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The gut microbiome may affect mental health symptoms like anxiety and depression, and possibly even autism

 autism gut microbiome imageSome very interesting work is being conducted to elucidate connections between the gut microbiome and mental health disorders such as anxiety, depression, and even autism. Scientific American has published several reviews on the subject. John Cryan and colleagues call it "a paradigm shift in neuroscience".

The gut is home to the enteric nervous system, which controls digestion and excretion locally. This "second brain" consists of sheaths of neurons, 100 million in all, embedded in the gut walls all the way from the esophagus to the anus. Neural communication between the brain and the enteric nervous system (gut-brain axis) goes in both directions with, surprisingly, as many as 90% of the fibers of the primary visceral nerve (the vagus) carrying information to the brain. More than 30 neurotransmitters are involved in the enteric nervous system (similar to the brain), and 95% of the body's serotonin is found in the gut. The enteric nervous system is thought to influence our state of mind and emotions. For example, electrical stimulation of the vagus nerve, which mimics and/or amplifies gut-to-brain neural activity, has been shown to be a useful treatment for depression.

The gut microbiota comprises about 100 trillion cells (several pounds of body mass) and represents up to 10,000 species of bacteria, eukaryotes, and viruses. The number of bacterial cells in the body outnumbers our own cells by 10 to 1, and the number of bacterial genes outnumbers our genes by 100 to 1.

Scientists now think that the gut microbiota play a key role in the gut-brain axis, using not only neural but also endocrine and immune pathways. In the last decade, gut microbiome influences in various mental health disorders including anxiety, depression, and autism have been reported.

  • In patients with irritable bowel syndrome (IBS), probiotics not only relieved gastrointestinal (GI) symptoms but also reduced anxiety and stress response and improved mood. Probiotics are bacterial strains thought to be beneficial to health; common species include lactic acid bacterial strains (eg, Lactobacillus acidophilus, L. rhamnosus, L. johnsonii, L. delbrueckii subsp. bulgaricus, and Streptococcus thermophilus). Live probiotic cultures are ingested as fermented dairy products, other fermented foods such as tempeh, miso, kimchi, or kefir, or manufactured freeze-dried in tablets or capsules.
  • Another study demonstrated reduced anxiety in rats and beneficial psychological effects and lower serum cortisol in human subjects when treated with L. helveticus and Bifidobacterium longum strains.
  • L. reuteri decreased anxiety in the mouse elevated plus maze model and reduced stress-induced corticosterone release; in this study, vagotomy prevented these effects, suggesting that parasympathetic innervation is involved.
  • B. infantis acted as an antidepressant in the forced swim test and relieved depression symptoms in the maternal separation model, both in rats.

Autism

Autism spectrum disorder (ASD) is a heterogeneous set of neurobehavioral diseases that can affect a patient's social interactions, communication (both verbal and nonverbal), behavior, and interests. The incidence of ASD in the US has increased dramatically from 1 in 150 children in 2000 to 1 in 68 in 2010, as reported by CDC, but it's not clear if that increase is due to increased surveillance and reporting, environmental factor(s), or other reasons. Many patients with ASD have GI comorbidities such as diarrhea, abdominal pain, IBS, and constipation, and altered GI motility and increased intestinal permeability have also been reported. Causes of these GI symptoms in patients with ASD are not clear, but Hsiao and colleagues list 8 studies from the literature in which an altered gut microbiome was identified in patients with ASD; elevated levels of Clostridium species were found in 3 of these studies.

In a recent review of this nascent field, Cheryl Rosenfeld summarizes the animal studies, human epidemiologic studies, and work on other microbiomes (eg, oral cavity, placenta), as well as possible mechanisms and therapies. I've selected one interesting animal study to review in detail.

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I've been hacked! My microbes made me eat that jelly doughnut!

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A hot topic these days is how the millions of bacteria in the digestive system, collectively known as gut microbiota, might be influencing many aspects of health, including mental health, autoimmune diseases, metabolic diseases, and some cancers. (A very similar term, microbiome, refers to the collective bacterial genome.) The journal Nature in conjunction with Scientific American published a supplement in February 2015 titled "Innovations in the Biome", and Scientific American has published several interesting articles on connections with obesity and inflammatory bowel disease.

The microbiome, described by Joshua Lederberg as "the ecological community of commensal, symbiotic, and pathogenic microorganisms that literally share our body space", comprises approximately 10,000 microbial species (bacteria, eukaryotes, and viruses). Almost all of the gut bacteria fit into 30 or 40 different species. We each host approximately 100 trillion microbial cells in the gut that account for several pounds of our total body mass. These bacterial cells outnumber our own cells by 10 to 1, and bacterial genes outnumber our genes by 100 to 1. Some of the well-characterized useful functions of gut bacteria include fermenting unused energy stores, training the immune system, preventing growth of pathogenic bacteria, regulating gut development, and producing vitamins and hormones. But they also seem to be influential in many organs and diseases outside the digestive system. Every time I turn on the TV or radio, or look at a newspaper, a magazine, or a research journal, there's something about the microbiome, antibiotics, probiotics, prebiotics, the enteric nervous system, the second brain, fiber, fermented foods, bacterial diversity. Just like the bacteria themselves, it's everywhere.

