Publication: “Monocyte-driven inflamm-aging reduces intestinal barrier function in females”

Click here to access: Monocyte-driven inflamm-aging reduces intestinal barrier function in females published in Immunity and Ageing, September 2024.

This publication by former PDF, Dr Candice Quin and team, discovers that inflammatory markers and gut permeability increase with age, but the leaky gut seems to be a female specific phenomena in both mice and humans.

Bluesky explainer thread below and here https://bsky.app/profile/msmacrophage.bsky.social/post/3l5ethyexgp2u

New publication alert! “Monocyte-driven inflamm-aging reduces
intestinal barrier function in females” by lead author Dr Candice Quin @uniofaberdeen.bsky.social. Read on for some surprising insights into sex differences in aging, the microbiome, inflammation, and the ‘leaky gut’ hypothesis….1/n

With age levels of inflammatory mediators (cytokines, CRP, & others) increase in the blood and tissues. This is often called ‘inflamm-aging’, and higher than age-average levels of these mediators are associated with chronic disease, frailty, and other age-associated ills. 2/n

Men & women age differently (‘men die quicker, women live sicker’)so it stands to reason they might ‘inflam-age’ differently, but very few studies on aging investigate sex differences in the aging trajectory. We looked at cellular & soluble inflammatory markers and saw sex differences! 3/n

We were surprised by the magnitude of sex differences but immunology is literally one of the worst disciplines when it comes to reporting by sex https://elifesciences.org/articles/70817
By why do we ‘inflamm-age’ in the first place? Might the mechanisms of inflamm-aging differ by sex 4/n

One of the major theories is that with age a dysbiotic microbiota causes the gut to become leaky (alternatively, the gut gets leaky with age and this alters the microbiota). Bacterial products leak out and cause inflammation. We’ve published in mice, others in other model organisms 5/n https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(17)30112-9?elsca1=etoc&elsca2=email&elsca3=1931-3128_20170412_21_4_&elsca4=Cell%20Press

Evidence for the ‘leaky gut’ hypothesis is weak in healthy humans (despite what the probiotic industry might say). Leakiness is generally found in people who have comorbidities, or are frail so we looked at healthy/non-frail male (41) females (54) btw 20-102 yrs and were surprised to find…6/n

…that women appeared to have leakier guts over the life course (as measured by the serum marker zonulin- imperfect), and only women had evidence of an age-associated increase in the bacterial product LPS in their serum. Could the leaky gut hypothesis be female specific? 7/n

Human studies are observational so we turned to mice to understand the chain of causality. Old female, but not male, mice did indeed have leakier guts and this seemed to be caused by TNF produced by the elevated number of circulating inflammatory monocytes. 8/n

Tl;dr The age-related leaky gut -> increased circulating bacterial products -> systemic inflammation hypothesis may only be true in females! (also – always investigate sex in your research) 9/n

Why? Well the female gut changes dramatically during pregnancy to increase nutrient absorption – perhaps that is why women seem to have more permeability over the life-course. We are doing some cool ongoing studies in vitro looking at male vs female monocytes ability to break the gut barrier. 10/n

Caveats: This was a non-frail, mostly white population – aging & immunology studies show tremendous differences by location so needs to be reproduced. Gut permeability measures were done by looking at serum markers – easy on the participant but indirect at best. 11/n

Thanks to the whole (unfortunately not on Bluesky team)! This was an incredibly fun and challenging project to work on but has cemented my commitment to considering sex in all the research we do. 👩‍🔬🧪🦠🚨 12/12

Podcast: Spreading awareness on peak asthma week

Spreading Awareness This Asthma Peak Week

Jessica Buckley, President and CEO of the Lung Health Foundation (LHF), and Dr. Dawn Bowdish, scientist and the Executive Director of the Firestone Institute for Respiratory Health and member of the Board of Directors of the LH talk how asthma, despite being common, can be complicated to diagnose and that many are living with uncontrolled asthma. Jessica and Dawn also share recent survey results of asthma patients’ experience, and how patients can set health goals with an asthma action plan and advocate for better air quality.

Publication: Chronic TNF in the aging microenvironment exacerbates Tet2 lost-of-function myeloid expansion

Download PDF here.

Link to journal here.

