News
The Gut’s Hidden Power: How the microbiota can enhance colorectal cancer treatment.
Immunotherapy has limited effectiveness in microsatellite-stable colorectal cancer (MSS-CRC). Combining immunotherapy with radiotherapy has potential to enhance therapeutic benefit, but other contributing factors are often overlooked. The gut microbiota is a complex system of microbes able to improve or diminish CRC treatment. It is largely misunderstood how it does this and the extent of its impacts on CRC treatment outcomes. Using an MSS-CRC mouse model this study investigated the efficacy of immunotherapy and radiotherapy as well as both in combination, and specifically the effect of antibiotic treatment to diminish the microbiota on these therapies' efficacy. They found reduced efficacy with antibiotic treatment, and identified Bacteroides fragilis and propionate as crucial factors that enhance therapy. They propose adjunct therapy with Bacteroides-containing probiotics or supplemental propionate as a mechanism to enhance established CRC therapeutics. This highlights the importance of understanding the microbiota’s extent of contribution to CRC and other cancers.
Source: https://rdcu.be/eA7zf
A new shot at beating tough cancers!
Locoregional therapies are cancer treatments that aim to directly target the tumour and surrounding tissues and are commonly used in colorectal cancer patients whose cancer has spread to the liver. Unfortunately, relapse is common following these treatments, and subsequent therapies often cannot cure the returning cancer. Recent research has shown that incorporating immunotherapies, which employ the immune system to fight cancer, with these tumour-targeting treatments may be a promising option for patients with liver metastasis. The success of these immunotherapies relies on the lymph nodes, which are vital for coordinating and sustaining the anti-cancer response.
Vaccines are a well-established way to prevent infections, but a new study has shown promising results that they could also extend the lives of colorectal cancer patients following locoregional therapies. A key problem with traditional vaccines is that they contain tend to have poor distribution to the lymph nodes. To give them the best chance of working as a cancer therapy, the researchers in this study created a vaccine that can ‘hitchhike’ on lipids in the blood to better reach the lymph nodes.
Their vaccine targets KRAS, a protein commonly mutated in cancer that is key to tumour’s ability to survive and grow. In the researchers’ first-in-human phase 1 clinical trial, this lymph-node targeting KRAS vaccine was given to five colorectal cancer patients who had residual disease following locoregional treatment. Following vaccination and over the course of monitoring, 60% of these patients had no detectable tumour DNA in their blood.
While this is an early-stage trial with a limited number of patients, the results suggest that lymph node-targeting vaccines could be a promising avenue for treating relapsing colorectal cancer which warrants further study. A phase 2 clinical trial is now underway to further explore these results.
The gut microbiome and anti-PD1 immunotherapy
PD1, however a large portion of patients do not respond favourably.Previous studies have hinted that the gut microbiota influences how well these therapies work, with the abundance of certain bacteria being linked to clinical outcomes. However, the precise ways these gut microbes activate the immune response in distant tumours were not fully understoodTo investigate this, researchers collected faecal samples from cancer patients undergoing PD-1 blockade therapy, categorising them as responders or non-responders.They found that patients who responded had an enrichment of bacteria belonging to the Ruminococcaceae family. From these responders' samples, they successfully isolated a previously unknown bacterial strain, YB328, belonging to the genus Hominenteromicrobium.Results Summary:
- Faecal Microbiome Transplants from human responders enhanced the anti-tumour effects of PD-1 blockade in mice
- Administration of the YB328 alone did not inhibit tumour growth, but when combined with anti-PD-1 treatment, it significantly boosted anti-tumour efficacy across multiple mouse cancer models
- YB328 primarily activated CD103+CD11b− conventional dendritic cells (cDCs) in the gut which subsequently migrated to the tumour microenvironment to prime and activate CD8+ T cells
https://www.nature.com/articles/s41586-025-09249-8
Restoring intestinal epithelial cell energy:
Creatine supplementation may help restore intestinal barrier function in inflammatory bowel disease:
Inflammatory bowel diseases (IBD) are characterised as the chronic inflammation of the digestive tract leading to the disruption of the intestinal epithelial cell lining. The intestinal epithelial cells have been shown to ineffectively use the energy from key molecules such as butyrate (a bacterial metabolite energy source) and creatine (an energy storer molecule) which restricts epithelial regeneration and barrier formation in IBD. In this study, the researchers used intestinal epithelial cell models (colonoids) derived from mice colonic biopsies to understand how the loss in the creatine kinase energy systems affects energy production and epithelial function.
