Rheumatoid arthritis (RA) is a complex, chronic inflammatory disease that is thought to affect about one percent of the world’s population. RA happens when a person’s own antibodies attack joint tissue, causing painful swelling, stiffness, and redness. Some research has suggested that there is a link between RA and gum disease.
Gum disease is estimated to affect up to 47 percent of adults, and in the disorder, oral microbes can move to the blood after the gums start to bleed. An increase in disease activity has been observed in RA patients who also have gum disease. Gum disease has been shown to be more common in RA patients who carry a certain type of antibodies, called anti-citrullinated protein antibodies (ACPAs), though ACPAs are often found in the blood of individuals with RA. The presence of ACPAs can often predate the diagnosis of RA by a few years.
A new study investigated the connections between these observations. In this work, the researchers collected blood samples from a small group of ten people with RA, five with and five without gum disease. These samples were collected every week for one year, and the investigators assessed the expression of both human and bacterial genes in those samples.
Certain types of inflammatory immune cells carried gene expression signatures that were associated with the autoimmune flares of arthritis patients who also had periodontal disease, as well as the presence of certain oral bacteria in the blood.
Many of these oral bacteria were chemically altered by deimination; they were citrullinated. Citrullination can change the structure and function of proteins. Although citrullination can be a part of the normal function of tissues, high levels of citrullination have been linked to inflammation.
Citrullination can also create targets for ACPAs; when the normal, unconverted forms of the oral bacteria were incubated with ACPAs, the antibodies did not react, but when the citrullinated oral bacteria were exposed to ACPAs, there was a reaction. ACPAs appear to be bound to oral microbes in RA patients.
The study noted that the immune response to oral microbes could be influencing RA flares, that oral microbes can trigger a specific antibody reaction in patients with both RA and gum disease, and that RA flares cause varying immune signatures, which could reflect different flare triggers.
It could be that gum disease repeatedly causes the immune system to respond, and as the immune system keeps reacting and repeatedly increasing inflammation, RA may eventually begin to emerge. More work will be needed, however, to fully understand whether gum disease is playing a causative role in the development of RA.
For many years, there was debate about whether chronic fatigue syndrome was a ‘real’ disorder. It took time, but patients were eventually validated, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was shown to be a disease that can cause various symptoms including fatigue, pain, cognitive difficulties, sleep problems, gastrointestinal issues, and post-exertional malaise. The causes of ME/CFS are still unclear and there is no way to treat it. But the gut microbiome has been shown to play a crucial role in many aspects of human health and disease, and now scientists have shown that the gut microbiomes of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) differ from those of healthy individuals. Two studies reported in Cell Host & Microbehave outlined these differences, showing that they might be used to diagnose ME/CFS. The gut microbiome may also present a treatment opportunity.
In one of the studies, researchers assessed the gut bacteria of 106 people with ME/CFS and 91 healthy controls by analyzing stool samples. This research showed that the diversity of species, quantity of microbes, metabolic interactions, and relationships among the gut microbes were different from controls.
ME/CFS patients had unusually low levels of several types of bacteria, including Eubacterium rectale and Faecalibacterium prausnitzii, which generate the short-chain fatty acid butyrate. Previous research has shown that butyrate, a microbial metabolic byproduct, plays a crucial role in gut health maintenance. Butyrate provides a source of energy for cells lining the gut, aids in protecting the cells from disease, and supports the immune system in the gut.
Additional work showed that the reduction of certain bacteria levels was linked to decreases in butyrate production. With fewer butyrate-producing bacteria present, there were other species to fill the void. ME/CFS patients had higher levels of nine microbes, including two that have been linked to autoimmune disorders and inflammatory bowel disease – Enterocloster bolteae and Ruminococcus gnavus.
Symptoms of fatigue were found to increase as levels of F. prausnitzii decreased in ME/CFS patients, which suggests that disease severity may depend on gut microbe levels. People with ME/CFS also had low levels of a microbe that generates acetate.
Biochemical processes in the gut, which are influenced by relationships among gut microbes, were also notably different from controls; the bacterial network seems to be totally altered in ME/CFS patients.