Abstract: Somatic mutations in the TET2 gene occur more frequently with age, imparting an intrinsic hematopoietic stem cells (HSCs) advantage and contributing to a phenomenon termed clonal hematopoiesis of indeterminate potential (CHIP). Individuals with TET2-mutant CHIP have a higher risk of developing myeloid neoplasms and other aging-related conditions. Despite its role in unhealthy aging, the extrinsic mechanisms driving TET2-mutant CHIP clonal expansion remain unclear. We previously showed an environment containing tumor necrosis factor (TNF) favors TET2-mutant HSC expansion in vitro. We therefore postulated that age-related increases in TNF also provide an advantage to HSCs with TET2 mutations in vivo. To test this hypothesis, we generated mixed bone marrow chimeric mice of old wild-type (WT) and TNF–/– genotypes reconstituted with WT CD45.1+ and Tet2–/– CD45.2+ HSCs. We show that age-associated increases in TNF dramatically increased the expansion
of Tet2–/– cells in old WT recipient mice, with strong skewing toward the myeloid lineage. This aberrant myelomonocytic advantage was mitigated in old TNF–/– recipient mice, suggesting that TNF signaling is essential for the expansion Tet2-mutant myeloid clones. Examination of human patients with rheumatoid arthritis with clonal hematopoiesis revealed that hematopoietic cells carrying certain mutations, including in TET2, may be sensitive to reduced TNF bioactivity following blockade with adalimumab. This suggests that targeting TNF may reduce the burden of some forms of CHIP. To our knowledge, this is the first evidence to demonstrate that TNF has a causal role in driving TET2-mutant CHIP in vivo. These findings highlight TNF as a candidate therapeutic target to control TET2-mutant CHIP.

Bluesky explainer thread here:
New Paper Alert: “Chronic TNF in the aging microenvironment exacerbates Tet2 lost-of-function myeloid expansion” published in Blood Advances #ImmunoSky #CHIP https://authors.elsevier.com/sd/article/S2473952924003860 (1/n)

Over time the progenitor cells (#stemcells) in our bone marrow acquire random mutations, with some genes being more likely to acquire these mutations than other. The Tet2 gene is one that acquires mutations. This is a problem because it regulates other genes through methylation (2/n)

Hematopoetic #stemcells with Tet2 mutations favour production of myeloid cells (#neutrophils #monocytes) over lymphoid cells (#Tcells #Bcells) and can outcompete stem cells that don’t have Tet2 mutations.(3/n)

If too many white blood cells originate from these mutants it is called Clonal Hematopoesis of Indeterminate Potential or #CHIP. CHIP is associated with an increase in mortality, and pneumonia (see prev paper), because immune cells with these mutations don’t work as well (4/n) https://shorturl.at/JNk6d

With age the proportion of Tet2 mutant cells increases and it is thought that the increased #inflammation that occurs with age contributes. Darwinian evolution happens in the bone marrow and stem cells with Tet2 mutations can outcompete (i.e. replicate more, make more white blood cells) than those without (5/n)

We investigated whether Tet2 mutant stem cells could outcompete others in the presence of the inflammatory cytokine TNF, which increases with age. We put a mix of normal and Tet2-/- stem cells into old mice that had lots of TNF and those with none (TNF KO). 6/n

Stem cells with Tet2 mutations could outcompete normal cells in old mice that had lots of TNF but not in TNF knockout mice. The aging inflammatory microenvironment contributes to CHIP! (7/n)

Cool finding- People with newly diagnosed #rheumatoidarthritis have lots of TNF and had low level of Tet2 and other CHIP mutants that went down as they started anti-TNF or anti-inflammatory therapy! Proof this happens in humans too (8/n)

Huge thank you to not on Bluesky Drs Michael Rauh (Queens), Candice Quin ( @uniofaberdeen.bsky.social ), Maggie Larche (UCalgary), Salman Basrai&Sagi Abelson @oicr.bsky.social and team. (9/9)

Dr. Bowdish will be performing at the 2024 Hamilton Fringe Festival

Born in September? Then you’re going to want to see Dr. Dawn Bowdish, scientist, and professor of medicine at McMaster University perform “The Perils of Being Born in the Fall” at this year’s Hamilton Fringe Festival (July 17-28th).

Dr. Bowdish is an award-winning scientist and first-time performer in the Hamilton Fringe Festival. Her solo show “The Perils of Being Born in the Fall” tours through the wackiness of early 19th century psychiatry, stealth mid-century reproductive rights activism, how the climate was once thought to affect your sex life, and why cold & flu season has an outsize impact on mental health.

“I’m excited to bring my love for science and science communication to a new audience. In my professional life, I need to provide facts and information in an objective and dispassionate way, but this show provides me an opportunity for me to share my passion, wonder, and amazement at the scientific process while introducing audiences to some quirky and important scientists they almost certainly wouldn’t have heard of before,” Bowdish said.

