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Mouse study highlights role of NOD2 gene in gut microbiota resilience following antibiotics

New investigations using a gene knockout mouse model showed that neonatal exposure to antibiotics had a long-lasting effect on both the microbial community and mucosal immunity in the gut. The data also shone light on how the Nod2 gene alters the risk of inflammatory disease.

The neonatal period is a known critical window during which microbiota colonizes the gut and influences the development of the mucosal immune system. During this period, the developmental processes of the gut microbiome and immune system are particularly sensitive to environmental disturbances, which can increase the susceptibility of an individual to certain diseases.

One well-documented environmental exposure is antibiotics. Both mouse and human studies have produced data that suggest neonatal exposure to antibiotics is associated with increased risks for inflammatory diseases like asthma or inflammatory bowel disease (IBD)— including Crohn’s and ulcerative colitis. Observational data also support the notion that early and repeated exposure to antibiotics significantly increases the risk of IBD.

However, in most immune related or inflammatory diseases, there is likely to be an interplay of environmental and genetic risk factors that lead to someone developing an inflammatory condition. One of the most important genetic risk factors for the development of Crohn’s disease, for example, is mutations in the Nod2 gene. This gene encodes for a protein that has an important role in immune function and is found immune system cells like monocytes, macrophages, and dendritic cells. Nod2 is therefore an interesting candidate for studies aimed a better understanding the role of host genetics in altering the varied and potentially long-lasting effects of antibiotic exposure and risks of inflammatory diseases.

The existence of a mouse breed without the Nod2 gene provided a team of researchers with the ideal model to investigate how Nod2 deficiency influenced the impact of antibiotic exposure on the mouse’s gut microbiota and susceptibility to colitis. The team, based at the University of Toronto and Mount Sinai Hospital in Toronto, included Dr.Kenneth Croitoru (a Microbiome Insights scientific advisory board member). Together with collaborators, Croitoru performed several experiments whereby wild type mice, those with unaltered Nod2 genes, and Nod2 knockouts (mice without any copies of the gene) were exposed to antibiotics.

In a set of experiments, the team gave both adult mice and neonates a treatment of antibiotics, and 5 weeks later experimentally induced colitis. They collected fecal samples from the mice in order to characterize the changes to the gut microbiota using 16S rRNA sequencing. The results showed that in adult mice the microbiota in both the wild type and knockout mice was changed by antibiotics, but the recovery time was delayed in the knockouts compared to the wild type.

A similar result was observed in the newborns. After antibiotic treatment, which was completed at the time of weaning, the gut microbiota of both groups of mice was “significantly changed.” And, similar to adults, the knockout mice maintained reduced microbial diversity in the gut 14 days after the antibiotic treatment was stopped. In terms of the development of colitis, treatment did not affect the susceptibility of adults to colitis, but the neonatal knockout mice developed a more severe colitis. Interestingly, the researchers could transfer this severe colitis phenotype to other germ-free Nod2 knockout mice through the gut microbiota. They also found that this severe colitis phenotype was associated with changes in the intestinal T cells as well as the suite of cytokines found in the gut following inflammation, which taken together, indicates that Nod2  “has a critical role in shaping gut microbial responses and resilience to perturbations” and that the time of exposure is important.

It was known from previous work that while antibiotics do transiently change the gut microbiota of humans, the microbiota is usually fairly resilient and reverts back to its normal pre-treatment composition. According to the investigators, the fact that the Nod2 knockouts showed a delay in the time it took to revert back demonstrates reduced resilience of the gut microbiota, and this is the first study to show a role for Nod2 in microbial resilience following antibiotic exposure. The study also highlights the “long-lasting influence of an altered neonatal microbiota on mucosal immune homeostasis and development of disease.”

Reference

Goethel A, Turpin W, Rouquier S, et al. Nod2 influences microbial resilience and susceptibility to colitis following antibiotic exposure. Mucosal Immunol. 2019; 12: 720-732.