The second report analyzed differences in the microbiomes of ME/CFS patients in different stages of disease. Health data, blood, and stool samples were analyzed from 149 ME/CFS patients; 74 of them had been diagnosed within the previous four years and were classified as short-term, while 75 had been diagnosed over a decade prior and were long-term. There were 74 healthy controls included in this work.
Those who were short-term had less diversity in their microbiomes and significantly lower levels of species that generate butyrate. Long-term patients had more stable microbiomes that were more similar to healthy controls, even while these individuals had more severe symptoms and worse metabolic disturbances. In all ME/CFS patients, tryptophan metabolism was decreased.
This work has shown that there could be biomarkers for ME/CFS in the microbiome, which could also help classify the disease and may lead to treatments, though a lot more research will be needed before those tests and treatments are realized.
Gut feelings can be very real. There are neurons that connect the gut directly to the brain, and this so-called gut-brain axis has a significant influence on the body.
The microbes in the gut can also affect the brain, and researchers are trying to decipher the complex relationship between the brain and microorganisms in the body. Recent work has shown how microbial metabolites can influence brain function. Neurotransmitters can also affect gut physiology. Now scientists have developed a process that can be used by other researchers to develop a deep understanding of how gut microbes impact the brain. The work has been reported in Nature Protocols.
“Currently, it is difficult to determine which microbial species drive specific brain alterations in a living organism,” said first study author, Dr. Thomas D. Horvath, an instructor at Baylor College of Medicine and Texas Children’s Hospital. “Here we present a valuable tool that enables investigations into connections between gut microbes and the brain.”
“Gut microbes can communicate with the brain through several routes, for example by producing metabolites, such as short-chain fatty acids and peptidoglycans; neurotransmitters, such as gamma-aminobutyric acid and histamine; and compounds that modulate the immune system as well as others,” added co-first study author Dr. Melinda A. Engevik, an assistant professor at the Medical University of South Carolina.
In this process, the researchers suggest creating a three-stage workflow. First, microbes should be prepared in a defined culture media. Next, intestinal organoids are injected with the microbes. Finally, animal models are used that have either complete gut microbiomes; germ-free mice that lack microbiomes; mice that began as germ-free but were colonized with gut microbiota that carried no pathogens; and mice that started out germ-free but were colonized with individual strains of a gut microbe – Bifidobacterium dentium or Bacteroides ovatus.
The short-chain fatty acids produced by gut microbes can have a physiological impact on the brain, and they can be isolated and analyzed by liquid chromatography–tandem mass spectrometry (LC/MS) along with any neurotransmitters that are derived from microbes.
This methodology is different from research that only assesses material in stool samples, because it encompasses many other things including in vivo models and cell cultures. The study authors estimated that the mouse colonization process requires about three weeks and LC/MS techniques take about another two weeks.
“We can expand our study to a community of microbes,” said study co-author Dr. Jennifer K. Spinler, an assistant professor at Baylor and the Texas Children’s Hospital Microbiome Center. “This protocol gives researchers a road map to understand the complex traffic system between the gut and the brain and its effects.”
We’ve all seen the latest historical interpretations on television, the movies, or even the stage. And while talented costumers, set producers, and makeup artists can work wonders in re-creating the past right down to unfortunate trends in premodern dental health, there’s something we don’t often see -or even think about- when it comes to human history: parasites.
Recently, the oldest known inscription (ever!) to use a phonetic alphabet was identified on a Canaanite comb from 4,000 years ago, The inscription reads, “May this tusk root out the lice of the hai[r and the] beard.” This find showcases what it meant -and still means- to be human, i.e., to live with parasites of all forms.
Paleoparasitology is a specialized field within archaeology (and paleontology) that focuses on human-parasite relationships that have dominated our history and prehistory globally. The types of parasites that pester human populations differ from group to group -or population to population- depending on several factors like which environments we are living in, what animals we are interacting with, and how people interact with one another. The types of parasites that archaeologists can study also differ situationally, that is, depending on the preservation: i.e. mummified human remains vs. excavating a latrine or cesspool.
