gut-microbiome

A worldwide collaboration led by researchers at Sanford Burnham Prebys has demonstrated a causal link between the gut microbiome and the immune system’s ability to fight cancer.

Together, the researchers identified a cocktail of 11 bacterial strains that activated the immune system and slowed the growth of melanoma in mice. The study also points to the role of unfolded protein response (UPR), a cellular signalling pathway that maintains protein health (homeostasis).

Reduced UPR was seen in melanoma patients who are responsive to immune checkpoint therapy, revealing potential markers for patient stratification.

“The investigators have pinpointed the UPR as an important link between the gut microbiota and anti-tumour immunity. Given previous work indicating a causal role for the host microbiota in the efficacy of checkpoint blockade immunotherapy, this additional mechanistic insight should help select patients who will respond to treatment and also help to guide new therapeutic development.” says Thomas Gajewski, the AbbVie Foundation Professor of Cancer Immunotherapy at the University of Chicago Medicine.

Although immune checkpoint therapies have significantly improved patient survival rates, metastatic melanoma remains the deadliest form of skin cancer, according to the American Cancer Society. Even when used as part of combination therapy, immune checkpoint inhibitors only benefit about half of patients, and these responses may involve autoimmune-related side effects, limited durability (the length of time a patient responds to treatment) and, at times, resistance to therapy.

Accumulating evidence supports the role of the gut microbiome in effective immune therapy: Antibiotics and select probiotics reduce treatment efficacy, while certain bacterial strains enhance efficacy. This study sheds new light on these observations.

“Our study establishes a formal link between the microbiome and anti-tumour immunity and points to the role of the UPR in this process, answering a long-sought question for the field,” says Ze’ev Ronai, senior author of the study and a professor at Sanford Burnham Prebys’ NCI-designated Cancer Center. “These results also identify a collection of bacterial strains that could turn on anti-tumour immunity and biomarkers that could be used to stratify people with melanoma for treatment with select checkpoint inhibitors.”

As part of this work, Ronai and his team are studying a genetic mouse model that lacks the gene for RING finger protein 5 (RNF5), a ubiquitin ligase that helps remove inappropriately folded or damaged proteins. While these molecular traits are critical for the current study, the mice don’t show any outward signs of disease.

“We call them the ‘boring mice’ because they don’t have a notable phenotype,” says Ronai. However, the RNF5-lacking mice were able to inhibit the growth of melanoma tumours, provided they had an intact immune system and gut microbiome. Treating these mice with a cocktail of antibiotics or housing the mice with their regular (wildtype) littermates abolished the anti-tumour immunity phenotype and consequently, tumour rejection indicating the important role of the gut microbiome in anti-tumour immunity. Mapping the immune components engaged in the process revealed several immune system components, including Toll-like receptors and select dendritic cells, within the gut intestinal environment. Reduced UPR was commonly identified in immune and intestinal epithelial cells and was sufficient for immune cell activation. Reduced UPR signalling was also associated with the altered gut microbiomes seen in the mice.

“We believe this research applies to another fundamental question pertaining to the balance between anti-tumour immunity and autoimmunity,” says Ronai. “Because mice that lack RNF5 are also prone to developing gut inflammation – a side effect seen for certain immune checkpoint therapies – we can exploit this powerful model to study how we may tilt the balance between autoimmunity and anti-tumour immunity, which could help more people benefit from these remarkable therapies.”

The study was published in Nature Communications (PDF).

organ-chip

A team led by investigators from Brigham and Women’s Hospital have developed an approach that could help prevent gastrointestinal disease.

In a study published in Nature Medicine, the researchers report new evidence suggesting that specifically targeting one version of the enzyme myosin light chain kinase (MLCK1) may be effective in both preventing and treating gastrointestinal disease by preserving and restoring barrier function, respectively.

“This represents a completely novel, non-toxic approach to intestinal barrier restoration and treatment of inflammatory bowel disease,” said corresponding author Jerrold Turner, MD, PhD, of the Department of Pathology at the Brigham.

“Our study indicates that MLCK1 is a viable target for preserving epithelial barrier function in intestinal diseases and beyond. This therapeutic approach may help break the cycle of inflammation that drives so many chronic diseases.”

Food allergies, coeliac disease, inflammatory bowel disease (IBD), diarrhoea and other gastrointestinal diseases have something in common: all have been linked to epithelial barrier loss. The gut epithelial barrier – that critical lining of cells in the gut that must allow nutrients into the body while keeping food-borne microbes out – can be compromised during intestinal inflammation and cause disease.

