Trends Cancer: Targeting the gut microbiota to treat colitis caused by immunotherapy in cancer patients

Immune checkpoint inhibitors (ICIs) are a revolutionary development in cancer treatment in the past decade.

Immunization prevention

 ICIs remove inhibitory T cell signals and tilt the balance toward T cell activation, thereby triggering the destruction of cancer cells.

ICIs are now widely used in the treatment of a variety of cancers, including melanoma and lung cancer, kidney cancer, bladder cancer, breast cancer, and head and neck cancer.

Breast Cancer FDA

Although ICI therapy has achieved promising results in improving progression-free and overall survival rates for many cancer types, there are still challenges, including relatively low overall response rates and immune-related adverse reactions (IrAEs).

More and more evidence shows that the intestinal microflora is essential for the effective anti-tumor response of ICI treatment, and the intestinal microflora may affect the development of irAEs.

Intestinal microbiota is to improve the intestinal microflora is to improve the ICI ICI efficacy and reduce the efficacy and reduce the irAEs irAEs potential targets of a potential target

The gut microbiota produces hundreds of metabolites.

The relationship between gut microbes and ICI efficiency and toxicity

The relationship between gut microbes and ICI efficiency and toxicity

The link between the gut microbiota and ICI efficacy and toxicity data from preclinical models and clinical observations indicates that the microflora is important in the development of anti-tumor responses and regulation of irAEs.

antibiotic

However, FMT has important limitations, including that the effects are unique to the donor and the nature of the transplanted microbiota that causes such effects is unclear, which may limit the reproducibility and scalability of the method.

In mouse models and human studies, the gut microbiota can also influence the development of irAEs.

Intestinal microbial metabolites as potential modulators of ICI therapeutic effect and toxicity

Intestinal microbial metabolites as potential modulators of ICI therapeutic effect and toxicity

The specific mechanism by which the gut microbiota regulates the host immune system of patients receiving ICIS has not yet been fully elucidated.

Butyrate is an anti-inflammatory metabolite that can treat ICI- colitis

Butyrate is an anti-inflammatory metabolite that can treat ICI- colitis

A variety of metabolites produced by gut microbes can affect the function of host cells.

One possible mechanism is to activate the receptor by activating peroxisome proliferators.

Resistant starch (probiotics) on the metabolism of butyric acid and its known effects on the colon

Resistant starch (probiotics) on the metabolism of butyric acid and its known effects on the colon

(A) Due to resistance to host amylase, resistant starch is transported to the colon without being medsci.

(A) Due to resistance to host amylase, resistant starch is transported to the colon without being medsci.

Butyrate as a treatment: Implications from other intestinal inflammatory diseases

ICI-induced colitis is a heterogeneous and incompletely understood disease process with the common characteristics of IBD and GVHD.

Prebiotics: a simple and effective way to manipulate the microbiome

Prebiotics: a simple and effective way to manipulate the microbiome

There are a variety of strategies available to regulate the microflora and its by-products.

The second method is to manage probiotics, which is a synthetic community defined as specific beneficial strains.
However, successfully transporting and maintaining these species in the gut ecosystem can be challenging.
In addition, unexpected negative effects may occur because it is reported that patients taking probiotics before ICI have lower microflora alpha diversity.
This finding is related to a decline in microbiota health and a broadly weakened response to ICI Related.

management

If the goal is to increase specific microbial metabolites, another method is to administer the metabolites directly, just like the butyrate enema or oral butyrate supplements for IBD patients.
These methods have significant limitations, since the upper including medsci.
cn/ipsen/sporty/show-details/3074/2">digestion and absorption channel, butyrate is not fully exposed to the entire gastrointestinal tract with enema and the need for frequent dosing, prescribed to the lack of reliable oral delivery butyrate To the distal colon of humans.