Apologies in advance if you feel itchy after reading.
Lice, Nits, and Otherwise Itchy Finds
In order to identify ectoparasites that live on humans, archaeologists need, well…humans. Or in some cases our clothing. Mummified human remains, particularly those with preserved hair or clothes are the best-case scenario when looking for prehistoric and historic ectoparasites.
Although eggs had been identified on both South American and Egyptian mummies prior to 1924, that was the year that the first adult lice were isolated and reported on from an Egyptian Mummy. Since then, nits, lice, and their eggs have been identified on mummies from various South American countries, Egypt, China, Greenland, and the Aleutian Islands (this is including both natural mummies and intentionally created mummies).
Lice have even been used to estimate when humans started to wear clothing by looking at when head lice evolved into body lice, approximately 70,000 to 170,000 years ago.
Our legacy with lice is a long one. Lice eggs collected from human remains in Brazil have been radiocarbon dated to 10,000 years ago. And while they didn’t have a special medicated soap to rid themselves of lice, special louse combs have been identified in Ancient Egyptian contexts from 6,500 years ago. Jumping to a little later in time, body lice eggs have also been found in 10th-14th century ‘Viking-Age’ Greenland.
And while head/body lice and nits are no fun for anyone, lets not forget the other sort of ectoparasite that’s followed humans around – Pthirus pubis L., or pubic lice- which have been found in Roman and medieval Britain.
Finally, and importantly, these parasites can spread more than just an itch, they can also spread disease. Lice and fleas in particular have been associated with several disease outbreaks in history. Most notably being the Bubonic Plague (associated with both fleas and lice), however molecular analysis has shown that louse-born infectious diseases played pivotal roles throughout history. For example B. quintana, which causes trench fever, “affected nearly one-third of Napoleon’s soldiers buried in Vilnius and indicate that these diseases might have been a major factor in the French retreat from Russia.”
Unfortunately for us, our external irritants are not the only parasites that have accompanied humans over time. Endoparasties, those that survive and reproduce inside of humans and animals, can also be identified by archaeologists.
The first endoparasite identified within mummified human remains was by Sir Marc Armand Ruffer in 1910. What he found were the calcified eggs of Schistosoma haematobium, the cause of schistosomiasis, in the preserved kidney of an Egyptian mummy dating to 3200 BCE. Today, the prevalence of schistosomiasis as a parasitic disease is second only to malaria worldwide.
Above Image: Life cycle of flatworms of the genus Schistosoma. Image Credit: CDC
More recently, Dr. Piers D. Mitchell and his colleagues, have reported on intestinal parasites identified at archaeological sites in the Mediterranean without having mummies. How did they do this you ask? Latrines.
Intestinal parasites like those reported on at these latrine sites, have complex life cycles that can be summarized as: growth, reproduction, and transmission. For the most part, it is the transmission phase that is identified archaeologically with latrines, i.e. eggs of these parasites identified in the soil that used to be an ancient or medieval latrine.
At a crusader-period site in modern Israel, roundworm (Ascaris lumbricoides) and fish tapeworm (Diphyllobothrium latum) were identified in latrine soils. This is particularly interesting given that this type of fish tapeworm was extremely uncommon in the eastern Mediterranean at the time. It was, however, very common in northern Europe. This case, as well as a recent case of ectoparasite DNA extraction, shows how regional parasites can spread with human migration and how we may be able to track prehistoric and historic human migration events and patterns using parasites.
However, it is also possible to find parasite eggs in other contexts. They have, so far, been identified in coprolites (preserved fecal matter), or even in soil samples taken from non-mummified human burials in the area that was the digestive system. Some parasites, like Echinococcus granulosus (causes Hydatid disease), can create calcified cysts in the human liver and lungs, that, given fantastic preservation, can also be identified in skeletonized inhumation burials (non-mummified). These cysts have been found in medieval Iceland and were likely accidentally spread to humans from domesticated animals.
While there is so much more to say about parasites and what we can learn from them throughout human history and prehistory, let’s leave it at this, the next time you sit back to watch your favorite historical drama remember, almost everyone was probably just really itchy.