Fe­cal Trans­plants in the "Good Old Days"

by Stan­ley Falkow

I had a con­ver­sa­tion with some col­leagues last week about "per­son­al­ized med­i­cine," which has been trans­formed now into the term "pre­ci­sion med­i­cine." The con­ver­sa­tion re­volved around what to do about the per­ceived ef­fects of an­tibi­otic treat­ment on the mi­cro­biota of in­di­vid­u­als. How does one treat a pa­tient with­out dis­rupt­ing their mi­cro­biota? Do we cre­ate new classes of an­timi­cro­bials that tar­get only a pre­cise pathogen? I opined that I thought the day was com­ing when all in­di­vid­u­als might have the mi­cro­biota from each anatomic site pre­served so that it could be re­con­sti­tuted af­ter some cat­a­strophic dis­rup­tion caused by an­timi­cro­bial ther­apy for an in­fec­tion, trans­plan­ta­tion, surgery etc. The topic of fe­cal trans­plan­ta­tion and how suc­cess­ful it has been for the treat­ment of in­tractable Clostrid­ium dif­fi­cle in­fec­tion then came up. Would fe­cal re­con­sti­tu­tion re­ally work?

I an­swered truth­fully that I did not know, but my ex­pe­ri­ence many years ago led me to be­lieve it would. One of the peo­ple in this con­ver­sa­tion, John Mekalanos, no stranger to stools, asked when I par­tic­i­pated in a fe­cal trans­plan­ta­tion study. It oc­curs to me that my ex­pe­ri­ence in this study it might be of in­ter­est, or at least tit­il­late, those who read this blog.

I was a 23-year-old med­ical tech­nol­o­gist (MT, ASCP) in 1957 work­ing as a jour­ney­man bac­te­ri­ol­o­gist in sev­eral clin­i­cal lab­o­ra­to­ries in Rhode Is­land and Mass­a­chu­setts. It was a time when the Staphy­lo­coc­cus au­reus 80/81 phage type was rais­ing a specter of un­con­trolled hos­pi­tal in­fec­tions. It was a time when large doses of an­tibi­otics were ad­min­is­tered to pa­tients pre-op­er­a­tively and con­tin­ued un­til they were dis­charged some days later. Many of these pa­tients re­ported to their physi­cians that they suf­fered from di­ar­rhea, flat­u­lence, in­di­ges­tion and gen­er­ally felt ter­ri­ble af­ter their surgery, though the op­er­a­tion was deemed a suc­cess. This was be­fore any­one knew about C. dif­fi­cle, of course, but an­tibi­otic-as­so­ci­ated di­ar­rhea was known even in those days. One of the in­ternists I knew well came to talk with me. I should point out that in the late 1950s many (most) of the physi­cians were fre­quent vis­i­tors to the bac­te­ri­ol­ogy lab­o­ra­tory be­cause they wanted to look at the Gram stains and the cul­tures ob­tained from their pa­tients. The physi­cian in ques­tion, who I will sim­ply call Dr. S, thought af­ter ex­am­in­ing and talk­ing to pa­tients who had not "felt right" af­ter their surgery had suf­fered from the af­ter­ef­fects of the an­tibi­otics that had been given them to ster­il­ize their bowel flora be­fore surgery. The fe­ces of many of these pa­tients would yield no growth on blood agar plates and Mac­Conkey agar for days af­ter their surgery. (We didn't do anaer­o­bic cul­tures in those days though). The stools were even odor­less. Few stools can make that claim. S thought that their nor­mal flora had been dis­rupted by the an­tibi­otics. 'Healthy bow­els, and reg­u­lar­ity made a happy pa­tient", he said.

Empty gelatin cap­sules, ready for fill­ing. Source

Dr S thought it would be pru­dent to ask pa­tients to bring in a stool spec­i­men when they came to the hos­pi­tal for their surgery. He said to me, "Now, Stan, how do we get it back into them?" We de­cided that gelatin cap­sules from the phar­macy might do the trick. The phar­ma­cies at that time still made a good deal of their own for­mu­lary. We set up a pro­to­col. Stools were ob­tained from the pa­tients im­me­di­ately af­ter ad­mis­sion. I would trans­fer the stool as quickly as pos­si­ble into 12 large gelatin cap­sules,. This was a messy and not a pre­cise or en­thu­si­as­tic process on my part. I would wash the cap­sules in wa­ter and rinse in a di­lute so­lu­tion of mer­curic chlo­ride to dis­in­fect the outer sur­face of the cap­sule, and then the cap­sules were rinsed again and put in a small ice cream car­ton and put in the re­frig­er­a­tor la­beled only with the patient's ini­tials.

