For today’s edition of Dear Mark, I’m handling just one question. I originally planned to answer more reader questions, but it turned into a complex answer that really made me dig deeper into something – butyric acid – I’d assumed was completely benign. I still do, mind you, for the most part. The position has just become more nuanced. Anyway, the question is from a reader who’s just seen a study that seems to implicate butyric acid, the primary short chain fatty acid that resistant starch-eating gut bacteria produce, in colon cancer. Was my ringing endorsement of resistant starch a mistake after all?
Did you see this new article? It seems to implicate resistant starch as being a cause of colon cancer by increasing butyric acid which increases tumor growth. Are we making a big mistake with all this potato starch, green banana stuff? It definitely seems like it’s improved my digestion and sleep, but I’m pretty worried about this cancer connection (a couple of relatives have died from it).
Looks scary at first glance, I agree. A metabolite of colonic bacteria usually assumed to be wholly good for us – butyric acid – increased colon cancer in genetically susceptible mice. That’s the same metabolite that resistant starch increases, and it’s often touted as one of the main reasons to even eat the stuff. What gives?
Here’s the study. Or the abstract, at least. The rodents used in the experimental group were mutants with a gene deletion, not “wild type” mice. The deleted gene coded for the MSH2 protein, a regulator of DNA mismatch repair. To understand why this matters, let me briefly (and superficially) explain DNA mismatch. During synthesis of new DNA, adenine (A) is supposed to pair with thymine (T) and guanine (G) is supposed to pair with cytosine (C) to form nucleotide base pairs along the double helix. If errors occur and A matches with C or G matches with A or T matches with C, the DNA won’t function properly. That’s where MSH2 comes in; it’s part of the protein complex that identifies the mismatch errors so that another set of proteins can come in and fix them.
What does this mean for you?
While MSH2 can be epigenetically silenced, we don’t know of any environmental triggers like diet, exercise, sleep, or stress (although a safe bet is to do healthy stuff regardless), and the vast majority of MSH2 defects stem from germline mutations which occur upon or shortly after conception, are highly heritable and immutable. Even among patients with confirmed epigenetic inactivation, 70% still have the germline mutation.
How common are MSH2 mutations overall? Well, a hereditary condition known as Lynch Syndrome is responsible for 3-5% of all colon cancer cases, and MSH2 mutations account for 40% of Lynch Syndrome cases. This condition is actually fairly rare in humans, and colon cancers associated with MSH2 irregularities account for “just” 2-4% of total colon cancer cases (I hate to use “just” when discussing cancer case statistics, because those percentage points represent afflicted people and families and friends, not abstract numbers – but it’s the best word we have). So as far as MSH2 goes, it’s not a huge contributor to colon cancer in the grand scheme of things.
This is an interesting study, but I don’t think it’s particularly relevant to the majority of people. The control mice, who should be roughly analogous to most people reading, didn’t experience an increase in cancer with increased butyrate.
The bulk of the available research points to butyrate production – and the resistant starch consumption that promotes it – as protective against colon cancer. Plus, eating resistant starch can protect against some of the risk factors linked to colon cancer:
- Inflammatory bowel disease – In induced IBD, resistant starch speeds up the healing of the intestinal wall and reduces the severity of the inflammation while increasing butyrate production and uptake by colonic cells. Colitis is often associated with a reduced uptake of butyrate by the cells of the colon, but resistant starch almost normalizes it. RS also regulates inflammatory cytokine secretion and T-reg cell release in the gut of IBD mice to control inflammation. Directly injecting butyrate into the colons of colitis patients reduces inflammation, bowel movement frequency, and blood in the stool.
- Abdominal obesity – A recent mouse trial randomized subjects into two groups. One received a high resistant starch diet, the other received a diet high in digestible starch. While both groups gained the same amount of weight, the digestible starch group’s weight gain was concentrated in the abdominal region. They also gained more body fat overall. The RS group gained less fat and more lean mass; these were rippling mouse Adonises, folks.
If those risk factors have a causative relationship to colon cancer (and even if they don’t, it’s nice to not have IBD or a lot of visceral belly fat) eating resistant starch should improve resistance.
A 2007 review paper looked at this apparent “butyrate paradox,” (PDF) finding that “time at which the colorectal lesions (early vs. late stage) are exposed to fiber/butyrate are all factors that may influence the protective role of fiber against CRC.” A few of their other findings:
- In early adenomas/polyps/benign colonic tumors, butyrate is highly protective, inhibiting growth and development into carcinomas.
- Chronic, low levels of butyrate exposure might be inadequate for protection and actually select for cancer cells that are resistant to the inhibitory effects of butyrate. Thus, if early adenomas are exposed to low butyrate levels, they can become butyrate-resistant (malignant) carcinomas if allowed to progress. “Go big or go home.”
- Most human colon cancer lines are greatly inhibited by butyrate infusion, but some are far more resistant to its effects.
- Butyrate/resistant starch is probably best at inhibiting the early stages of tumor development and less effective in later stages.
From my reading of the research, resistant starch (and the resultant butyrate) has an overall beneficial, preventive effect on colon cancer risk. That relationship may change or become more complicated in advanced colon cancer, and the story may be entirely different for people carrying the MSH2 mutation from today’s highlighted study, but that remains to be seen. For now, I’m still incorporating RS into my diet.
If you’re worried, ask your doctor about getting an MSH2 status test. And review your family history of cancer. Was it colon? Was it a DNA repair mismatch-related case? Even if you do have the MSH2 mutation and a family history of Lynch Syndrome, don’t fear fermentable fibers, resistant starches, and butyrate. Your colonic cells run on butyrate. It’s their primary energy source. And all the other myriad benefits of prebiotics remain relevant. Besides, this is one study. It’s not proof or confirmation of anything. Not yet.
Thanks for reading, everyone! Let’s hear what you think about all this in the comment section.