The results from this study showed that a loss in creatine kinase led to an altered creatine energy pathway, energetic stress, and reduced intestinal epithelial cell function. An oral supplementation of phosphocreatine given to mice showed that this could potentially rescue the intestinal epithelial cell defects and restore the creatine kinase energy pathways.
This research indicates that creatine kinase supplementation may be a potential new strategy to help restore the creatine kinase energy levels to support intestinal epithelial cell barrier function in IBD.
Source: https://www.cmghjournal.org/article/S2352-345X(25)00098-0/fulltext
M.gnavus: a new biomarker for Spondyloarthritis in Crohn's disease patients
Spondyloarthritis is a common complication for Crohn’s disease patients, with approximately a third experiencing joint pain. It is thought to be caused by gut bacteria that escape the lumen when the intestinal barrier breaks down, triggering immune responses. Researchers from Weill Cornell Medicine recently investigated whether different types of bacteria are particularly responsible for these interactions and could be used as potential biomarkers.
To do this, they performed IgG sequencing on stool samples from 106 people (including CD patients without joint inflammation, those with peripheral spondyloarthritis, those with axial spondyloarthritis and healthy controls) and analysed the samples to determine which bacteria were associated with each group. The results showed that CD patients, with or without spondyloarthritis, had distinct and less diverse bacterial communities. These populations also differed between CD patients with peripheral or axial spondyloarthritis. Of these bacteria, Mediterraneibacter gnavus was highlighted as having elevated IgG in CD patients with both peripheral and axial spondyloarthritis. This IgG coating level also correlated with spondyloarthritis disease activity scores.
This research indicates that IgG reactivity against M. gnavus could serve as a biomarker to distinguish and monitor spondyloarthritis severity in Crohn’s disease patients, and may also be a potential target for future therapies. While these results are promising, it is important to note that additional studies are needed to confirm this potential biomarker in larger patient groups.
World IBD Day!
IT'S A WRAP
As the year comes to an end, I would like to take this opportunity to thank all who contributed to the Gut Health Network news items, it has been truly enlightening. We thank all our members for their continued support and wish all our patients and whānau a Merry Christmas and a Happy New Year. We will resume our website activities mid January, 2025. However, please feel free to reach us through contacts. We will be actively monitoring it over the holidays. Hope you all have a lovely break with friends and family. See you in 2025.
IgG glycosylation signatures predict future Crohn’s disease onset
Crohn’s disease is an inflammatory bowel disease that significantly affects quality of life. It is characterised by inflammation through the gut and the exact aetiology of the disease remains largely unknown. Research by Gaifem et al published in Nature Immunology investigated preclinical signs of Crohn’s disease in an effort to predict disease onset and perhaps prevent it.
By analysing serum samples up to 6 years prior to Crohn’s disease diagnosis, it was discovered that some circulating antibodies had a specific glycosylation signature in those eventually diagnosed with disease. This feature also correlated with increased levels of anti-microbial antibodies. Using a mouse model, it was determined that these antibodies reprogram innate immune cells to become more pro-inflammatory and increase susceptibility to colitis.
Altogether, this research indicates potential for a biomarker used to identify those with increased risk to progress to Crohn’s disease. Future research may determine ways to target these specific antibodies to prevent disease onset.
Source: https://www.nature.com/articles/s41590-024-01916-8
Anti-TNF therapy for IBD patients is associated with increased risk to Immune Mediated Inflammatory Diseases
Anti-TNFs are primary therapies for several immune-mediated inflammatory diseases (IMIDs). However, case studies have revealed the paradoxical occurrence of IMIDs in patients treated with anti-TNF. The authors in this study conducted 2 nationwide cohort studies comprising all patients with IBD in Denmark (2005–2018) and France (2008–2018). They showed that anti-TNF was associated with an increased risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa in both the Danish and the French cohort. Anti-TNF was also associated with an increased risk of the outcomes when compared with azathioprine suggesting that anti-TNF therapy was associated with an increased risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa.
