Identification of a Key Genetic Factor Governing Arabinan Utilization in the Gut Microbiome Suggests a Novel Therapeutic Target for Constipation

Abstract

Probiotics have been widely used to improve impaired gastro-intestinal motility, yet their efficacy varied substantially across strains. Here, by a large-scale genetic screen plus in vivo measurements, we identified a key genetic factor (abfA cluster governing arabinan utilization) in probiotic Bifidobacterium longum harnessing the treatment efficacy against functional constipation (FC). Intriguingly, it also presents in a range of gut resident microbiota and played a protective role against FC. Next, our longitudinal multi-omics study in humans revealed that the exogenous abfA-cluster-carrying B. longum can well establish itself in the gut, and enrich arabinan-utilization residents and beneficial metabolites (e.g., acetate, butyrate, chenodeoxycholic acid and uracil). Finally, transplantation of abfA-cluster-enriched human microbiota to FC-induced germ-free mice recapitulated the marked gut-motility improvement and elevated production of beneficial metabolites. Collectively, our proof-of-concept study actively demonstrated a critical yet underexplored role of microbial abfA cluster in ameliorating FC, establishing generalizable principles for developing functional-genomics-directed probiotic therapies.

Note:
Clinical Trial Registration Details: Complete clinical trial registration is deposited at the Chinese Clinical Trial Registry (ChiCTR2000034415 and ChiCTR2100041925, http://www.chictr.org.cn/).

Funding Information: This work was supported by the National Natural Science Foundation of China [No. 32021005, 32122067 and 31820103010].

Declaration of Interests: The authors declare no competing interests.

Ethics Approval Statement: Clinical trials were approved by the Medical Ethics Committee of the Affiliated Hospital of Jiangnan University (IEC2020061204 and IEC2020092903). Human tissue samples were obtained from individuals who provided informed consent.

The animal experimental protocols were approved by the Ethics Committee of Jiangnan University, Wuxi, China (JN. No20180615b0950901[164], JN.No20190315b0940423[28], JN.No20190315b0940423[28], JN.No20200710b0700820[158], JN.No20210630b0400820[221]), and were performed in accordance with the guidelines established by the European Community (Directive 2010/63/EU).