Could a healthy microbiome affect genes linked with colon cancer?
Writing in Nature Communications, the team said short chain fatty acids (SCFAs) produced by beneficial gut bacteria appear to influence gene regulation in the gut lining.
Activity levels of a complex process called histone crotonylation are linked to an enzyme called histone deacetylase-2 (HDAC2), said the research team led by the Babraham Institute, Cambridge, UK.
High levels of HDAC2 expression may be involved in colon cancer development, previous research has suggested.
When the scientists induced lower numbers of gut bacteria in mice using antibiotics, they found a reduction in the amount of SCFAs present, accompanied by a decrease in histone crotonylation. The researchers also found higher amounts of an enzyme called histone deacetylase-2 (HDAC2) in the microbiota-depleted mice.
Further investigations showed that HDACs induced a decrease in crotonylation levels, but that SCFAs prevented this process by blocking the effect of the HDACs.
“We show that known HDAC inhibitors, including the gut microbiota-derived butyrate, affect histone decrotonylation. Consistent with this, we find that depletion of the gut microbiota leads to a global change in histone crotonylation in the colon,” wrote first author, Rachel Fellows.
Microbiome link with chromatin
The scientists also proposed that SCFAs and HDACs, through crotonylation, might therefore provide the explanation as to how the gut microbiota influence a substance called chromatin.
Chromatin is critical to “regulating, organizing, safeguarding and packaging the genetic material,” in the human body, said lead researcher Dr Patrick Varga-Weisz.
Maintaining an adequate production level of SCFAs through a healthy diet incorporating high intakes of fibre-containing fruit and vegetables, may therefore be important to colon health, suggest the scientists.
"Our intestine is the home of countless bacteria that help in the digestion of foods such as plant fibres. They also act as a barrier to harmful bacteria and educate our immune system. How these bugs affect our cells is a key part of these processes. Our work illuminates how SCFAs contribute to the regulation of proteins that package the genome and, thus, they affect gene activity,” commented Varga-Weisz.
Although SCFAs are widely recognised as a valuable source of energy for cells in the gut lining and are recognised as HDAC inhibitors, this is the first study to identify their influence on crotonylation.
The findings are significant, as high levels of HDAC2 have been linked to the development of colon cancer.
The researchers believe that changes in crotonylation can alter gene activity by switching genes on or off. If confirmed, this could eventually lead to cancer prevention strategies, which might target the regulation of crotonylation in gut cells.
"Short chain fatty acids are a key energy source for cells in the gut but we've also shown they affect crotonylation of the genome. Crotonylation is found in many cells but it's particularly common in the gut. Our study reveals why this is the case by identifying a new role for HDAC2. This, in turn, has been implicated in cancer and offers an interesting new drug target to be studied further," said Fellows.
“Future studies will examine how HDAC2 expression, microbiota, and SCFAs are linked and how this affects histone crotonylation over specific genes and cancer progression in the colon,” she concluded.
The results also highlight the importance of a healthy microbiome and diet containing fruit and vegetables.
Source: Nature Communications
Published online, doi: 10.1038/s41467-017-02651-5
“Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases”
Authors: Rachel Fellows, Patrick Varga-Weisz et al