Benefits of Proactive Drug Monitoring for Ustekinumab in IBD Patients
A recent study conducted by researchers at Harvard Medical School has identified improved outcomes for patients with inflammatory bowel disease (IBD) receiving ustekinumab therapy alongside proactive therapeutic drug monitoring (TDM).
Ustekinumab, marketed under the brand name Stelara, is funded in Aotearoa New Zealand for individuals with IBD who do not respond to other biologic therapies. This monoclonal antibody treatment targets interleukin pathways to reduce inflammation, however, its long-term effectiveness is not fully established.
This study is the first to explore the role of proactive TDM in optimising ustekinumab treatment. Proactive TDM involves regularly monitoring drug levels in patients which allows clinicians to adjust dosages before clinical symptoms of treatment failure arise. This approach differs from reactive TDM, where drug adjustments are made after a patient experiences a flare-up or shows signs of suboptimal treatment response.
Key findings from the study showed that patients undergoing proactive TDM had higher rates of ustekinumab persistence and fewer IBD-related hospitalisations compared to those who only received reactive TDM. These results were consistent in patients with Crohn’s disease and those that had been previously exposed to other biologics.
These findings highlight the use of proactive TDM as a strategy for maintaining the long-term effectiveness of ustekinumab, to prevent treatment failure and improve patient outcomes. This study builds upon previous research on other biologics like infliximab, adalimumab, and vedolizumab, where proactive TDM has also shown improved drug persistence and reduced risk of treatment failure, surgery, and hospitalisation.
Persistent dysbiosis in pediatric Crohn’s disease patients after resolution of inflammation
A recent study, published in Nature by the University of Virginia school of Medicine, has uncovered that children who achieve clinical remission in Crohn’s disease continue to show signs of microbial dysbiosis which could explain future relapses. This study found lower microbial diversity and notable taxonomic differences, such as decreases in the Lactobacillus and Streptococcus species in the pediatric cohorts’ microbiome. Opposingly, they saw an increase in species such as Oribacterium and Prevotella, which have been previously associated with inflammation. Using flow cytometry, they also noticed an increase in CD4+ T cells which may contribute to the triggering of a future inflammatory flare ups instigated by the increase of pathogenic bacteria. Interestingly, in this study they identified dysbiosis of patients that were in ‘clinical remission’. Previously dysbiosis has been associated with a loss of epithelial integrity. However, in this study, patients had surprisingly strong intestinal epithelial barriers. This contradictory discovery suggests that while current treatments are effective in resolving disease briefly, they may not be targeting the core of the issue.
This study contributes valuable insights into the microbiome involvement in pediatric CD and provides a mechanism behind the cause of disease relapse. This study also highlights the importance of considering the microbiome in CD treatment management even after clinical remission is achieved.
Testin: a new epithelial target to protect leaky guts in CD patients
The causes of the intestinal barrier dysregulation in inflammatory bowel diseases such as Crohn’s disease (CD) and Ulcerative colitis (UC) are unknown. CD is characterised by the persistent chronic inflammation impacting the gastrointestinal tract and is associated with decreased intestinal mucosal barrier integrity.
In a recent publication, researchers have introduced testin as a potential target for IBD patients. The authors show that testin protects the intestinal barrier integrity of mice with Crohn’s disease-like colitis. Their results show that CD patients and TNBS-treated mice have depleted levels of testin (an intercellular linker protein of the epithelium) at baseline compared to healthy controls. Increasing the expression of testin in TNBS-treated mice and LPS intestinal organoids resulted in improved barrier function via the regulation of the tight junction proteins (ZO-1 and Claudin-1). Furthermore, increased expression of testin downregulated the inflammatory cytokines (TNF-α, IL-1β, and IL-6) and suppressed the JNK/P38 downstream signalling pathway to protect the intestinal epithelial barrier. The findings from this study shows a promising new target to improve the intestinal barrier function of CD patients.