medsci.
cn/ipsen/sporty/show-details/3074/2">digestion

Another way to circumvent many of the above-mentioned challenges is to use probiotics, which are nutrients or foods that can selectively induce the growth and activity of specific microorganisms, and then produce the required metabolites.
This approach has several advantages, including ease of administration, good safety, low cost, and the potential to achieve more uniform and longer-lasting butyrate levels by inducing the resident microbiota to produce butyrate.
In a small controlled pilot study of IBD patients, the use of oat bran as a dietary probiotic can increase fecal butyrate and lead to improved symptom control compared with the control group, without obvious adverse reactions, which indicates that it is based on probiotics Butyric acid regulation of bacteria may be able to reduce colon inflammation [16].
One type of prebiotic that has been studied for microbiome manipulation is resistant starch (RS), a dietary starch molecule that can resist digestion by host amylase.
RS is decomposed into mono/oligosaccharides by primary starch-degrading bacteria such as bifidobacteria and rumen cocci.
The decomposition products produced by these primary starch-degrading bacteria serve as nutrients for secondary fermentation bacteria (such as Firmicutts and Bacteroidetes), and these secondary fermentation bacteria produce single-chain fatty acids (SCFA), including butyrate.
In turn, these single-chain fatty acids provide energy for the colonic epithelium and affect host physiology through a variety of mechanisms.
63 healthy volunteers were well tolerated by taking RS in their diet, and their fecal butyrate levels increased [62, 63].
This effect was also observed in the study population without controlling the overall diet of the subjects, indicating that this method may be feasible and can be widely used.
These data increase that RS may be a simple, safe and practical way to increase butyrate levels in the colon, thereby reducing colitis and diarrhea caused by ICI .

RS RS may be a simple, safe and practical way to increase the level of acid in the colon, thereby reducing may be a simple, safe and practical way to increase the level of acid in the colon, thereby reducing ICI ICI caused Colitis and diarrhea caused by colitis and diarrhea

Probiotics butyrate to prevent ICI colitis: additional considerations

Probiotics butyrate to prevent ICI colitis: additional considerations

Although the anti-inflammatory function of butyrate in the intestine is well known, its effect may be related to the disease background.
In severely damaged epithelium, butyrate inhibits colonic stem cells from forming a complete epithelial monolayer, which increases the possibility that butyrate can prevent the damaged intestinal epithelium from healing in patients with severe ICI colitis.
Therefore, when testing lactic acid bacteria probiotics for intervention and prevention, it is important to stop using probiotics if severe ICI colitis occurs.
In some cases, butyric acid produced in the intestine may enter the blood circulation and affect the whole body.
When conducting lactic acid-type probiotic intervention trials in patients receiving ICI , it will be important to evaluate the local ( intestinal ) and systemic effects of the microflora in increasing butyric acid production .

Stem Cell Acceptance Acceptance of the ICI the ICI patients were lactic acid probiotics intervention trial evaluating the microflora increase local production butyrate patients undergoing treatment lactic acid probiotics intervention trial evaluating the microflora increased production of butyric acid Local ( ( intestinal intestine ) ) and systemic effects will be important and systemic effects will be important

The microbiota is a complex ecosystem, in which the interaction network between microbes is an important factor that determines the final metabolic output of the gut microbiota.
Therefore, the full effects of using tyrosyl prebiotics may be difficult to predict and vary from individual to individual.

ICIs have changed cancer treatment, but irAEs remain a challenge.
Intestinal flora seems to affect not only the efficacy of ICI treatment, but also the development of diarrhea and colitis, two diseases that are important and often limit treatment irAEs.
Butyrate has an anti-inflammatory effect in the colon, so it may have a protective effect against colitis / diarrhea caused by ICI .
The use of prebiotics that promote butyric acid is a promising new method to prevent colitis caused by ICI , and it is even possible to increase the efficacy of ICI treatment by increasing tolerance to treatment and promoting the expansion of the types of microorganisms that are beneficial to treatment.
Curative effect .

Butyrate has anti-inflammatory effect in the colon, and therefore likely to have anti-inflammatory role of butyrate in the colon, and therefore might be the ICI the ICI colitis induced colitis induced / / diarrhea protective effect.
The use of prebiotics that promote butyric acid has a protective effect on preventing diarrhea.
Promote the use of butyric acid prebiotic prevention ICI ICI new promising method for colitis caused, there may even be improved by increasing the resistance to the expansion of microbial species and promote beneficial in the treatment of therapy -induced one kind of colitis promising new approach may even be expanded by increasing the tolerance of microbial species and promote beneficial in the treatment of treatment to improve the ICI ICI therapeutic effect of treatment efficacy

In the context of clinical trials, there are many unresolved issues and considerations regarding the implementation of this probiotic method to prevent ICI-induced colitis (see Highlighted Issues).
These factors include the selection, time, dosage, and durability of the best preparation for microbiota changes, as well as the influence of the patient's dietary habits and the local intestinal microflora.
This intervention may shift immune homeostasis to tolerance, or increase plasma butyrate levels, which suggests that careful evaluation of the effect on ICI treatment is needed.
In addition, manipulation of the gut microbiota with probiotics may result in additional changes in the microbiota, not just an increase in butyrate production.
Therefore, in well-designed prospective clinical trials, a comprehensive assessment of the changes in the intestinal microbiota, local and systemic effects and their clinical significance will be crucial.

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