Upon dis­charge, Dr. S and one other physi­cian who be­came a con­vert to this "pro­to­col" would ob­tain the cap­sules from me. They would tell the pa­tient to keep them re­frig­er­ated, to take 2 twice a day un­til they were all con­sumed. At least Dr. S told them, "Eat lots of salad." This un­con­trolled trial con­tin­ued for some months, and, ac­cord­ing to the anec­do­tal re­ports of Dr. S and his col­league Dr. B was quite suc­cess­ful in com­par­i­son to the pa­tients of other physi­cians who did not have the ben­e­fit of the au­to­ge­nous fe­cal sand­wich. I don't re­call that we ever thought about the ethics of this. It was a time be­fore in­formed con­sent. I'm pretty sure, how­ever, that the es­thet­ics of this prac­tice was un­der­stood and that the pa­tients in ques­tion never knew the con­tents of the cap­sules they in­gested.

The chief hos­pi­tal ad­min­is­tra­tor dis­cov­ered what was up. He con­fronted me and ex­claimed, "Falkow, is it true you've been feed­ing the pa­tients s**t!" He used the An­glo-Saxon phrase for fe­ces. I re­sponded: Yes I had been a par­tic­i­pant in a clin­i­cal study that in­volved the pa­tients in­gest­ing their own fe­ces. You're fired! was the re­ply, al­though Dr. S came to my res­cue. I was re­hired two days later. Thus, the "ex­per­i­ment" came to an abrupt end. I left in June, 1958 to study for my PhD with C. A. Stu­art and Sey­mour Leder­berg at Brown Uni­ver­sity.

Now I am not go­ing to claim that I knew that feed­ing pa­tients their own fe­ces af­ter in­tense an­tibi­otic ther­apy would be ben­e­fi­cial. Dr. S was sure it was the case based on his years of clin­i­cal ex­pe­ri­ence. I un­der­stood the point that the in­dige­nous flora was im­por­tant. I had ex­am­ined hun­dreds of stool spec­i­mens from sick and well peo­ple for too long. I rou­tinely Gram-stained fe­cal sam­ples and ex­am­ined them in a wet mount. I didn't have deep se­quenc­ing but I could dis­cern dif­fer­ences in the flora of in­di­vid­u­als. One fe­cal flora did not re­flect all. I un­der­stood this even bet­ter af­ter I met Rene Du­bos and Rus­sell Schaedler at the Armed Forces Epi­demi­ol­ogy Board in the early 1960s and even more when I read the won­der­ful book by Theodor Rose­bury, Life on Man.

My ex­pe­ri­ence pre­saged the cur­rent ex­cite­ment and ex­cit­ing in­for­ma­tion that has del­uged us in the past few years about the won­ders of the hu­man mi­cro­biota. The un­der­stand­ing and the ap­pre­ci­a­tion for the sanc­tity of the "nor­mal flora," how­ever, is not a new thing. Fe­cal trans­plants, of a sort, were prac­ticed some 50 years ago be­cause of the rec­og­nized un­to­ward ef­fects of an­tibi­otic ther­apy. Mekalanos af­ter hear­ing this story said: It once was "Eat s**t and die!" Maybe now it will be "Eat s**t and live!"

This ex­pe­ri­ence also re­minds me of some­thing I have learned over the years. Ex­pe­ri­ences that oc­cur dur­ing ex­per­i­ments or facts learned in a sem­i­nar or read in a pa­per have a way of reap­pear­ing, of­ten decades later, with new mean­ing.

Stan­ley Falkow is the Robert W. and Vi­vian K. Cahill Pro­fes­sor Emer­i­tus of Mi­cro­bi­ol­ogy and Im­munol­ogy and Med­i­cine in the De­part­ment of Mi­cro­bi­ol­ogy and Im­munol­ogy at Stan­ford Uni­ver­sity.