This show is a fun mix of education and entertainment, and you are guaranteed to leave with fun facts to share with your family and friends.

“The Perils of Being Born in the Fall” will be performed at as part of the Hamilton Fringe Festival at the Hamilton Theatre Inc, 140 M MacNab St N, Hamilton, ON L8R 2M3 at 7 p.m. on July 18,19,20, 25, 26, and 1.pm on July 27,and 28th.

Buy tickets here (or at the venue): https://hftco.ca/events/?mc_cid=eda1dd0bcd&mc_eid=2146b47461

For more information,follow Dr. Bowdish on Bluesky (https://bsky.app/profile/msmacrophage.bsky.social) or Instagram (https://www.instagram.com/msmacrophage/).

Publication: Neutrophil-mediated innate immune resistance to bacterial pneumonia is dependent on Tet2 function

https://bsky.app/profile/msmacrophage.bsky.social/post/3kubwknbcts2e
Click here for the full thread from Bluesky highlighting the major findings of the paper.
To see the full paper click here:
To see the commentary click here:



Bluesky thread:

Let me tell you about the #BowdishLab & friend’s most recent paper “Neutrophil-mediated innate immune resistance to bacterial pneumonia is dependent on Tet2 function”, led by Dr. C. Quin (now at @uniofaberdeen.bsky.social) @jclinical-invest.bsky.social https://www.jci.org/articles/view/171002
Tet2 is gene that is involved with methylating genes and therefore changing gene expression. Sometimes spontaneous mutations of Tet2 in hematopoetic stem cells (HSC) occur. These mutants tend to produce more myeloid cells (monocytes/neutrophils).
These myeloid producing HSCs tend to be more fit in the aging bone marrow (Darwinian survival of the fittest) and overtime, more and more of your myeloid cells are made from these Tet2 mutant clones.
In extreme cases this can lead to myelodysplastic disorders or cancer, but sub-clinical CHIP or clonal hematopoeisis of indeterminant potential occurs in many older adults.
People with CHIP (i.e., too many of their myeloid cells are made from Tet2 mutant progenitors) are prone to all sorts of conditions (e.g., heart disease) and pneumonia. We hypothesized that pneumonia risk might be due to changes in innate immune/myeloid cell function.
Mice defective in Tet2 did very poorly during Streptococcus pneumoniae infection (the most common cause of community acquired pneumonia in older adults), because their neutrophils were less able to kill bacteria.
We are excited about this @jclinical-invest.bsky.social publication because it is the first mechanistic explanation for the increased risk of pneumonia in CHIP. Generally CHIP is thought to affect macrophage function, but it clearly affects neutrophil gene expression & function as well.
Many thanks to Dr. Elsa Bou Ghahem for her most excellent Commentary https://www.jci.org/articles/view/181064 and for the great editorial & reviewer experience @jclinical-invest.bsky.social
Research Team:Candice Quin, Erica N. DeJong, Elina K. Cook, Yi Zhen Luo, Caitlyn Vlasschaert, Sanathan Sadh, Amy J.M. McNaughton, Marco M. Buttigieg, Jessica A. Breznik, Allison E. Kennedy, Kevin Zhao, Jeffrey Mewburn, Kimberly J. Dunham-Snary, Charles C.T. Hindmarch, Alexander G. Bick, Stephen L. Archer, Michael J. Rauh, Dawn M.E. Bowdish

Measles is not a harmless childhood infection – Dr. Bowdish explains.

See Dr. Bowdish’s op-ed piece in the Globe & Mail.

The G&M article is paywalled so you can also read the text below with some additional links to relevant publications:

Dr. Dawn Bowdish is the executive director of the Firestone Institute for Respiratory Health, the Canada Research Chair in Aging and Immunity, and a professor of medicine at McMaster University.

Measles infections are on the rise, particularly in Europe and the U.S., while vaccination rates have declined – but too many have dismissed these trends, seeing measles as just a harmless childhood infection. But it is, in fact, the cause of the most deaths of all the vaccine-preventable infections. Canadian deaths from measles may be rare due to excellent medical care, but measles can have long-term consequences that are worth avoiding.

Before antibiotics were available, measles killed more people than influenza. When a child develops the high fever and rash characteristic of measles, the virus infects and destroys white blood cells, specifically those called lymphocytes. This leads to a period of immune-system suppression, where bacteria that normally live on and inside us without serious issue can cause deadly pneumonia or other infections.

