Hot Shit!

I'm just reading an article from the May 2014 journal Cell Death and Differentiation, titled "Gut microbiome and anticancer immune response: really hot Sh*t!." (hattip Gemma, who also helped me write this!)

I read lots and lots of scientific papers, too many, in fact.  But this one has really captured my attention.  It kind of cuts through a lot of the BS and narrows into what is really important when it comes to gut health.

Importance of Butyrate

One area we lose sight of too easily is the importance of butyrate production by gut microbes. Everyone has the gut bacteria in-place to produce butyrate. Many different species can turn food we eat into butyrate, these species are mainly in the Clostridium family. I've yet to see a gut test from anyone that doesn't have lots of butyrate producing microbes.

Measuring butyrate is a whole 'nother issue. I had a butyrate test last summer, and it showed that my butyrate level was in the highest percentile. The low acceptable range was way, way lower than my test. In all of the many papers I've read on the importance of butyrate, none have ever given a specific amount required for gut health.

My Butyrate was 27mM/g.  Normal is "above 3.9"

A problem encountered in butyrate measurement is that the amount seen in feces can be misleading. If we have a gut that is starved of butyrate, the cells that use butyrate will be weakened and less butyrate will be utilized, showing up instead in your feces. The accurate way to measure butyrate would be to install a permanent tap on the portal vein and measure the butyrate as it enters your bloodstream. Several studies have done exactly this on pigs and rats, but not humans. A study in the '80's measured blood butyrate as found in human victims of tragic accidents, but unless the autopsy was performed within an hour or so, the results were not conclusive.

As we have no way of accurately accessing the butyrate required to produce beautifully healthy guts, and in turn, a robust immune system, all we can do is eat foods that are known to produce butyrate when fermented by out gut bugs.

From the "Hot Sh*t" paper:

Prebiotics refer to indigestible food ingredients that selectively promote the colonization of healthy commensals such as the dietary fiber inulin that promotes Bifidobacteria growth. More specifically, cancer-preventive antioxidants include dietary polyphenols (flavonoids, phenolic acids, lignins present in tea, wine, nuts, fruits, and so on, and ellagic acid metabolized by colonic microbiota into urolithins exhibiting antiestrogenic and anti-COX2 activities). Another polyphenol called ‘daidzein’, a soy isoflavone metabolized by gut microbiota into equol and only detected in a fraction of individuals (harboring sulfate-reducing bacteria), may protect against breast and prostate cancer, mostly in Asia. The fiber has been involved in the prevention of colorectal cancers and butyrate, one of the most abundant short-chain fatty acids resulting from the bacterial fermentation of fibers and selectively transported into the colon epithelium is the most compelling tumor-suppressive molecule. Butyrate has both cell autonomous and cell extrinsic antitumor effects. It decreases proliferation and promotes apoptosis of tumor cells, ameliorates inflammation associated with colitis and favor expansion of peripheral Treg. Most of these effects result from epigenetic regulation, butyrate acting as an endogenous HDAC inhibitor.

Lots of words, and in an article on prevention of cancer, not on "fiber" or gut health, specifically. It says butyrate acts as an HDAC inhibitor (HDI). HDAC inhibition is kind of the 'holy grail' in many health problems. Man-made HDIs are used as mood stabilizers and in epileptic treatments as well as cancer and treating auto-immune diseases. HDI's are a huge industry...yet if we eat right, we can simply make our own!

Also, did you notice the author singled out inulin as a prebiotic, and mentioned its promotion of Bifidobacteria. Had they looked a bit harder they would have also discovered RS, pectin, glucomannan and all the other fibers that act similarly to inulin. It was nice to see them also mention the polyphenols found in foods that are also associated with good gut health and anti-cancer activities. This fits in nicely with what we have been saying all along:  Try to eat lots of fiber, but also important are the compounds found in real foods and not available as a supplement.

Here's a bit more from the paper on butyrate from our gut bugs:

Moreover, the intestinal microbiota can also influence systemic immune responses. A recent work highlighted the role of certain metabolites (short-chain fatty acid butyrate and to a lesser extent propionate) produced by commensal bacteria in dictating the extrathymic differentiation of periph- eral regulatory T cells. Butyrate acts within T cells to enhance acetylation of the Foxp3 locus and protein, as well as DCs to decrease their proinflammatory NF- k B-dependent cytokine secretion profile through an HDAC inhibitory activity.

Did you get that?  Yes, you probably need a doctorate degree in biology to understand what they are saying, but bottom-line, they are saying that butyrate from our gut bacteria is needed to ensure a healthy immune system. "Butyrate acts within T cells to enhance acetylation of the Foxp3 locus and protein," without going into a lot of detail, this says that butyrate is the fuel that runs our immune system.

Leaky Gut, Chemotherapy, and Fiber

This "Hot Sh*t" paper is not about butyrate or fiber, it's about a new theory on how chemotherapy works in cancer treatments. This theory revolves around chemotherapy agents creating a "leaky gut" situation which allows certain beneficial bacteria from our small intestines to leak into our bloodstream where it is seen as harmful and our own immune system is called into action.

Gram-positive commensal bacteria translocate during chemotherapy and prime pathogenic Th17 (pTh17) cells contributing to the tumoricidal activity of cytotoxic compounds.