The National Institutes of Health (NIH) created the Human Microbiome Project in 2008 to facilitate work in the area of the human microbiome. Their initial projects focused on developing metagenomics databases and computational tools for characterizing the microbiome in healthy adults and in cohorts of patients with specific microbiome-associated diseases.

In 2012, researchers at the University of Colorado Boulder launched the American Gut Project, a crowd-funded, open-assess project where anyone can pay for sequencing of their gut bacteria. Participants provide samples along with personal health information. In turn, this provides the researchers with data they can use for basic research. Michael Pollan, a bestselling author and journalist who writes about food and agriculture, is one of the thousands of people who have participated.

In the area of metabolic syndrome and obesity, I found two research papers especially interesting. In the first, researchers were able to bring on metabolic syndrome in germ-free wild-type (WT) mice by transplanting gut microbiome extracts from mice with metabolic syndrome symptoms and then reverse these symptoms with antibiotics. In the second study, scientists were able to induce obesity in germ-free mice by transplanting fecal microbiome samples from an obese human subject. These studies are described in more detail below.

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Could a video game be an FDA-approvable medical device?

video game

In a recent Commonwealth Club talk, Adam Gazzaley, MD, PhD, director of a cognitive neuroscience research laboratory at the University of California, San Francisco (UCSF) described efforts to design video games that could be used for brain training, specifically in the treatment of senior mental decline as well as ADHD and autism. Researchers in the Gazzaley Lab at UCSF study the neural mechanisms of memory, attention, and perception and are evaluating innovative video games as a therapeutic approach to alleviate cognitive defects. Their "Project: EVO" platform is being productized by Akili Interactive, a Boston-based company. These video games are designed to sensitively quantitate neural function and/or intervene in any measured deficits. Akili is currently planning or conducting clinical trials using Project: EVO games in patients with ADHD (partner: Shire Pharmaceuticals), Alzheimer's disease (detection, not treatment; partner: Pfizer Pharmaceuticals), autism (partner: Autism Speaks/DELSIA), depression (partner: National Institute of Mental Health), and traumatic brain injury.

In Gazzaley's lab, researchers are evaluating a prototype, NeuroRacer, a custom-designed 3-D video game that looks like a driving simulator, in the treatment of cognitive decline in the elderly. It is designed to improve multitasking ability by training the brain to lessen the impact of interference. The idea behind this is that attention remains roughly the same at all ages, but the ability to ignore interference (interruptions and distractions, both auditory and visual) decreases with age. Thus older people tend to be poorer multitaskers than younger people. However, the brain is quite plastic and responds to training. Training in this case is delivered via a fast-paced video game that is targeted, personalized, multimodal, and closed loop. The game challenges attention, working memory, and processing speed. It is unpredictable and engaging, with adaptable difficulty, feedback (error messages, motivating rewards), richness, and immersiveness.

Gazzaley intends to seek FDA approval for NeuroRacer as a medical device. As Roland Nadler points out in his blogpost, the FDA's definition of medical device is quite broad and could encompass this technology. It would not be the first time that approval was sought for a software package: Brain Plasticity Inc, a technology incubator located in San Francisco, initiated a similar process in 2011.

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Antibiotics show promise as primary treatment in patients with acute uncomplicated appendicitis

Appendicitis image

The appendix is a blind-ended tube connected to the cecum in the colon. It may be vestigial, but it also seems to act as a repository of useful bacteria that can replenish the gut microbiome after disease has depleted it. Acute appendicitis can result from viral, bacterial, or fungal infection and obstruction of the appendix lumen. Bacteria in the appendix multiply rapidly, causing swelling, and the walls of the appendix gradually break down. Appendix rupture can occur, which can result in peritonitis and eventually sepsis.

Since the late 1800s, physicians have assumed that without surgery, uncomplicated appendicitis cases would progress to perforated appendicitis. Thus, appendectomy has been the standard of care for treatment of acute appendicitis ever since. Starting in the early 1980s, appendectomy has been performed laparascopically.

As Dr. Edward H. Livingston points out in a recent JAMA editorial, while the standard of care for appendicitis treatment has not changed in over 100 years, advances in computed tomography (CT) imaging have nearly perfected diagnostic accuracy. In addition, new broad-spectrum antibiotics show promise in effectively wiping out the organisms that cause serious complications in appendicitis. Two recent studies that compared appendectomy vs. antibiotics as primary treatment for acute appendicitis are summarized here:

The Appendicitis Acuta (APPAC) study, conducted by Finnish researchers and reported in JAMA June 16, 2015, compared antibiotic therapy with appendectomy in the treatment of acute appendicitis. In this multicenter, randomized, open-label noninferiority study, 530 patients ages 18 to 60 years with acute uncomplicated appendicitis confirmed by CT scan were enrolled. Patients were randomly assigned 1:1 to either standard open appendectomy or antibiotic therapy (IV ertapenem 1 g/d for 3 days, followed by oral levofloxacin 500 mg/d and metronidazole 500 mg tid for 7 days). Treatment success was defined in the surgery group as successful completion of the appendectomy and in the antibiotic group as discharge from the hospital without the need for surgery and no recurrent appendicitis during a 1-year follow-up period. A noninferiority margin of 24% was predefined.

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