Bacteroidetes: The Jekyll and Hyde of the Human Gut Microbiome

The phylum Bacteroidetes comprises approximately 30% of the bacterial microbiota of the collective genetic content of the human gut microbiome. This varies depending on factors such as population, geography, age, and diet.¹

Several genera comprise Bacteroidetes, for example, the microbiota of the Bacteroides genus, which are gram-negative, non-spore forming, obligately anaerobic, rod-shaped bacteria. Approximately 2 dozen Bacteroides species have been identified.²

This discussion focuses on the 2 most-characterized species: Bacteroides fragilis and Bacteroides thetaiotaomicron. In this brief overview, we describe some of the key features of this keystone phylum.

These plus some other lesser understood characteristics are shown in the Figure. Fortunately, most of the time Dr Jekyll outweighs his counterpart Mr Hyde in terms of the range of ecological impact.

The relative abundance of gram-negative Bacteroidetes to other phyla, such as gram-positive Firmicutes, is essential to maintain biodiversity and human gut health, or “eubiosis,” where metabolism, immune function, and colonization resistance are in homeostasis. The hypothesis of microbial networks highlights this co-occurrence in ecosystems, which was described in the term “keystone taxa" by Paine in 1966, in which Paine suggests that such taxa are important for the integrity and structure of communities.³

These taxa play a crucial role in microbiota communities and their removal can lead to a dramatic detrimental shift in the microbiome structure and function termed “dysbiosis.”⁴ Bacteroidetes is a keystone taxon; however, certain conditions catalyze its conversion from itspositive Dr Jekyll attributes to its potentially negative effects, which are analogous to the famous Dr Jekyll and Mr Hyde personality switch in the 1886 Stevenson novella.⁵

The Good Dr Jekyll Personalities of Bacteroidetes

Bacteroides fragilis

B. fragilis is mostly recognized for its role in infections, yet this is an oversimplification of this species. More significantly, its colonization in the gut imparts several beneficial effects via microbiota-host and co-microbiota interactions.

Bacteroidetes are friendly commensals, proficient in a polysaccharide fermentation that produces a pool of short-chain fatty acids, such as acetate, butyrate, and other vital molecules. These may be reabsorbed through the large intestine and serve as an energy source for the host.

Further, B. fragilis, expresses bile salt hydrolase, which is the first step needed to convert primary conjugated to deconjugated bile acids for further metabolism to secondary bile acids. A lower ratio of primary to secondary bile acids is associated with dysbiosis.⁶

There is a direct link between protection from recurrent Clostridiodes difficile infection with fecal microbiota transplantation and bile salt hydrolase activity.⁷

In addition, Bacteroidetes occupy space to optimize colonization resistance of the host against opportunistic pathogens, such as C. difficile, the leading cause of nosocomial infection. A person’s susceptibility to C. difficile is associated with microbiota structures related to a loss of Bacteroidetes.

B. fragilis has been shown to exert protective effects in a murine model of C. difficile infection by modulating gut microbiota and alleviating barrier destruction, thereby relieving epithelial stress and pathogenic colitis triggered by C. difficile.⁸

Bacteroidetes are quite adept at degrading polysaccharides for nutritional value and Bacteroidetes can assemble polysaccharides to facilitate immune system evasion from harm. The capsular composition of gut bacteria has a marked impact on the host.

One zwitterionic capsular polysaccharide—in particular from B. fragilis, polysaccharide A—has been shown to promote immunological tolerance in gnotobiotic mice and even suppress the development of experimental colitis induced by the pathobiont Helicobacter hepaticus.⁹

An increase in Bacteroidetes in recipients of allogeneic hematopoietic cell transplantation has been demonstrated to be associated with reduced graft-versus-host disease, a pathological process caused by an exaggerated donor lymphocyte response. More specifically, administration of B. fragilis through oral gavage in a murine model has been shown to increase gut microbiota diversity, improve gut tight junction integrity, and reduce inflammatory cytokine production by pathogenic T-cells.¹⁰

Bacteroides thetaiotaomicron

B. thetaiotaomicron has been shown to be important in the generation of sphingolipids, essential eukaryotic signaling molecules in the regulation of inflammation and immunity. Sphingolipids have been identified as the most differentially abundant metabolite in stool from patients with inflammatory bowel disease (IBD).

Colonization of germ-free mice with a sphingolipid-deficient B. thetaiotaomicron strain resulted in increased intestinal inflammation.¹¹ Previous studies have demonstrated that B. fragilis sphingolipids influence the function of natural killer T-cells in the intestine and the progression of a murine model of colitis.¹²

In a more direct example, B. thetaiotaomicron has been shown to directly protect mice in a model of infection by C. difficile possibly by altering the bile acid profile.¹³

Mr Hyde: The Evil Side of Bacteroidetes

Bacteroides fragilis

B. fragilis can be associated with abdominal infections when the intestinal wall integrity is compromised such that B. fragilis escapes from its residence in the gut. B. fragilis infection is often part of a polymicrobial infection due to this pathogenesis. Sepsis caused by B. fragilis most commonly occurs in patients with underlying conditions, such as IBD, diabetes, congestive heart failure, and cancer.

Bacteremia secondary to B. fragilis is associated with a high mortality of 27%.¹⁴ In addition to immediate complications from infections, the inflammation associated with B. fragilis has been postulated to be associated with an increased risk in colon cancer, although the research on this topic is ongoing.¹⁵

Bacteroides thetaiotaomicron

B. thetaiotaomicron can enhance disease progression of the enteric pathogen enterohemorrhagic Escherichia coli. Infection with a homologous natural mouse pathogen in B. thetaiotaomicron-reconstituted mice results in increased gut permeability compared with mice deplete of microflora.¹⁶

Similar studies corroborate the idea that B. thetaiotaomicron can provide a competitive advantage to enteric pathogens. Colonization of gnotobiotic mice with sialidase-deficient mutant B. thetaiotaomicron reduces free sialic acid levels resulting in a downregulation of the sialic acid catabolic pathway and increased growth of C. difficile and Salmonella typhimurium.¹⁷

These findings show that certain enteric pathogens have evolved to exploit otherwise friendly commensal microbiota to enhance their virulence.

What causes the shift from the Dr Jekyll to the Mr Hyde version of Bacteroidetes?

It is widely accepted that the balance of the gut microbiome is essential for human health. The abundance of Bacterioidetes and Firmicutes provides many benefits, some of which are described above.

Disturbance of this balance leads to dysbiosis. We understand that overuse of certain antibiotics and other agents shift the microbiome, which may play a role in the conversion from the good version to the harmful version of Bacteroidetes. This occurs via upregulation of mechanisms of antimicrobial resistance, such as efflux pumps of B. fragilis.⁶

Most importantly we must better understand and appreciate the Dr Jekyll—or good side—of Bacteroidetes. Although many health care providers associate B. fragilis with abdominal infections, it is the Bacteroidetes phylum that is a keystone taxon in human gut homeostasis.

A dysbiotic gut microbiome deficient in Bacteroidetes is susceptible to C. difficile and other pathogens. The maintenance and restoration of Bacteroidetes is essential for human health.

References

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Disclosures

Jae Shin, MD, has nothing to declare. Tiffany MacKenzie, PhD, is an employee of Ferring, and Glenn Tillotson, PhD, is a consultant to Ferring Pharmaceuticals, Spero Pharmaceuticals, and Hikma Pharmaceuticals.