gut barrier function was assessed using the urinary fractional excretion of lactulose-to-mannitol ratio (LMR). Microbiome composition was assessed by sequencing fecal 16S ribosomal RNA. The cohort was divided into a discovery cohort (n = 2472) and a validation cohort (n = 655). A regression model was used to assess microbial associations with the LMR. A random forest classifier algorithm was performed to assess microbial community contribution to barrier function.

RESULTS: Individuals with impaired barrier function (LMR >0.025) had reduced alpha-diversity (Chao1 index, P = 4.0e-4) and altered beta-diversity (Bray-Curtis dissimilarity index, R = 0.001, P = 1.0e-3) compared with individuals with an LMR ≤0.025. When taxa were assessed individually, we identified 8 genera and 52 microbial pathways associated with an LMR >0.025 (q < 0.05). Four genera (decreased prevalence of Adlercreutzia, Clostridia UCG 014, and Clostridium sensu stricto 1 and increased abundance of Colidextribacter) and 8 pathways (including decreased biosynthesis of glutamate, tryptophan, and threonine) were replicated in the validation cohort. The random forest approach revealed that the bacterial community is associated with gut barrier function (area under the curve, 0.63; P = 1.4e-6). 2

CONCLUSIONS: The gut microbiome community and pathways are associated with changes in gut barrier function. These findings may identify potential microbial targets to modulate gut barrier.

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Altered Gut Microbiome Composition and Function Are Associated With Gut Barrier Dysfunction in Healthy Relatives of Patients With Crohn’s Disease

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