 

New work shows gut microbial taxa might vary, but function is stable in people with Crohn’s disease in remission

The numbers, types, and functions of gut microbes and the molecules they produce vary greatly over time and between individuals; however, there is new evidence showing that the metabolic function these microbes perform is conserved in some cases. This new data comes from an analysis of the gut microbiome from several individuals with Crohn’s disease throughout a whole year. The study further showed that the conserved functions are redundant across multiple phyla in the gut microbiome and that gut microbiome metabolism is driven by a web of interconnected reactions and enzymes.

Research has revealed that the gut microbiome plays a fundamental role in our overall health. The microbiome is involved in several vital biological functions including, metabolism, digestion, and immunity. Scientists have shown that there is an enormous amount of variability in the species making up the gut microbiome of any one individual, and this variability is even greater in people with inflammatory bowel disease (e.g. Crohn’s disease).  This makes any investigation into why a microbiome is not functioning properly extremely difficult. To get around this, researchers posed the question of whether microbial composition was really the best way to seek answers.

The group carrying out this work included researchers from all over the US and included Microbiome Insights Scientific Advisory Board member Dr. Janet Jansson ofthe Pacific Northwest National Laboratory in Richland, Washington. Their approach was to focus on discrete “metabolic modules” within a gut microbiome instead of taxa or genetic relationships, the idea being that different bacteria can perform similar metabolic functions; so while two humans have a different make-up of species, their microbiomes on the whole could be functioning similarly. With this concept, the researchers wanted to tackle an open question in microbiome and inflammatory bowel disease (IBD) research—how does the observed volatility in the microbiome composition of patients with IBD influence the functions of the microbiome?

Fecal samples from individuals with Crohn’s following resection surgery and in remission were collected at 5 time points throughout a year and a dual metagenomics/metaproteomics approach applied: they used shotgun metagenomics sequencing to identify genes from the microbiome species and two-dimensional liquid chromatography tandem mass spectrometry to isolate the proteins. They found that the metaproteomes (the collections of proteins expressed by microbes in the samples) were highly personalized, meaning all the samples taken from an individual more closely resembled each other than they did any sample from another individual. There was, however, still a great deal of variability between the samples taken at different times from a single person. Next they identified “metabolic modules” of proteins known to be involved in certain pathways and functions. In doing so they observed that there were similar and redundant metabolic functions across the different phyla observed over time and between individuals. By further combing through the modules, a clear path from carbohydrate, lipid, and amino acid degradation to central metabolism and finally the production of fermentation products could be found.  According to the researchers, the modules show the interconnectedness of gut microbiome metabolism, meaning that the overall operation of the microbiome should be thought of as network focused on metabolic function.  

This study was not specifically designed to compare healthy vs. unhealthy individuals, says the research team, but because this population is known to have a wide range of taxonomic variability they were chosen to investigate how variation affects function. According to researchers, “the data revealed that microbiomes of these post-surgery individuals had significant variability in taxa, genes, and proteins; however, key metabolic modules associated with central metabolism were seen in all samples, even though the phyla of origin was often different.” Furthermore, they believe this approach provides a unique way to follow metabolic reactions and enzymes, even when the species and proteins involved vary. 

Blakeley-Ruiz JA, Erickson AR, Cantarel BL, et al. Metaproteomics reveals persistent and phylum-redundant metabolic functional stability in adult human gut microbiomes of Crohn’s remission patients despite temporal variations in microbial taxa, genomes, and proteomes. Microbiome. 2019; 7:18.

 

 

PRESS RELEASE: Rebiotix and Microbiome Insights collaborate on a microbiome IBD tool for clinical development

Recent study provides proof of concept for using novel scoring system to define IBD-related changes in microbiome

With a growing body of science linking gut microbiota to inflammatory bowel disease (IBD), a need exists in clinical settings to understand changes in the gut microbial community as they relate to IBD and its management.
Two leading microbiome companies, Rebiotix (part of the Ferring Pharmaceuticals Group) and Microbiome Insights, are collaborating to validate one such tool: a proprietary analysis to determine how closely a patient’s microbiome resembles that of someone with IBD. Microbiome Insights’ bioinformaticians developed an IBD Microbiome Score, based on a vast dataset of over 1600 individuals with IBD and healthy controls. The metric combines the latest understandings of the gut microbiome as a complex ecosystem with information on hundreds of taxa in the bacterial community, rather than the presence or absence of specific taxa. Based on fecal microbial characterization by sequencing, the IBD Microbiome Score can be assigned for each individual patient at diagnosis and at different times throughout treatment, making the Score practical for clinical use. Leveraging Rebiotix’s proprietary Microbiota Restoration Therapy™ (MRT) drug development platform, the Score is being evaluated in active clinical trials to treat IBD.