With antibiotics, we can help children through this risky period, although the rise of antibiotic-resistant bacteria means that we can’t be as confident as we once were. What we can’t fix, however, is the damage that measles does to lymphocytes.

Our lymphocytes are essential to the generation of immune responses to new infections and vaccinations, but also in the system’s ability to “remember” the immune responses we’ve already generated. Measles infects and kills these critical immune cells. As a result, we know that a child who contracts measles will probably have more infections and more antibiotic prescriptions for at least five years after their infection, likely because they are getting sick with things that they once had immune protection from. We also know that even as their lymphocyte numbers recover, some are lost and the quality of others are reduced. This is why deaths from many unrelated infections also decreased when the measles vaccines were rolled out; measles no longer caused those children to “forget” their learned immune response.

Measles during pregnancy is dangerous. Miscarriage, premature labour, congenital birth defects, neurodevelopment disorders, or even the death of both mother and baby are all very real possibilities. In some parts of the world, when a woman plans to get pregnant and there is any doubt about her vaccine status, her healthcare provider will test for antibodies to make sure she is protected or recommend vaccination. In Canada, however, this is rare. Pregnant women are often not against being vaccinated, but often feel that not getting vaccinated is safer than getting vaccinated. This, compounded by a well-organized and concerted misinformation campaign about the measles vaccine that began in the 1990s, means that many people born in this era are now entering their child-bearing years having never received their childhood vaccines.

Measles is the most infectious virus we know of, and the increasing number of measles infections locally and globally mean that we can expect to see its tragic effects in pregnancy once again. Midwives, family doctors, and caregivers need to recommend vaccination for measles and other vaccine-preventable infections in the strongest possible terms.

There are some “known unknowns” that make the recent measles outbreaks particularly worrisome. We don’t know whether measles-induced immune suppression will make COVID, respiratory syncytial virus (RSV), streptococcal infections and other surging issues worse. We don’t know what proportion of Canadians have waning measles immunity and whether this means we need booster campaigns. We don’t know if people on immunosuppressant drugs or chemotherapy have lost their protective measles immunity, and if they have, we don’t know if our long-term care homes and cancer centres are at risk of outbreaks – though we do know that our strained healthcare and public health systems are under-resourced and will struggle to cope.

Misinformation, pandemic-related gaps in vaccine delivery, and the continuing countrywide shortages of family doctors means that many Canadians have not been vaccinated. But it’s not too late. The National Advisory Council on Immunization has clear guidance on how people of any age can catch up on their vaccines. If you have any doubt as to whether you were vaccinated, especially if you are thinking about becoming pregnant, speak to your health care provider or public health unit. Even if it turns out you were vaccinated and didn’t know it, there is no safety concern around getting vaccinated again. Children can also be vaccinated if they’ve missed their vaccines for any reason. And we should continue to enforce existing rules that require vaccines to go to school and work in certain sectors.

The terrible consequences of measles in pregnancy and childhood were known to our grandparents and great-grandparents. They are not a lesson that any of us need to learn again.

See also: https://www.nature.com/articles/s41467-018-07515-0

Dr. Bowdish discusses the lab’s research on microbiota and healthy/unhealthy aging on the Agora Health Podcast

Or listen on

Apple podcasts https://podcasts.apple.com/co/podcast/how-the-microbiome-can-affect-your-overall-health-and/id1712499485?i=1000642050180&l=en-GB

Spotify: https://open.spotify.com/episode/0flH90zGfa5bXAVoy1ZiiF?si=f3680075df4b4a2a

Amazon Music: https://music.amazon.com/podcasts/2e2f7513-9491-40e9-a9dc-a31859560d1d/episodes/fce86aa3-0d05-4245-ab87-08be6b86323b/decoding-healthcare-research-how-the-microbiome-can-affect-your-overall-health-and-its-effects-on-aging-ep-15

The Bowdish lab is no longer taking thesis or project students for the 2024/25 academic year, but click here for an opportunity for students interested in aging research.

Unfortunately the Bowdish lab is at capacity for undergraduate students for next year; however, if you are looking to meet supervisors doing research in aging MIRA (McMaster Institute for Research on Aging) is partnering with McMaster’s Association for Undergraduate Research on Aging (AURA) to host Meet Your Supervisor – an in-person, networking and informational session aimed at connecting undergraduate students seeking research experience with MIRA Researchers. MIRA will also share information about the MIRA Undergraduate Summer Research Fellowships.

RSVP to attend.

Event details:

WHEN: Monday January 22nd ,  4 – 5:30 PM

WHERE: Farncombe Atrium, HSC 3N4

Please RSVP by January 15, 2022