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

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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.

 

‘What to expect when you’re expecting to grow old’: An interview with Whole Body Microbiome co-authors, Drs. Jessica and Brett Finlay

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As microbiome science advances rapidly, the number of books on microbiome-related topics is growing—yet it can be difficult to find reliable, science-based information. The hottest new microbiome book not only contains robust scientific information, but has suggestions on how to apply the findings throughout the lifespan: The Whole-Body Microbiome, written by Microbiome Insights co-founder Dr. Brett Finlay, along with his daughter Dr. Jessica Finlay, an environmental gerontologist.

The new book is a practical take on how to use the latest knowledge about the microbiome for healthy aging, with the father-daughter pair offering perspectives from multiple scientific fields and different points in the lifespan. Jessica Finlay brings to bear her pioneering work in the area of ‘applied clinical geography’, while Brett Finlay (a recent Canadian Medical Hall of Fame inductee) brings decades of insights gained from his scientific work in medical microbiology and immunology.

In this interview, the Drs. Finlay describe how their personal worlds were changed by their knowledge about the human microbiome—and how their book can be put to use, not only by members of the general public, but also by fellow scientists and medical professionals.

What gap did you hope to fill by writing this book?

 JF: What to expect when you’re expecting to grow old? While there is an entire industry devoted to preparing expectant parents, scant resources guide us on how to grow old. This is especially true if you’re looking for scientifically-based, accurate information to inform lifestyle, diet, household, and health practices. The major gap we aimed to fill was scientifically-based knowledge on aging and longevity, distilled for a wide audience. The microbiome’s effects on healthy aging has not yet been covered in popular literature.

While there is a lot of hype about the gut microbiome, we in fact know that microbial communities all over our bodies affect how our brain, teeth, skin, heart, gut, bones, immune system, and nearly every other body part functions as we progress through life. Our wellbeing is also intimately to the microbes that surround us – on our cellphones, kitchen sponges, houseplants, pets, and desks. In the book we take a holistic approach to the microbes in and around us (not just in the gut) to explore how they are integral to a healthy and long life.

We focus on aging as a lifelong process in Whole-Body Microbiome. You don’t just suddenly ‘flip the switch’ and become old at, say, 65. We accumulate health risks and liabilities throughout our entire lifetimes. The book offers lifestyle strategies and “quick tips” that we can all take advantage of, whether we’re eighteen or eighty.

BF: Having already written a book for parents on early life microbes—and not getting any younger—we wanted to discuss microbes and healthy aging. It was important to us not just to focus on ‘the elderly’, but on the entire aging process, which includes adults of all ages.

What are a few of the main messages in your book?

BF:  We live in harmony (usually) with our microbes, and they play a much larger role in our body’s functions than we once thought.  By paying attention to our microbes, we can have significant effects on many aging processes.

JF: Yes, the first main message is to embrace our microbes! They are lifelong partners who are heavily impacted by our lifestyle decisions, and necessary for our health and longevity.

We detail three overarching strategies that intertwine healthy microbes and healthy aging:

(1) Consume a balanced diet filled with fiber (e.g., fruits, nuts, vegetables, whole grains, berries), fermented foods, and limited meat and refined sugars.

(2) Stay active: This doesn’t necessarily mean marathon training, but rather moving around regularly throughout the day, engaging in varied aerobic and strength activities.

(3) Stay engaged with others: Regular social contact with family, friends, and extended networks is important for our wellbeing – and our microbes as well! We deposit, swap, and share microbes every time we shake hands, hug, play cards, eat communally, and share spaces.

As scientists, how has the microbiome changed the way you think?

BF:  I now see the world through a veneer of microbes! Even though we can’t see them, they are there and can affect many things.

 JF: My outlook on the world has also shifted: I now pause to consider my microbes when shopping for groceries, brushing my teeth, sending a text message, washing my hands, talking to my doctor, hugging a family member, going for a run, and gardening.

I also now see microbial connections in my research as an environmental gerontologist: when I consider the level of cleanliness and sanitization in a private home or assisted living facility; microbial exposures in later life through pets, socializing, hospitalizations, and even houseplants; and everyday diet, lifestyle, and health habits that impact older people’s microflora.

How can your professional colleagues make use of this book?

BF: It is based on peer-reviewed science, so scientists will appreciate it. They can use it for their own personal improvement, or if they specialize in one area, they can get a broad overview of the wonderful and amazing invisible world of microbes that live in and on us.

JF: We distill peer-reviewed scientific research and include interviews with leading scientific and medical experts in each chapter. Taking into account the rapid scientific advances and exploding knowledge, we take the current ‘pulse’ of microbiome research as it relates to adult health and longevity.

In addition to providing relevant information that can inform personal health and diet/lifestyle decisions, we aim to inspire our professional colleagues and fellow scientists to keep pursuing this fascinating and important area of research. This includes figuring out specific microbial genes and mechanisms responsible for particular effects in and on our bodies. We need more studies and data!

What tips do you have about microbiome-related science communication?

BF: Some of us scientists work with microbes and see evidence of what they do every day. But most people have a hard time appreciating microbes because they can’t see them. Convincing people of the invisible is hard. However, we know they have profound effects on both health and disease—and it is these aspects that we can focus on.

JF: There is a lot of hype and misinformation surrounding microbiome-related science: from misleading websites, to health claims (say, for probiotics) not supported by adequate clinical trials. It is important to be clear about what statements are supported by rigorous science, what statements are ‘not quite there yet’ (in terms of extrapolating findings from existing data), and what statements are downright wrong. This was an important task for us when writing the book. Beyond this, we recommend directing audiences to valid sources of information, such as PubMed and other academic search engines, for peer-reviewed articles/reviews, to stay informed.