To further this theory, they show that chemotherapy is not effective on animals that have been given large doses of antibiotics. With germ-free animals, there is no bacteria left to leak into the blood to evoke the immune stimulating response.

The skewed gut microbial communities and the leaky gut barrier leads to a generalized activation of self-reactive B and T cells and production of autoantibodies. Therefore, we surmise that any compound compromising the intestinal barrier integrity and/or the innate mucosal immunity and/or directly the gut microbiota will affect the functional equilibrium of this compartment and cause symptoms, as well as distant immunological perturbations.

They are saying here that they believe the effectiveness in disrupting the gut's barrier results in boosting of the immune system. This makes me believe that all of this talk of "leaky gut" is possibly nature's way of boosting our immune system. Unfortunately, when we are eating total crap food, ie. artificial colors, flavors, chemicals, and processed oils, and also having guts that have been destroyed by antibiotics, there is no telling what will leak into our body and what the consequences will be.

First, we observed that certain bacterial species of the SI can selectively and efficiently translocate within 24–48 h after exposure to an alkylating agent, [chemotherapy], yet administered at a metronomic regimen only reducing B-cell numbers. Second, at these early time points, the permeability of the intestinal barrier was readily increased, whereas the number of Th17 cells and CD103þ DCs accumulating in the LP significantly decreased, setting the stage for bacterial translocation.

Possibly when eating as humans are meant to eat (omnivores eating real food) then this leakiness is a natural function to restore immune system health.

Oncologists have been using "platinum salts" for many years in chemotherapy with some good success. One standard explanation is that plantinum salts "trigger apoptosis" or cause the cancer cells to self-destruct. The "Hot Sh*t" paper proposes that platinum salts work by causing gut leakiness and a resulting immune response. The side effects of platinum salts are many: nausea, vomiting, kidney damage, nerve damage, among a long list.

Gut Enterotypes

Just as people can be genetically thin, fat, or of medium build, it seems that our gut flora also tends to gravitate towards three types:

Recently, an interesting but still controversial notion has emerged as to the existence of ‘enterotypes’ characterized by dominant genera ( Bacteroides , Prevotella and Ruminococcus ) and their co-occurring phylogenetic traits that could be associated with long-term dietary habits.

• The Bacteroides enterotype was associated with animal protein and saturated fats,
• The Prevotella enterotype was predominantly observed with high fiber/plant-based nutrition and high carbohydrates (low meat and dairy consumption). 
• The  Ruminococcus enterotype often merged with the Bacteroides one.

I am simply amazed at how hard these cancer researchers looked into the contributions of the gut when writing this paper!

These findings represent a paradigm shift in our understanding of the mode of action of many compounds having an impact on the host–microbe mutualism.

It appears the gut is no longer being overlooked by cancer researchers!  Let's hope this trend continues.

The microbiome present in the distal gut performs myriad functions protecting the host against pathologies. Indeed, the host–microbiota symbiosis has evolved in three directions.

• First, colonization by commensal microorganisms is key to immune development. 
• Second, the commensal community keeps in check invading pathogens and prevents them from expressing virulence. 
• Third, the intestinal microbiota appears to digest glycans and regulate fat storage in mice and potentially in humans. Exemplifying the host–microbe mutualism, the microbial genome is highly enriched in hundred families of glycoside hydrolases and in more than 20 families of polysaccharide lyases, whereas the human genome is relatively devoid of these carbohydrate-metabolizing enzymes. 

Implications for cancer

I think it has been well-established that a healthy immune system is the first line of defense against diseases like cancer. But how, exactly, to get a healthy immune system has eluded us. Here we see these researchers recognizing the gut microflora as a key contributor to the immune system:

Recently, we and others reported that gut microbiota is indispensable for the immunomodulatory and antitumor effects of certain anticancer therapeutics including chemotherapy and platinum salts.

If anyone reading this has cancer, or knows someone who has cancer, maybe this advice will help:

Future prospects for a better management of cancer patients aim at:

• (i) diagnosing patients dysbiosis (metagenomics, metatranscriptomics, epidemiology on diet, medications and exercise, and so on), 
• (ii) compensating dysbiosis by appropriate ‘immunogenic probiotics’
• (iii) prebiotics synergizing with probiotics to set the stage for a healthy intestine that has been compromised by DNA-damaging agents, 
• (iv) monitoring the immune responses raised against the relevant commensals to establish a correlation with longterm benefit and immune fitness.

In other words: No cancer treatment should proceed without consideration of prebiotics, probiotics, and testing to ensure there are healthy levels of "good" microbes in the gut!

 Conclusion

My thoughts are that if you want to avoid a date with platinum salts, just keep your immune system in top-notch condition at all times!  This simply involves eating foods that produce butyrate (prebiotic fibers) and a wide range of colorful fruits and veggies, nuts, and other healthy foods every day. Fermented foods and probiotics are also important! 

As of now, we don't know exactly what the "perfect" microbiome looks like, how much butyrate we need exactly, and which fibers are required for immune system perfection. Might as well just eat the foods we know are good for all this and avoid the ones that we know cause harm. A fiber supplement on top of a healthy diet will help to ensure enough butyrate!