While many of the molecular mechanisms that trigger gastrointestinal diseases remain a mystery, previous research has found that one enzyme, known as myosin light chain kinase (MLCK), plays a critical role. MLCK, however, is also essential for critical functions in gut epithelia and other cell types. This makes direct inhibition of MLCK impossible, as it would result in many toxic and systemic side effects.

Other forms of MLCK can be found throughout the gut lining, in various epithelia and in smooth muscle. But the MLCK1 isoform is particularly expressed in the villous enterocytes – intestinal cells that sit in the finger-like projections that extend into the lumens of the small intestine – and corresponding surface cells of the colon.

To lay the groundwork for targeting only MLCK1, Turner and his team solved the crystal structure of the region that distinguishes MLCK1 from other variants. They then used computer modelling to screen approximately 140,000 molecules, looking for one that could dock into this region like a key in a lock.

The team found a molecule, which they named Divertin, that fits neatly into this pocket. Divertin prevented inflammation-induced barrier loss without compromising key MLCK enzymatic functions in epithelia and smooth muscle.

In mouse models of inflammatory bowel disease and diarrhoea, Divertin corrected barrier dysfunction and reduced disease severity. When given prophylactically, Divertin prevented disease development and progression. This suggests that Divertin might be a new, non-immunosuppressive means to maintain remission, and prevent disease flares, in patients with IBD.

Turner and colleagues note that targeting MLCK1 to prevent barrier loss and restore function could also be useful in other diseases where the epithelial barrier is compromised, including coeliac disease, atopic dermatitis, pulmonary infection and acute respiratory distress syndrome, multiple sclerosis, and graft versus host disease (GVHD).

In a study published recently in The Journal of Clinical Investigation, the same research team presented evidence that MLCK drives the continuation of GVHD, a complication that can arise after a transplant when donor immune cells begin attacking the organs of a transplant recipient. While Divertin was not tested in GVHD, the data suggest that it may be an effective therapy.

 

parasite

A study has identified the master regulator that maintains a healthy gut and limits damage by parasitic whipworms. Researchers from the Wellcome Sanger Institute and collaborators have revealed that the interleukin 10 receptor (IL-10R) is critical to prevent uncontrolled whipworm infection in mice and a damaging immune response in the gut.

The study helps to understand the signalling mechanism that maintains a balance between the host, whipworms and gut bacteria. Unravelling this signalling mechanism will help scientists understand immune response to other parasites and will shed light on pathways that could be involved in the control of other diseases such as inflammatory bowel disease and allergies.

The gut is home to millions of bacteria, known as the microbiota, and also to parasites such as whipworms. The human whipworm – Trichuris trichiura – infects approximately 500 million people globally, causing the neglected tropical disease Trichuriasis, and has evolved over millennia to infect the intestines and reproduce there.

The health of the host is important for a parasite, as it needs a live host to survive and reproduce. The researchers found that the worm, the gut, the immune system and the microbiota form a finely balanced ecosystem.

Dr Maria Duque-Correa, first author from the Wellcome Sanger Institute, said: “This work shows how any change in the host or microbiota will also change the response to whipworms. Interactions between the host cells, microbiota and whipworms, enable the whipworms to survive in infected individuals and now we’ve found a master regulator of those interactions.”

Certain immune signalling molecules – called interleukins – had previously been implicated in host immune response to worm infection, regulating inflammation in the gut. To further understand their role in this balanced ecosystem, researchers studied mice that were missing genes from the interleukin 10 (IL-10) superfamily of receptors to see how they responded to whipworm infection.

The researchers discovered that a specific IL-10R receptor was critical for regulation. They found that lack of IL-10R regulation led to an uncontrolled immune response that damaged the gut lining and failed to produce protective mucus. The worms invading the gut-lining cells, destroyed the barrier between the gut and the host, enabling bacteria to cross over into the rest of the body, causing fatal infection.

Prof Richard Grencis, an author from the University of Manchester, said: “This is the first study revealing the master role of IL-10R in regulating the response to whipworm, and controlling the microbiota. We discovered the absence of this crucial signalling pathway leads to disturbed microbiota and uncontrolled inflammation that destroys the gut lining allowing microbes to invade and cause liver failure.”

Dr Matt Berriman, senior author from the Wellcome Sanger Institute, said: “Our discovery of the importance of the IL-10R signalling pathway for gut regulation not only helps us understand the immune response to parasites, it also has implications for other diseases. Further research to better understand this immune signalling pathway could open up new ways of finding treatments for diseases caused by an over-active immune system such as allergies, inflammatory bowel disease or asthma.”

The study was published in PLOS Pathogens.