It’s been known for quite a long time that shift workers are at an increased risk for developing a number of diseases. Observational studies have found a strong association between shift work and heart and cerebrovascular diseases. (1) Other studies have noted robust correlations between shift-work and the risk of obesity (2) (3), diabetes (4), hypertension (5) and breast cancer (6).

A recently published study conducted in mice may offer an explanation for these findings. (7) What this study found was that disrupting the light:dark sleep cycles of mice induced increased intestinal permeability that in turn led to endotoxemia and liver damage.

Before determining whether shifting light:dark cycles would affect gut permeability in regular mice, these researchers studied mice genetically bred to have disturbed circadian rhythms. As I explained in a previous post:

“A circadian rhythm (from the Latin “circa diem” or “about a day”) is any biological process that occurs in a 24-hour period in response to external stimuli. Circadian cycles are self-sustaining, however, even in the absence of the stimuli that originally influenced them. A wide range of biological functions are regulated by the circadian clock including energy metabolism, cell cycles and repair, body temperature, hormone secretion and of interest to us today, sleep.

This rhythm is under the control of a “master” biological clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus.

But the SCN is not the only biological clock in the body, although it is the most important. In fact, most tissues within the body express peripheral or “slave” clocks that also regulate sleep. Whether these peripheral clocks respond to light is still unknown, but they do respond to feeding, temperature, activity, hormones and neuronal signals. It would not surprise me that beneficial gut bacteria also influence these secondary clocks. Interestingly, while the SCN usually coordinates these “slave” clocks, they are capable of functioning independently of the “master” clock.

In the hypothalamus, the SCN receives information about light from the ganglion cells in the retina via the retino-hypothalamic tract. Synchronization with actual day-night light cycles occurs through a process called entrainment. SCN rhythms can be shifted by exposing a person to a new light/dark schedule although this takes time as anyone who has experienced jet lag or shift work can tell you.”

The disruption of circadian rhythm in these genetically altered mice is being used by researchers to discover what is likely to happen in humans when these cycles are environmentally affected in us. What the researchers of this paper discovered was that these mice experience increased intestinal permeability in contrast to their wild-type litter mates. What is particularly alarming about these results is that increased permeability was not localized to the small intestine, but rather the colon.

Mice were fed separate markers to measure gut leakiness. Sucrose (aka sugar) to measure duodenal permeability, mannitol or lactulose to measure permeability in the jejunum and ileum and finally sucralose to measure colonic permeability. There were no significant differences between either group when it came to small bowel permeability, not so with the colon.

As the colon has the highest microbial count in both mice and humans, any increase in intestinal permeability here would contribute the most to endotoxemia, liver damage and systemic inflammation. Couple this with colonic dysbiosis caused by an overgrowth of gram-negative gut pathogens, and their highly inflammatory lipopolysaccharide (LPS) cell-wall components, and the chances for chronic disease increases exponentially when gut-wall barrier function is compromised in this part of the digestive tract.

Returning to our mice experiment, feeding both groups of mice alcohol exacerbated intestinal permeability. This isn’t surprising as alcohol reliably does this in both the small and large intestine, hence the reason binge drinking and alcoholism increase the risk of cancer, stroke, heart disease, liver disease, etc. As these researchers noted:

“Similar to our previous study, we found that alcohol caused significant intestinal hyperpermeability. We also found that circadian disruption led to earlier onset and greater magnitude of alcohol-induced gut leakiness: alcohol-fed Clock mutant mice [circadian-disrupted genetic mice] exhibited significantly elevated urinary sucralose levels compared to alcohol-fed wild-type mice that were evident after the first week on the full concentration of alcohol in the diet and remained significantly elevated after four weeks.”

To see if these results would hold true in non-genetically altered mice, regular mice were subjected to twelve-hour light shifts in their light:dark cycles every week for three months:

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Courtesy: Disruption of the Circadian Clock in Mice Increases Intestinal Permeability and Promotes Alcohol-Induced Hepatic Pathology and Inflammation

The light-shifted (S) mice are represented by the bar on the right. As in the previous experiment, intestinal permeability was significantly higher in this group in contrast to the non-shifted (NS) mice. And once again, the part of the digestive tract most affected was the colon.

The addition of alcohol to both sets of mice did neither group any favors when it came to permeability in the colon. However, it impacted the circadian-disturbed mice far more than the mice who maintained stable day-night hours.

Madam? Would you like some gut pathogens with your third Cosmo? No? Oops, too late!

I began this post with a series of observations about the deleterious effects of shift work on human health. This study suggests that the reason for these observations is disruption of intestinal barrier function in the colon leading to endotoxemia, liver damage and systemic inflammation.

These results are likely due to disturbances in the tight junctions that bind colonic epithelial cells together. These researchers found that in the mice experiencing the most leakiness, levels of the tight-junction protein occludin were decreased. What isn’t known, because it wasn’t tested, were the effects of circadian disruption on gut flora populations.

Gut dysbiosis reliably increases intestinal permeability. Had these researchers tracked changes in the microbial composition in the colons of these rodents, I have no doubt they would have observed shifts away from beneficial species towards pathogenic ones, explaining the disruption in tight-junction and gut-wall barrier function.

The rise of industrial capitalism in the 19th century, along with the invention of artificial lighting, has led to an exponential increase in shift work throughout the world. And many other non-industrial workers like emergency responders, hospital staff, hotel workers, military personnel, infrastructure and telecommunications workers, airline personnel and some food and retail workers are also subjected to these shifting time schedules.

Couple these work environments with after-work binge drinking, and the damage is worsened. And what’s true for these workers is also true for jet setters who often start their journeys in high spirits, often because they’re drinking them, only to find themselves sick or worse during or shortly after their world travels.

I’ve received more than a few emails from customers who trace their GI troubles to a trip abroad. While it is conceivable that a foreign bug or parasite hitched a ride home in their digestive tract, it is also possible that time shifts coupled with a bit of uninhibited drinking may be the real initiating cause of their later gut problems.

Of course, binge drinking isn’t the only bad dietary habit that can compound the problem of circadian disruption. Diets lacking in the prebiotic fibers that feed colonic bifidobacteria will also add to increased colonic permeability.

Apart from out competing other potentially troublesome bacteria, bifidobacteria produces the short-chain fatty acid known as butyrate as a normal byproduct of fermenting these prebiotics. Butyrate, as you all recall, feeds and strengthens epithelial cells lining the digestive tract. And it is also essential for maintaining the tight junctions that bind these cells together.

The last thing in the world a shift worker or jet setter needs is depleted colonies of bifidobacteria. I would imagine that most of the negative impacts to the health of the mice studied in this paper could have been mitigated or entirely eliminated by the augmentation of bifidobacteria.

So my advice to all you shift workers and jet setters out there is to cool it on the binge drinking, and increase the levels of bifidobacteria in your colons. Otherwise, you risk having your career come to an abrupt and premature end.

 

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