Researchers have identified a class of microbial enzymes originating from the gut resident Bacteroides vulgatus that drive ulcerative colitis


Ulcerative colitis, a subtype of inflammatory bowel disease, is a chronic ailment of the colon affecting nearly one million individuals in the United States. It is thought to be linked to disruptions in the gut microbiome – the bacteria and other microbes that live inside us – but no existing treatments actually target these microorganisms.

In a study publishing on January 27, 2022 in Nature Microbiology , researchers at University of California San Diego School of Medicine have identified a class of microbial enzymes that drive ulcerative colitis, and have demonstrated a potential route for therapeutic intervention.

“Studies continue to show correlations between gut health and microbial constituents, but these trends don’t exactly explain how the bacteria cause disease or what we can do about it,” said study co-senior author David J. Gonzalez, Ph.D., associate professor of pharmacology at UC San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences.

“This is the first study with experimental evidence that pinpoints a specific microbe driving ulcerative colitis, the protein class it expresses, and a promising solution.”

Gonzalez and his collaborators are leaders in multi-omics – an approach that combines state-of-the-art genomics, proteomics, metabolomics and peptidomics to uncover the contents of a biological sample with unprecedented detail. The process of “digitizing” a sample allows the team to examine its biology at multiple scales and develop new hypotheses of disease progression.

“What makes UC San Diego special is our highly collaborative science, where world leaders in all the different ‘omics’ can come together to break new ground,” said study co-senior author Rob Knight, Ph.D., professor and director of the Center for Microbiome Innovation at UC San Diego. “This study showcases the power of combining these technologies to explore biology in new ways.”

Digitized number 2: stool samples reveal microbial enzyme driving bowel disease
Researchers hypothesize that ulcerative colitis may be triggered by bacterial proteases that damage the colonic epithelium and allow an influx of immune cells to drive further inflammation. Credit: University of California – San Diego

To study the gut microbiome, Gonzalez said the most useful biological sample is patient stool. It is also far less invasive to collect than more traditional blood or tissue samples.

“Once we had all the technology to digitize the stool, the question was, is this going to tell us what’s happening in these patients? The answer turned out to be yes. We’ve shown that stool samples can be extremely informative in guiding our understanding of disease. Digitizing fecal material is the future.”

The team found that roughly 40 percent of ulcerative colitis patients show an overabundance of proteases – enzymes that break down other proteins – originating from the gut resident Bacteroides vulgatus.

They then showed that transplanting high-protease feces from human patients into germ-free mice induced colitis in the animals. However, the colitis could be significantly reduced by treating the mice with protease inhibitors.

The team suggested that a stressor in the gut, such as nutrient deprivation, may increase protease production in an attempt to use proteins as an alternative nutrient source. However, these bacterial proteases may be damaging to the colonic epithelium or lining of the colon, allowing an influx of immune cells to then further exacerbate the disease.

Authors hope the study will inspire future work to confirm this hypothesis and develop protease-blocking drugs for use in humans. Now that a specific family of proteins has been implicated in this form of ulcerative colitis, they said, clinicians may also one day use antibody tests to quickly discern if a patient is a good candidate for protease treatment.

The researchers said their approach to stool analysis and multi-omic data integration might also be used to study other diseases, including diabetes, cancer, rheumatic and neurological conditions.

Bacteroides, one of the most abundant genera in the mammalian colon, has been a primary candidate for next-generation probiotics and has attracted considerable attention due to its role in the prevention of a series of metabolic disorders, including obesity [1, 2], diarrhea [3], viral encephalitis [4], and enteritis [5].

In particular, the protective effects of Bacteroides on inflammatory diseases in the gut are a hot topic. The results of human studies have indicated that the relative abundance of Bacteroides in patients with inflammatory bowel disease (IBD) is markedly lower than that in healthy participants [6, 7]. Furthermore, animal studies related to colitis have demonstrated that several strains of Bacteroides, including Bacteroides fragilis NCTC 9343, Bacteroides thetaiotaomicron DSM 2079, and Bacteroides cellulosilyticus DSM 14838, can expand the population of interleukin- (IL-) 10-producing CD4+CD45RBlow T cells [8], ameliorate the histopathological damage of the gut [9], and increase the levels of anti-inflammatory IL-10 and Treg cells [10].

