Could gut bacteria cause joint pain? By Tim Newman

Finding a link between osteoarthritis and the bacteria in our guts seems unlikely. However, new research concludes that they could, in fact, be bedfellows.

Obesity comes with a raft of related health risks, including diabetes and cardiovascular disease. It is also intimately tied to osteoarthritis.

Often referred to as the "wear and tear" arthritis, osteoarthritis involves the slow degradation of cartilage, or the padding between bones in a joint.

In the United States, osteoarthritis affects an estimated 31 million people and is a leading cause of disability, globally. As it stands, osteoarthritis cannot be cured.

People who carry excess weight put extra strain on their joints. This, it was thought, explained the increased risk of osteoarthritis that comes with obesity.

A new study, published this week in the journal JCI Insight, looked at a more intriguing mechanism that might link these two conditions: gut bacteria.

We have billions of bacteria living in our intestines. They are vital for good health and, over recent years, just how vital they are has become increasingly clear.

Researchers from the University of Rochester Medical Center in New York set out to explore what links there might be between diet, obesity, gut bacteria, and osteoarthritis.

Fattening up mice

To begin with, the researchers fed mice a high-fat diet over a 12-week period. They quickly became diabetic and obese, doubling their percentage of body fat. Next, the bacterial residents of the animals' colons were assessed.

As expected, their microbiomes were off-kilter; their bowels were overrun with pro-inflammatory bacteria and had a distinct lack of healthy, probiotic bacteria, such as Bifidobacteria.

At the same time, the scientists observed body-wide inflammation in the obese mice, including the knee joints. To induce osteoarthritis, the researchers tore the animals' menisci, or the cushion of cartilage between the shin and thigh bones. This type of injury commonly causes osteoarthritis.

In the obese mice, osteoarthritis developed much more quickly than in the control mice. In fact, within 12 weeks, virtually all of the obese mice's cartilage had gone.

"Cartilage," says Michael Zuscik, Ph.D., an associate professor of orthopaedics in the Center for Musculoskeletal Research, "is both a cushion and lubricant, supporting friction-free joint movements.

"When you lose that," he says, "it's bone on bone, rock on rock. It's the end of the line, and you have to replace the whole joint. Preventing that from happening is what we, as osteoarthritis researchers, strive to do — to keep that cartilage."

Can cartilage degradation be slowed?

For the next phase of the study, the scientists started the protocol again: they fattened up mice with a 12-week, high-fat diet. But this time, they included a prebiotic called oligofructose.

Prebiotics — not to be confused with probiotics — cannot be broken down by mouse (or human) guts. However, many beneficial bacteria, such as Bifidobacteria, thrive in their presence.

This subtle but important change in diet promoted the growth of healthy bacteria and produced a marked reduction in pro-inflammatory bacteria.

Importantly, it also reduced inflammation in the joints, and the knee cartilage of the obese mice was indistinguishable from that of the non-obese control mice.

The addition of a prebiotic to the diet also reduced diabetic symptoms. But it made no difference to the amount of weight that the mice gained.

So, even though the joints were subjected to the same amount of strain, they were healthier. This supports the theory that inflammation, rather than mechanical strain, is the key driver of osteoarthritis.

"That reinforces the idea that osteoarthritis is another secondary complication of obesity — just like diabetes, heart disease, and stroke, which all have inflammation as part of their cause."

Robert Mooney, Ph.D., a professor of pathology and laboratory medicine

"Perhaps," adds Prof. Mooney, "they all share a similar root, and the microbiome might be that common root."

A note of caution

It is vital to remind ourselves that, though the findings are exciting, there are significant differences between the mouse microbiome and our own. The next step, therefore, will be to move this line of investigation into humans.

The leaders of this study plan to team up with the Military and Veteran Microbiome: Consortium for Research and Education at the U.S. Department of Veterans Affairs in Denver, CO.

They hope to compare the microbiomes of veterans with and without obesity-related osteoarthritis. They will supplement some of these participants with prebiotics to gauge how much benefit this intervention might have in humans.

New colon cancer drugs may arise from protein discovery By Honor Whiteman

Better treatments for colon cancer may be in sight, thanks to a new study, which reveals new ways in which a single protein could stop the disease in its tracks.

Researchers found that a protein known as APC can "put the brakes" on a number of pathways that drive the development of colon cancer.

This discovery could open the door to new drugs for the condition.

Study co-author Dr. Yashi Ahmed — who works in the Norris Cotton Cancer Center at Dartmouth College's Geisel School of Medicine in Hanover, NH — and colleagues recently reported their results in the journal Developmental Cell.

Colorectal cancer — which begins in the colon or the rectum — is now the third most common cancer in the United States. It is also the third leading cause of cancer-related death.

This year, around 97,220 new cases of colon cancer are expected to be diagnosed in the U.S.

Scientists have already pinpointed APC — which is a protein endowed by the APC gene — as a possible target for the prevention of colorectal cancer; the protein regulates the growth and division of cells, stopping them from spiraling out of control and forming tumors.

On the other hand, the deactivation of APC can spur the development of colorectal cancer.

Role of APC 'broader and multifaceted'

Dr. Ahmed and colleagues explain that when it comes to the cancer-protecting role of APC, it was believed that the protein targets and destroys a single "activator" — specifically, a protein called beta-catenin — to prevent colon cancer.

By studying the APC-deficient cells of fruit flies — which harbor around 75 percent of the genes that cause human disease — the researchers uncovered other mechanisms by which APC can halt colon cancer.

"Unexpectedly," the authors say, "we find that blocking Wnt receptor activity in APC-deficient cells inhibits Wnt signaling independently of Wnt ligand. We also show that inducible loss of APC is rapidly followed by Wnt receptor activation and increased beta-catenin levels."

Dr. Ahmed says that these findings challenge the currently accepted view of how APC prevents colon cancer, "revealing that APC's role is much broader and multifaceted."

What is more, the researchers believe that their discovery could lead to new treatments for one of the most commonly diagnosed cancers.

"Because this new role of APC involves proteins on the cell surface," explains Dr. Ahmed, "targeting colorectal cancers may become easier. For example, therapeutic antibodies, which normally cannot work inside the cell, can now be used to treat colorectal cancers that have APC mutations."

Study co-author Dr. Ethan Lee, of the Department of Cell and Developmental Biology at Vanderbilt University in Nashville, TN, adds that their study may also help researchers to understand why APC mutations appear to be a key player in specific cancers.

"Certain tissues may have a backup mechanism to put the brakes on the pathway when APC is mutated," Dr. Lee speculates.

The researchers conclude that further studies are needed to uncover the deeper details of how APC can stop colon cancer.