“The microbiome field is enormously complex,” says Dr. Ken Blount, Rebiotix’s Chief Scientific Officer. “With the use of the first-in-class Rebiotix MRT platform continuing to expand into complex conditions such as IBD, it is critical to have strong, scientifically-validated tools to understand the dynamics of the microbiomes changes within our patients. We’ve seen first-hand how the novel platform and expertise of Microbiome Insights has the potential to rapidly advance not only our understanding of the impact of MRT on patients, but also to uncover valuable microbiome findings for the entire industry.”

“Our scientific team has consulted with leading gastroenterologists to explore ways of leveraging the science on the microbiome and IBD in the clinical setting,” says Microbiome Insights CEO Malcolm Kendall. “Now we have developed the first scientifically robust tool for tracking the microbiome of people with IBD and understanding its link to clinical outcomes. The ability to work with Rebiotix on this path to discovery underscores the future utility of our platform in the clinical setting.”

The companies are continuing to explore applications of Rebiotix interventions and Microbiome Insights’ personal health platform in other microbiome-related diseases.

About Rebiotix
Rebiotix Inc., part of the Ferring Pharmaceuticals Group, is a late-stage clinical microbiome company focused on harnessing the power of the human microbiome to revolutionize the treatment of debilitating diseases using drug products built on its pioneering Microbiota Restoration Therapy™ (MRT) platform. The MRT platform is a standardized, stabilized drug technology that is designed to rehabilitate the human microbiome by delivering a broad consortium of live microbes into a patient’s intestinal tract via a ready-to-use and easy-to-administer format. For more information on Rebiotix and its pipeline of human microbiome-directed therapies, visit www.rebiotix.com.

About Microbiome Insights
Microbiome Insights, Inc. is a global leader providing end-to-end services for microbiome DNA sequencing, including state-of-the-art bioinformatic analysis. Based in Vancouver, Canada, the company’s customized suite of services enables researchers and clinicians to easily and effectively include microbiome analysis in studies across a range of human, animal, agricultural and environmental applications. The multidisciplinary team of researchers and knowledge leaders at the company provide access to decades of expertise in traditional sciences such as ecology, microbiology, infectious diseases, and genetics. Microbiome Insights’ award-winning team is committed to providing clients with fast, dependable, cost-effective results.

See the original Business Wire press release here.

Events

Digestive Disease Week 2019

Microbiome Insights will be attending Digestive Disease Week (DDW) 2019 in San Diego (USA) from May 18 to May 21st, 2019! This annual conference is known as the largest North American gathering of physicians and researchers in the fields of gastroenterology, hepatology, endoscopy, and gastrointestinal surgery. This is an excellent opportunity to meet thought leaders, stay up to date on cutting-edge research, and network with colleagues from around the world. The program of DDW includes presentations, roundtable discussions, workshops, and other learning opportunities. Our team looks forward to deepening our knowledge in this area as we prepare to launch our first product related to inflammatory bowel disease later this year. We hope to see you there! 

Crohn’s and Colitis Congress

Microbiome Insights will be heading to Las Vegas February 7th-9th to attend the 2019 Crohn’s and Colitis Congress, hosted by the Crohn`s & Colitis Foundation and the American Gastroenterological Association. The congress will bring together healthcare professionals and researchers to share knowledge and perspectives relating to the care of individuals with inflammatory bowel disease (IBD). A diverse range of sessions will be offered, including pertinent workshops on topics such as IBD in pediatric populations and nutritional therapy for IBD.