These findings indicate that Bacteroides strains could be beneficial to the restoration of gut health in patients with intestinal inflammatory diseases. However, some studies have shown inconsistent results. One study found that the oral administration of enterotoxigenic B. fragilis 86-5443-2-2 isolated from piglets induced colitis in mice, which was manifested by the severe damage of colon tissue [11].

In addition, Bacteroides eggerthii 12986 has been reported to reduce survival, accelerate body weight loss, and increase intestinal bleeding in dextran sulfate sodium- (DSS-) treated mice, which then enhanced the severity of their colitis [12]. These reports suggest that the effects of Bacteroides on intestinal inflammatory diseases are species or even strain-specific.

The varying effects of different strains may be attributable to their physiological characteristics. The colonization ability of strains is a physiological characteristic related to the protective functions of some strains against intestinal inflammatory disease. The type VI secretion system (T6SS) [13], antibacterial proteins [14], or capsular polysaccharides [15] of certain Bacteroides strains may increase their competitive fitness in the gut. Colitis-related studies have indicated that a high competitive colonization ability of B. fragilis could inhibit the intestinal adhesion of and further exposure to toxic pathogenic bacteria, and thus, prevent colitis [16].

The compounds produced by various strains also play a role in the development of intestinal inflammatory disease. For example, short-chain fatty acids (SCFAs), especially butyrate, may promote the intestinal epithelial barrier function [17], inhibit the central regulator of the inflammatory NF-κB signaling pathway [18], and decrease oxidative stress [19], thereby preventing pathological damage of the colon associated with intestinal inflammatory disease. One study found that the administration of B. fragilis could improve the tight junction (TJ) integrity of the gut by increasing the number of SCFAs [20].

However, enterotoxins secreted by B. fragilis VPI 13784 have been reported to induce inflammation and significant colon tissue damage in lambs, rabbits, and rats after injection of the strain into their intestinal ligated loops [21]. The surface antigens of some strains can also affect intestinal inflammatory diseases. For example, polysaccharide A, a type of capsular polysaccharide present on B. fragilis NCTC 9343, has been reported to alleviate colitis [22] and colitis-associated colorectal cancer [23].

Another capsular zwitterionic polysaccharide TP2 from B. fragilis ZY-312 has been reported to protect rats from 2,4-dinitrobenzenesulfonic acid-triggered enteritis by reducing the degree of intestinal adhesion and the area of intestinal ulcers [5]. Moreover, the sphingolipids of B. fragilis NCTC9343 have been found to attenuate oxazolone-induced experimental colitis [24].

These results indicate that the effects of Bacteroides and even probiotics on alleviating intestinal inflammatory diseases are closely related to their physiological characteristics. Notably, the phenotype of bacteria is determined by their genome, and some studies have revealed that the functional differences between various probiotic strains on colitis remission are strongly associated with their genome [25, 26].

Bacteroides vulgatus is a representative species of the Bacteroides genus and is known to have a beneficial effect on the human colon health [27, 28]. Some studies have reported that B. vulgatus mpk can inhibit Escherichia coli-induced colitis [29] or Yersinia enterocolitica-induced inflammation [30], whereas other studies have demonstrated the proinflammatory effect of certain B. vulgatus strains. One study showed that B. vulgatus DESEP-B could induce colitis in HLA-B27 transgenic rats [31].

Another study found that B. vulgatus TUSVM 40G2-33 led to the enhancement of carrageenan-induced colitis in guinea pigs [32]. These results imply that the protective effect of B. vulgatus is strain-dependent. Furthermore, a previous study has revealed the considerable differences in inflammatory responses of guinea pigs administrated with seven different B. vulgatus strains in an experimental model for ulcerative colitis [33].

This demonstrated the variable ability of various B. vulgatus strains in the enhancement of colitis. However, most investigations of the effect of B. vulgatus on colitis have only focused on a single strain. Hence, it is important to investigate the complex relationship between B. vulgatus strains and colitis and the reasons for the varying effects of different strains.

In this study, we selected four B. vulgatus strains with large differences in their genomes and assessed their roles in alleviating colitis. Due to its simplicity, reliability, and applicability, we used DSS to induce colitis in mice [34]. We then analyzed the genomic characteristics of the selected B. vulgatus strains to identify the functional genes that may play a role in alleviating the intestinal damage caused by the DSS.

reference link :

More information: Robert H. Mills et al, Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity, Nature Microbiology (2022). DOI: 10.1038/s41564-021-01050-3


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