Commensal gut microbiota-based strategies for oral delivery of therapeutic proteins

Abstract

Therapeutic proteins are rarely available in oral dosage form because the hostile environment of the human gastrointestinal (GI) tract and their large size make this delivery method difficult. Commensal bacteria in the gut face the same situation; however, they not only survive but low levels of their structural components such as lipopolysaccharide (LPS), peptidoglycan, and flagellin are also consistently detectable in the circulatory systems of healthy individuals. This opinion article discusses how gut bacteria survive in the gut, how their components penetrate the body from the perspective of the bacteria's and the host's proactivity, and how orally administered therapeutic proteins may be developed that exploit similar mechanisms to enter the body.

Keywords: bacterial evasion; gut microbiota; oral delivery; therapeutic proteins.

Figure 1.. Proposed oral delivery strategies for therapeutic proteins.

(A) The extreme pH in stomach, the tight junctions at the intestinal epithelium and the lymphoid follicles, e.g. Peyer’s patch, are the major barriers for oral delivery of therapeutic proteins. (B) Biofilm can protect therapeutic (Tx) proteins from denaturation by stomach acid but must be degraded by anti-microbial peptides (AMP) in the intestine. Tagging bacterial peptide on Tx proteins can avoid the detection by antigen-presenting cells (APCs) and mucosal antibodies. Partial components of commensal bacteria can be used as conjugates of prodrugs to escape phagocytotic clearance but must be cleaved by the enzymes in the circulation or action sites. The Tx proteins that evade the mucosal immunity then enter the lymphatic circulation and subsequently the central circulation, and lastly are eliminated by the liver. (C) To use commensal bacteria in drug delivery, we must consider their strains and prevalence and implement quantitative control. To tag on bacterial peptides or encapsulate using partial bacterial structures to avoid host’s immunosurveillance, we must prevent functional interference of Tx proteins and ensure selective delivery and their eliminations.