Acute infections represent frequent and violent tissue perturbations from which the immune system must rapidly rebound. Fonseca et. al.
Researchers have long believed that infections can kick off inflammatory diseases, but the link between an infection and a long term illness has been hard to substantiate. How infections could turn into a long-term inflammatory state has been mostly a mystery as well. A recent study that dug deep into the gut, however, is providing some answers.
Fonseca DM, Hand TW, Han SJ, Gerner MY, Glatman Zaretsky A, Byrd AL, Harrison OJ, Ortiz AM, Quinones M, Trinchieri G, Brenchley JM, Brodsky IE, Germain RN, Randolph GJ, Belkaid Y. Microbiota-dependent sequelae of acute infection compromise tissue-specific immunity. Cell (2015).
This mouse study found that a single gut infection was capable of permanently altering the structure of the gut and the gut flora. That didn’t happen in all the mice and it wouldn’t happen in all humans but it shows how an infection that has been successfully fought off could set the stage for a later disease.
The study was not conceptually difficult. The researchers simply dedicated themselves to very, very closely examining the changes that occurred in the gut during an infection.
They infected mice with a bacterium called Yersinia pseudotuberculosis which causes a tuberculosis-like illness (but not TB). The symptoms it produces include fever, abdominal pain, joint stiffness and skin problems. (It’s very close genetically to the bacterium that causes plague.)
They knew that Y. Pseudotuberculosis would reach its peak load in about a week, that the adaptive immune response would kick in at about two weeks, and the infection would be fully controlled in about three.
It all went like clockwork. All the mice successfully cleared the virus but as they did so a significant number of them developed what the researchers termed “immune scarring” in their lymphatic vessels.
The researchers knew that the lymphatic vessels would undergo huge changes as the immune system swarmed to attack the invader. Human studies have found that an Y. Pseudotuberculosis infection results in swollen, abscess-ridden lymph vessels.
No one had ever determined, though, if those changes remained after the infection or what consequences they might have for the patients immune health. This kind of single-minded approach – focusing almost entirely on the dynamics of fighting the infection – while ignoring the possible consequences of that fight has permeated infectious disease research.
Immune System Takes a Hit
This study found, though, that the immune response to the infection had consequences long after the infection had cleared. Nine months later the lymphatic vessels still demonstrated dramatic structural alterations and remained swollen and abcess ridden. One gut infection had permanently altered the structure of one of the major players in the immune systems of 70% of the mice.
The effects of the altered lymphatic regions were significant. The mice with the lymphatic damage were unable to produce normal levels of the regulatory T cells which suppress inflammation and prevent allergic responses. That alone could set them (or a human) up for an inflammatory disease later on.
Upon challenge testing the mice displayed a delayed type hypersensitivity reaction; i.e. an exaggerated immune response. Anaphylaxis and allergy are two forms of a hypersensitivity reaction, and the authors suggested that allergic responses to food could result. (Both the big CFI immune and the recent McNaughton immune study found elevated levels of eotaxin – an allergic factor – in ME/CFS patients.)
The TH17 response that helps clear infection and plays a role in autoimmunity was dramatically impaired. Pathogen recognition was hindered. The dendritic cells (DC’s) had trouble conveying antigens to the immune cells in the altered lymph vessels. In fact, some of them missed the now strange-looking lymphatic vessels entirely and ended up in the fatty tissues -where they were doing no good at all.
Without the DC’s conveying evidence of a pathogen to the T-cells inside the lymph vessels the adaptive immune response might never kick in. That suggested the mice would probably have trouble fighting off infections.
The lymph vessels had also been so altered by the infection that they leaked substances back into the gut.
The authors stated that the gut problems seen could result in multiple immune defects including the development of Th17 cells, T-regulatory and B cell responses in the GI tract.
The Gut Flora Connection
“…these data reveal a central role for the microbiota in the maintenance of the immune defects induced by acute infection. Fonseca et. al.
The most interesting part of the study came, though, when they altered the gut flora. Knocking out the mouse’s gut flora with an antibiotic resulted in major improvements in the lymph vessels. The success of the antibiotic suggested that manipulating the gut flora using probiotics could reverse much of the “immune scarring” and inflammation the infection had left behind.
Because the gut flora of the mice which developed inflammation did not differ from the mice which did not, it appears that the infection itself permanently altered the composition of the gut flora. The authors suggested the leaky lymphatic vessels might be to blame.
The study found that a single gut infection can drastically and permanently alter the structure of the lymphatic vessels in mice. The altered lymph vessels could result in chronic inflammation and increased difficulty in finding and fighting off further infections. They also appear to negatively alter the gut flora in such a way as to maintain the “immune scarring” that occurred.
The good news in this otherwise seemingly bleak scenario is that altering the gut flora may be able to reverse much of the “immune scarring” that took place – and return the immune system to normal.
The study was done in mice, but it suggests what some researchers have been contemplating for quite a while: that some of those gut infections could predispose some of us to chronic illnesses years later. As the authors of the study pointed out children tend to experience many gut infections. Children who experience immune scarring as a result of them could be set for chronic inflammatory diseases (such as ME/CFS and FM?) years later. It’s perhaps notable that gut disturbances are common in both diseases.
That kind of time lag is not unusual at all. Early life stressors have been shown to predispose people to a increased risk of inflammatory and other disorders decades later. In a recent Simmaron Research Institute talk, Ian Lipkin explained how events at different times during pregnancy can have effects years later. A bout of infectious mononucleosis/glandular fever as a teenager increases the risk of coming down with multiple sclerosis as an adult.
Gut infections later in life such as giardiasis have been associated with chronic fatigue syndrome. It could be, though, that a gut infection early in life could set one up for a poor response to another type of infection later in life. It’s possible that the infection which appeared to have begun your illness may not have been the ultimate source at all.
This study will surely prompt more research into the already hot field that’s examining the effects of probiotics and gut flora manipulation on health.
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